neuropeptide-y and Anorexia

Contribution to Special Issue on Fast effects of steroids. There is now compelling evidence for membrane-associated estrogen receptors in hypothalamic neurons that are critical for the hypothalamic control of homeostatic functions. It has been known for some time that estradiol (E2) can rapidly alter hypothalamic neuronal activity within seconds, indicating that some cellular effects can occur via membrane initiated events. However, our understanding of how E2 signals via membrane-associated receptors and how these signals impact physiological functions is only just emerging. Thus, E2 can affect second messenger systems including calcium mobilization and a plethora of kinases to alter cell excitability and even gene transcription in hypothalamic neurons. One population of hypothalamic neurons, the anorexigenic proopiomelanocortin (POMC) neurons, has long been considered to be a target of E2's actions based on gene (Pomc) expression studies. However, we now know that E2 can rapidly alter POMC neuronal activity within seconds and activate several intracellular signaling cascades that ultimately affect gene expression, actions which are critical for maintaining sensitivity to insulin in metabolically stressed states. E2 also affects the orexigenic Neuropeptide Y/Agouti-related Peptide (NPY/AgRP) neurons in similarly rapid but antagonistic manner. Therefore, this review will summarize our current state of knowledge of how E2 signals via rapid membrane-initiated and intracellular signaling cascades in POMC and NPY/AgRP neurons to regulate energy homeostasis.

Topics: Agouti-Related Protein; Animals; Anorexia; Appetite Regulation; Estradiol; Homeostasis; Humans; Hypothalamus; Neurons; Neuropeptide Y; Pro-Opiomelanocortin; Signal Transduction

Ghrelin is the orexigenic peptide produced in the periphery, and its plasma level shows remarkable pre/postprandial changes. Ghrelin is considered a pivotal signal to the brain to stimulate feeding. Hence, characterizing the target neurons for ghrelin in the hypothalamic feeding center and the signaling cascade in the target neurons are essential for understanding the mechanisms regulating appetite. Anorexia and cachexia associated with gastric surgery, stress-related diseases, and use of anti-cancer drugs cause the health problems, markedly deteriorating the quality of life. The anorexia involves several neurotransmitters and neuropeptides in the hypothalamic feeding center, in which corticotropin-releasing hormone (CRH), urocortine, serotonin (5HT) and brain-derived neurotrophic factor (BDNF) play a pivotal role. A Japanese herbal medicine, rikkunshito, has been reported to ameliorate the anorexia by promoting the appetite. This review describes 1) the interaction of ghrelin with the orexigenic neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC) and underlying signaling cascade in NPY neurons, 2) the anorectic pathway driven by BDNF-CRH/urocortine and 5HTCRH/ urocortine pathways, 3) the effect of rikkunshito on the interaction of ghrelin and NPY neurons in ARC, and 4) the effect of rikkunshito on the interaction of 5HT on CRH neurons in paraventricular nucleus (PVN).

Topics: Animals; Anorexia; Appetite Regulation; Appetite Stimulants; Drugs, Chinese Herbal; Energy Intake; Ghrelin; Humans; Hypothalamus; Lipid Metabolism; Neurons; Neuropeptide Y; Neurotransmitter Agents; Signal Transduction

Hyperactivity in anorexia nervosa is difficult to control and negatively impacts outcome. Hyperactivity is a key driving force to starvation in an animal model named activity-based anorexia (ABA). Recent research has started unraveling what mechanisms underlie this hyperactivity. Besides a general increase in locomotor activity that may be an expression of foraging behavior and involves frontal brain regions, the increased locomotor activity expressed before food is presented (food anticipatory behavior or FAA) involves hypothalamic neural circuits. Ghrelin plays a role in FAA, whereas decreased leptin signaling is involved in both aspects of increased locomotor activity. We hypothesize that increased ghrelin and decreased leptin signaling drive the activity of dopamine neurons in the ventral tegmental area. In anorexia nervosa patients, this altered activity of the dopamine system may be involved not only in hyperactivity but also in aberrant cognitive processing related to food.

Topics: Analgesics, Opioid; Animals; Anorexia; Disease Models, Animal; Dopamine; Ghrelin; Humans; Hyperkinesis; Leptin; Melanocortins; Neurobiology; Neuropeptide Y

Feeding behavior is tightly regulated by peptidergic transmission within the hypothalamus. Neuropeptide Y (NPY) is one of the most potent known stimulators of food intake and has robust effects on the hypothalamic feeding neuronal networks. A vast body of literature has documented the substantial effects of NPY on feeding behavior. However, the cellular mechanisms underlying the actions of NPY have only recently begun to be explored. The NPYergic signal, including its expression in hypothalamic neurons, its release into the synaptic space, and its direct or indirect receptor-mediated actions, is highly responsive to decreases in the metabolic state. The orexigenic NPY signal can suppress the anorexigenic drive to restore energy balance homeostasis when energy levels are low, such as after food deprivation. The NPY signal interacts with glucose- and fat-sensitive signals arriving in the hypothalamus and effects changes in anorexigenic pathways, such as those mediated by the melanocortins. Recent applications of electrophysiological methods to examine the neuronal activity and pathways engaged by NPY-mediated signaling have advanced our understanding of this orexigenic system. Furthermore, crucial roles for NPY pathways in the development of hypothalamic feeding circuitry have been identified by these means. Orexigenic NPY signaling is critical during development and its absence is lethal in adults, thus reflecting the essential role of NPY for the regulation of energy homeostasis.

Topics: Animals; Anorexia; Appetite Regulation; Behavior, Animal; Disease Models, Animal; Feeding Behavior; Hypothalamus; Neuropeptide Y; Obesity; Rats

Cancer anorexia frequently characterizes the clinical journey of patients with cancer and affects patients' morbidity, mortality, and quality of life. A constellation of symptoms concur to the diagnosis of anorexia, and early satiety, changes in taste/smell, and nausea are the more frequently reported. The pathogenesis of cancer anorexia is multifactorial, but accumulating evidence indicates that the hypothalamic melanocortin and neuropeptide Y systems become resistant to peripheral inputs. This results in increased melanocortin activity and reduced neuropeptide Y function, thereby leading to the promotion of catabolic stimuli (i.e., reduced energy intake, increased energy expenditure, possibly increased muscle proteolysis, and adipose tissue loss). Interestingly, hypothalamic proinflammatory cytokines and serotonin, among other factors, are key in triggering hypothalamic resistance. In the clinical setting, cancer anorexia develops with heterogeneous presenting symptoms (i.e., early satiety and/or nausea and/or changes of taste) and varying degrees of severity. Available evidence suggests that the constellation of symptoms characterizing this syndrome should be considered, at least in part, as different phenotypes of common neurochemical/metabolic alterations in the presence of a chronic inflammatory state.

Topics: Anorexia; Biogenic Monoamines; Brain; Humans; Hypothalamus; Melanocortins; Neoplasms; Neuropeptide Y

Cachexia or wasting disease occurs commonly in diseases that have an overproduction of proinflammatory cytokines associated with them. The hallmarks of cachexia are loss of lean and adipose tissue, anorexia, anemia, memory disturbance, and sickness behavior. This review suggests that increased inducible nitric oxide synthase production in the hypothalamus leads to severe anorexia and that this is the pathway through which proinflammatory cytokines produce anorexia. Orexigenic peptides, such as neuropeptide, ghrelin, and orexin A, and anorectic peptides, such as leptin, produce their effects through neuronal nitric oxide synthase. Activation of neuronal nitric oxide synthase results in increased adenosine monophosphate kinase and a decrease in malonyl coenzyme A, leading to increased food intake.

Topics: Anorexia; Cachexia; Cytokines; Eating; Female; Humans; Hypothalamus; Male; Neuropeptide Y; Nitric Oxide Synthase

The role of neuropeptides in nervous system function is still in many cases undefined. In the present study we examined a possible role of the 36-amino acid neuropeptide Y (NPY) with regard to three functions: axon guidance and attraction/repulsion, adult neurogenesis, and control of food intake.. Growth cones from embryonic dorsal root ganglion neurons were studied in culture during asymmetrical gradient application of NPY. Growth cones were monitored over a 60-min period, and final turning angle and growth rate were recorded. In the second part the NPY Y(1) and Y(2) receptors were studied in the subventricular zone, the rostral migratory stream, and the olfactory bulb in normal mice and mice with genetically deleted NPY Y(1) or Y(2) receptors. In the third part an anorectic mouse was analyzed with immunohistochemistry.. 1) NPY elicited an attractive turning response and an increase in growth rate, effects exerted via the NPY Y(1) receptor. 2) The NPY Y(1) receptor was expressed in neuroblasts in the anterior rostral migratory stream. Mice deficient in the Y(1) or Y(2) receptor had fewer proliferating precursor cells and neuroblasts in the subventricular zone and rostral migratory stream and fewer neurons in the olfactory bulb expressing calbindin, calretinin or tyrosine hydroxylase. 3) In the anorectic mouse markers for microglia were strongly upregulated in the arcuate nucleus and in projection areas of the NPY/agouti gene-related protein arcuate system.. NPY participates in several mechanisms involved in the development of the nervous system and is of importance in the control of food intake.

Topics: Animals; Anorexia; Axons; Disease Models, Animal; Eating; Feeding Behavior; Mice; Neurogenesis; Neuropeptide Y

Cachexia is among the most debilitating and life-threatening aspects of cancer. Associated with anorexia, fat and muscle tissue wasting, psychological distress, and a lower quality of life, cachexia arises from a complex interaction between the cancer and the host. This process results from a failure of the adaptive feeding response seen in simple starvation and includes cytokine production, release of lipid-mobilizing and proteolysis-inducing factors, and alterations in intermediary metabolism. Cytokines play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin, a hormone secreted by adipose tissue, which is an integral component of the homeostatic loop of body weight regulation. The two major options for pharmacological therapy have been either progestational agents or corticosteroids. However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome continues to lead to effective therapeutic interventions for several aspects of the syndrome. These include antiserotonergic drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic acid, cannabinoids, melatonin, and thalidomide, all of which act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release. The outcomes of drug studies in cancer cachexia should focus on the symptomatic and quality-of-life advantages rather than simply on nutritional end points, since the survival of cachexia cancer patients may be limited to weeks or months due to the incurable nature of the underlying malignancy. As weight loss shortens the survival time of cancer patients and decreases their performance status, effective therapy would extend patient survival and improve quality of life.

Topics: Adipose Tissue; Agouti Signaling Protein; Anorexia; Anti-Anxiety Agents; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Appetite Stimulants; Cachexia; Cytokines; Energy Metabolism; Gastrointestinal Agents; Glucocorticoids; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Neoplasms; Neuropeptide Y; Patient Care Team; Progesterone; Signal Transduction; Starvation; Syndrome

Zinc is an essential nutrient that is required in humans and animals for many physiological functions, including immune and antioxidant function, growth and reproduction. Many aspects of zinc deficiency-induced anorexia have been well studied in experimental animals, most notably the laboratory rat. There is evidence that suggests zinc deficiency may be intimately involved with anorexia in humans: if not as an initiating cause, then as an accelerating or exacerbating factor that may deepen the pathology of the anorexia. The present review describes recent research investigating the relationship between zinc deficiency and the regulation of food intake, along with advances in the understanding of the food intake and body weight regulation systems. For more comprehensive reviews of zinc nutrition and zinc deficiency, readers are referred to the other reviews in this volume and the review text of Mills (1989). An excellent review focused solely on zinc status and food intake has been presented by O'Dell and Reeves (1989).

Topics: Animals; Anorexia; Appetite Regulation; Feeding Behavior; Galanin; Humans; Leptin; Neuropeptide Y; Zinc

Anorexia and body weight loss are characteristic of many diseases, including cancer and AIDS. Recent studies indicate that inflammatory cytokines, such as interleukin 1, the interleukin 6 subfamily and tumor necrosis factor, induce anorexia and cachexia by inhibiting the normal adaptive feeding response to energy deficits. Here, I discuss the evidence for and against a central role for neuropeptide Y and leptin in anorexia and cachexia.

Topics: Animals; Anorexia; Appetite; Cachexia; Cytokines; Humans; Hypothalamus; Neuropeptide Y; Syndrome; Wasting Syndrome

Unexplained weight loss during the latter stages of aging is commonly preceded by a spontaneous diminution in food intake. Multiple etiologies of age-related anorexia in humans, ranging from social isolation to impaired gastrointestinal function, have been proposed. The observation of this phenomenon in older laboratory animals suggests that physiological changes play a significant causal role. A continually expanding body of information on the neurochemical control of food intake supports a contribution of altered neurochemistry to dysregulated feeding behavior. This review provides an update on the relationship between declining food intake during advanced age and physiological (specifically neurochemical) function. The complexity of the control of food intake as well as the variety of investigative methods used in this field of study render the identification of definitive causes difficult. Evidence presented here is evaluated and possible etiologic factors are suggested.

Topics: Aging; Animals; Anorexia; Appetite Stimulants; Disease Models, Animal; Feeding Behavior; Humans; Leptin; Narcotics; Neuropeptide Y; Neurotransmitter Agents; Proteins

The hypothalamus, long known to play a determinant role in food intake and satiety, has recently been shown to exert this homeostatic function via peptidergic neuronal circuits. The major peptide that has been identified as orexigenic, namely neuropeptide Y (NPY), is suppressed by leptin, an adipocyte-derived hormone, in a potential circuit that seems to function as an adipostat. Information regarding energy balance is fed back to the paraventricular nucleus of the hypothalamus where a complex interplay between thyrotropin-releasing hormone (TRH) and corticotrophin-releasing hormone (CRH) determines consequent effects in thermogenesis and stress reactions. Inflammatory mediators that have been implicated in anorexia simultaneously suppress TRH in a dominant way that overcomes the feedback effects of the thyroid hormones. Moreover, endogenous opioids and melanotropic peptides modulate orexigenic and thermogenic effects in a complex, yet poorly understood, way. However, TRH metabolism, which is affected by dietary modifications, seems to be involved in the orexigenic events that take place in the hypothalamus. It is, therefore, evident that TRH is directly involved in the complex hypothalamic networks that establish energy balance by modulation of food intake, satiety, thermogenesis, and other autonomic responses.

Topics: Animals; Anorexia; Appetite; Corticotropin-Releasing Hormone; Humans; Leptin; Neuropeptide Y; Proteins; Thyrotropin-Releasing Hormone

To explore the dynamic change and clinical efficacy of acupuncture at Sifeng (EX-UE 10) on appetite regulating factors in the serum of infantile anorexia.. Eighty cases, in compliance with the diagnostic criteria, aged from 3 to 6 years were randomized into an acupuncture group and a medication group, 40 cases in each one. Additionally, a healthy control group (30 cases) was set up. In the acupuncture group, the pricking method was adopted at Sifeng (EX-UE 10) with the three-edged needle. A few light yellow, transparent viscous liquid or blood was squeezed out after pricking. The treatment was given once a week, for 4 weeks totally. In the medication group, erkangning syrup was administered, 3 times a day, for 4 weeks totally. The ghrelin, leptin and neuropeptide Y (NPY), and the clinical efficacy were observed before and after treatment in each group.. The levels of ghrelin and NPY before treatment in acupuncture group and the medication group were lower apparently than those in the healthy control group (all P < 0.01), but the level of leptin was higher appa-rently than that in the healthy control group (P < 0.01). After treatment, the levels of ghrelin and NPY were higher apparently than those before treatment in the acupuncture group (both P < 0.01), and the level of leptin was lower apparently than that before treatment (P < 0.01). All of the above indices in the acupuncture group were improved obviously after treatment as compared with those in the medication group (all P < 0.01). The remarkable and effective rate were 82.5% (33/40) and 32.5% (13/40) and the total effective rate were 95.0% (38/40) and 45.0% (18/40) in the acupuncture group and medication group separately, the results in the acupuncture group were superior to the medication group (both P < 0.01).. Acupuncture at Sifeng (EX-UE 10) effectively promotes the secretion of ghrelin and NPY and inhibit leptin. It effectively promotes appetite for the children and the efficacy is superior to erkangning syrup.

Topics: Acupuncture Points; Acupuncture Therapy; Anorexia; Appetite; Child, Preschool; Female; Ghrelin; Humans; Leptin; Male; Neuropeptide Y; Treatment Outcome

The purpose of this study was to investigate whether serum β-endorpin and neuropeptide Y were associated with changes in levels of thyroid hormones in children suffering from anorexia. One hundred and five anorexic children admitted to Xianning City Central Hospital, China, from August 2019 to July 2021, were selected as case group, while 105 normal children were selected as normal control group. Serum β-endorpin and neuropeptide Y levels in the case group were lower than those in the normal control group (both p<0.001), and serum triiodothyronine and thyroxine levels were also lower (both p<0.001). Serum β-endorpin and neuropeptide Y levels in the case group were positively correlated with triiodothyronine and thyroxine. There is a reduced level of serum β-endorpin, neuropeptide Y, and thyroid hormones in anorexic children, and it is possible that they are connected and work together in regulating ingestion.

Topics: Anorexia; beta-Endorphin; Child; Humans; Neuropeptide Y; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine

Patients with AN often express psychological symptoms such as body image distortion, cognitive biases, abnormal facial recognition, and deficits in working memory. However, the molecular mechanisms underlying the impairment of cognitive behaviors in AN remain unknown. In the present study, we measured cognitive behavior using novel object recognition (NOR) tasks and mRNA expressions in hypothalamic neuropeptides in female C57BL/6J mice with activity-based anorexia (ABA). Additionally, we evaluated the effects of antagonists with intracerebroventricular (icv) administration on the impairment of cognitive behavior in NOR tasks. Our results showed that NOR indices were lowered, subsequently increasing mRNA levels of agouti-related peptide (AgRP) and neuropeptide Y (NPY), and c-Fos- and AgRP- or NPY-positive cells in the hypothalamic arcuate nucleus in ABA mice. We also observed that icv administration of anti-NPY antiserum (2 µl), anti-AgRP antibody (0.1 μg), and Y5 receptor antagonist CPG71683 (15 nmol) significantly reversed the decreased NOR indices. Therefore, our results suggest that increased NPY and AgRP signaling in the brain might contribute to the impairment of cognitive behavior in AN.

Topics: Agouti-Related Protein; Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Cognition; Female; Humans; Hypothalamus; Mice; Mice, Inbred C57BL; Neuropeptide Y; RNA, Messenger

Exposure to high ambient temperatures (HAT) is associated with increased mortality, weight loss, immunosuppression, and metabolic malfunction in birds, all of which are likely downstream effects of reduced food intake. While the mechanisms mediating the physiological responses to HAT are documented, the neural mechanisms mediating behavioral responses are poorly understood. The aim of the present study was thus to investigate the hypothalamic mechanisms mediating heat-induced anorexia in four-day old broiler chicks. In Experiment 1, chicks exposed to HAT reduced food intake for the duration of exposure compared to controls in a thermoneutral environment (TN). In Experiment 2, HAT chicks that were administered an intracerebroventricular (ICV) injection of neuropeptide Y (NPY) increased food intake for 60 min post-injection, while TN chicks that received NPY increased food intake for 180 min post-injection. In Experiment 3, chicks in both the TN and HAT groups that received ICV injections of corticotropin-releasing factor (CRF) reduced food intake for up to 180 min post-injection. In Experiment 4, chicks that were exposed to HAT and received an ICV injection of astressin ate the same as controls in the TN group. In Experiment 5, chicks exposed to HAT that received an ICV injection of α-melanocyte stimulating hormone reduced food intake at both a high and low dose, with the low dose not reducing food intake in TN chicks. In Experiment 6, there was increased c-Fos expression in the hypothalamic paraventricular nucleus (PVN), lateral hypothalamic area (LHA), and the nucleus of the hippocampal commissure (NHpC). In Experiment 7, exposure to HAT was associated with decreased CRF mRNA in the NHpC, increased CRF mRNA in the PVN, and decreased NPY mRNA in the arcuate nucleus (ARC). In sum, these results demonstrate that exposure to HAT causes a reduction in food intake that is likely mediated via downregulation of NPY via the CRF system.

Topics: alpha-MSH; Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Chickens; Corticotropin-Releasing Hormone; Eating; Fornix, Brain; Hot Temperature; Injections, Intraventricular; Male; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Peptide Fragments; Proto-Oncogene Proteins c-fos; RNA, Messenger

Obesity-associated low-grade inflammation favors weight gain, whereas systemic infection frequently leads to anorexia. Thus, inflammatory signals can either induce positive or negative energy balance. In this study, we used whole-cell patch-clamp to investigate the acute effects of three important proinflammatory cytokines, tumor necrosis factor α (TNF-α), interleukin-6, and interleukin-1β (IL-1β) on the membrane excitability of agouti-related peptide (AgRP)- or proopiomelanocortin (POMC)-producing neurons. We found that both TNF-α and IL-1β acutely inhibited the activity of 35-42% of AgRP-producing neurons, whereas very few POMC neurons were depolarized by TNF-α. Interleukin-6 induced no acute changes in the activity of AgRP or POMC neurons. Our findings indicate that the effect of TNF-α and IL-1β, especially on the activity of AgRP-producing neurons, may contribute to inflammation-induced anorexia observed during acute inflammatory conditions.

Topics: Agouti-Related Protein; Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Energy Metabolism; Humans; Hypothalamus; Inflammation; Interleukin-1beta; Interleukin-6; Mice; Neurons; Neuropeptide Y; Obesity; Patch-Clamp Techniques; Pro-Opiomelanocortin; Tumor Necrosis Factor-alpha

Central administration of neuropeptide K (NPK), a 36-amino acid peptide, is associated with anorexigenic effects in rodents and chickens. The mechanisms underlying the potent anorexigenic effects of NPK are still poorly understood. Thus, the aim of the present study was to identify the hypothalamic nuclei and neuropeptides that mediate anorexic effects of NPK in 7 day-old Japanese quail (Coturnix japonica). After a 6 h fast, intracerebroventricular (ICV) injection of NPK decreased food and water intake for 180 min post-injection. Quail injected with NPK had more c-Fos immunoreactive cells in the arcuate nucleus (ARC), lateral hypothalamus, and paraventricular nucleus (PVN) compared to the birds that were injected with the vehicle. In the ARC of NPK-injected quail, there was decreased neuropeptide Y (NPY), NPY receptor sub-type 1, and agouti-related peptide mRNA, and increased CART, POMC, and neurokinin receptor 1 mRNA. NPK-injected quail expressed greater amounts of corticotropin-releasing factor (CRF), CRF receptor sub-type 2, melanocortin receptors 3 and 4, and urocortin 3 mRNA in the PVN. In conclusion, results provide insights into understanding NPK-induced changes in hypothalamic physiology and feeding behavior, and suggest that the anorexigenic effects of NPK involve the ARC and PVN, with increased CRF and melanocortin and reduced NPY signaling.

Topics: Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Corticotropin-Releasing Hormone; Coturnix; Drinking; Eating; Gene Expression Regulation; Humans; Hypothalamus; Infusions, Intraventricular; Nerve Tissue Proteins; Neuropeptide Y; Pro-Opiomelanocortin; Proto-Oncogene Proteins c-fos; Receptors, Melanocortin; Tachykinins; Urocortins

Microglia are highly sensitive to dietary influence, becoming activated acutely and long-term by high fat diet. However, their role in regulating satiety and feeding in healthy individuals remains unclear. Here we show that microglia are essential for the normal regulation of satiety and metabolism in rats. Short-term microglial depletion in a Cx3cr1-Dtr rat led to a dramatic weight loss that was largely accounted for by an acute reduction in food intake. This weight loss and anorexia were not likely due to a sickness response since the rats did not display peripheral or central inflammation, withdrawal, anxiety-like behavior, or nausea-associated pica. Hormonal and hypothalamic anatomical changes were largely compensatory to the suppressed food intake, which occurred in association with disruption of the gustatory circuitry at the paraventricular nucleus of the thalamus. Thus, microglia are important in supporting normal feeding behaviors and weight, and regulating preference for palatable food. Inhibiting this circuitry is able to over-ride strong compensatory drives to eat, providing a potential target for satiety control.

Topics: Animals; Anorexia; Appetite; Body Weight; Brain; Diet; Disease Models, Animal; Eating; Energy Metabolism; Feeding Behavior; Ghrelin; Hypothalamus; Male; Microglia; Midline Thalamic Nuclei; Neuropeptide Y; Rats; Rats, Wistar; Satiety Response; Weight Loss

Topics: Acyl-CoA Dehydrogenase, Long-Chain; Adipocytes; Adipogenesis; Adipose Tissue; Adiposity; Animals; Animals, Newborn; Anorexia; CCAAT-Enhancer-Binding Proteins; Chickens; Female; Gene Expression Regulation; Male; Neuropeptide Y; Obesity; Poultry Diseases; PPAR gamma; Time Factors; Weight Gain

Burn injury is a severe form of trauma associated with pain, metabolic abnormalities, susceptibility to infections, muscle loss, mental and emotional distress. Conventional therapies as well as some recent approaches for the treatment of burned patients are currently in use. Nutritional therapy is also suggested as a supplementary option in major burns. Within this context, hormones involved in the regulation of appetite will have a paramount importance. The aim is to evaluate the interactions among ghrelin, some inflammatory parameters and the burn injury. Asprosin is also involved into this discussion due to its ghrelin-like actions. Aside from the consideration of insulin as well as stress hormones (cortisol, epinephrine, norepinephrine), an orexigenic, anti-inflammatory hormone, ghrelin affecting both metabolic and inflammatory systems is also involved in the protocols designed for burn treatment. Ghrelin's actions exerted by way of growth-hormone secretagogue receptor, neuropeptide Y, agouti-related protein, proopiomelanocortin and gamma amino butyric acid are being investigated. Asprosin, one of the remarkably few hormones identified as appetite stimulator, acts as another orexigenic hormone by using almost the same signalling pathways as those of ghrelin. Interleukin-6 should also be evaluated both as a reliable biomarker of inflammation and also with its inhibitory effects on TNF-α within the scope of burn injury. In conclusion, treatment protocols during burn injury may be designed to raise decreased concentrations of ghrelin and to repress increased levels of inflammatory agents such as TNF-α. IL-6 may be evaluated from an entirely different aspect. The potential therapeutic use of asprosin may be considered within an integrative approach with a focus on cachexia-anorexia developed in severe burn trauma.

Topics: Animals; Anorexia; Burns; Cachexia; Cytokines; Epinephrine; Fibrillin-1; Ghrelin; Hormones; Humans; Inflammation; Interleukin-10; Interleukin-6; Mice; Microfilament Proteins; Models, Theoretical; Neurons; Neuropeptide Y; Peptide Fragments; Peptide Hormones; Treatment Outcome; Tumor Necrosis Factor-alpha

The Virginia lines of chickens have been selected for low (LWS) or high (HWS) juvenile body weight and have different severities of anorexia and obesity, respectively. The LWS that are exposed to stressors at hatch are refractory to neuropeptide Y (NPY)-induced food intake and the objective of the present study was to determine the underlying mechanisms. Chicks were exposed to a stressor (-20°C for 6 minutes and 22°C and delayed access to food for 24 hours) after hatching and the hypothalamic nuclei, including the lateral hypothalamus (LH), paraventricular nucleus (PVN), ventromedial hypothalamus (VMH) and arcuate nucleus (ARC), were collected 5 days later. In LWS but not HWS, stress exposure up-regulated corticotrophin-releasing factor (CRF), CRF receptor subtypes 1 and 2 (CRFR1 and CRFR2, respectively), melanocortin receptor 4 and urocortin 3 in the PVN, as well as CRFR2 mRNA in the VMH and ARC. In LWS, stress exposure was also associated with greater NPY and NPY receptor subtype 5 mRNA in the ARC and PVN, respectively, as well as decreased agouti-related peptide mRNA in the ARC. In HWS, stress exposure was associated with increased CRFR1 and decreased cocaine- and amphetamine-regulated transcript in the ARC and PVN, respectively. Refractoriness of the food intake response to NPY in LWS may thus result from the over-riding anorexigenic tone in the PVN associated with CRF signalling. Indeed, the orexigenic effect of NPY was restored when LWS were injected with a CRF receptor antagonist, astressin, before stress exposure. The results of the present study provide insights into the molecular basis of eating disorders and suggest that CRF signalling in the PVN may exacerbate the anorexic phenotype in the presence of environmental stressors.

Topics: Animals; Anorexia; Avian Proteins; Chickens; Corticotropin-Releasing Hormone; Female; Hunger; Male; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Receptor, Melanocortin, Type 4; Receptors, Corticotropin-Releasing Hormone; RNA, Messenger; Signal Transduction; Stress, Physiological; Urocortins

Phenylpropanolamine (PPA)-induced appetite control is associated with oxidative stress in the hypothalamus. This study explored whether hypothalamic antioxidants participated in hypothalamic ghrelin system-associated appetite control in PPA-treated rats. Rats were given PPA daily for 4 days, and changes in food intake and the expression of neuropeptide Y (NPY), the cocaine- and amphetamine-regulated transcript (CART), superoxide dismutase, catalase, ghrelin, acyl ghrelin (AG), ghrelin O-acyltransferase (GOAT) and the ghrelin receptor (GHSR1a) were examined and compared. Results showed that both food intake and the expression of NPY and ghrelin/AG/GOAT/GHSR1a decreased in response to PPA treatment with maximum decrease on Day 2 of the treatment. In contrast, the expression of antioxidants and CART increased, with the maximum increase on Day 2, with the expression opposite to that of NPY and ghrelin. A cerebral infusion of either a GHSR1a antagonist or reactive oxygen species scavenger modulated feeding behavior and NPY, CART, antioxidants and ghrelin system expression, showing the involvement of ghrelin signaling and oxidative stress in regulating PPA-mediated appetite control. We suggest that hypothalamic ghrelin signaling system, with the help of antioxidants, may participate in NPY/CART-mediated appetite control in PPA-treated rats.

Topics: Animals; Anorexia; Appetite; Body Weight; Eating; Feeding Behavior; Ghrelin; Hypothalamus; Male; Neuropeptide Y; Oxidative Stress; Peptide Hormones; Phenylpropanolamine; Rats; Rats, Wistar; Reactive Oxygen Species; Receptors, Ghrelin

Severe appetite and weight loss define the eating disorder anorexia nervosa, and can also accompany the progression of some neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Although acute loss of hypothalamic neurons that produce appetite-stimulating neuropeptide Y (Npy) and agouti-related peptide (Agrp) in adult mice or in mice homozygous for the anorexia (

Topics: Animals; Anorexia; Cell Survival; Longevity; Mice; Mice, Transgenic; Neuropeptide Y; Phenotype; Point Mutation; Receptor Protein-Tyrosine Kinases

The mechanisms involved in septic anorexia are mainly related to the secretion of inflammatory cytokines. The term endozepines designates a family of neuropeptides, including the octadecaneuropeptide (ODN), originally isolated as endogenous ligands of benzodiazepine receptors. Previous data showed that ODN, produced and released by astrocytes, is a potent anorexigenic peptide. We have studied the effect of sepsis by means of a model of cecal ligation and puncture (CLP) on the hypothalamic expression of endozepines (DBI mRNA and protein levels), as well as on the level of neuropeptides controlling energy homeostasis mRNAs: pro-opiomelanocortin, neuropeptide Y, and corticotropin-releasing hormone. In addition, we have investigated the effects of two inflammatory cytokines, TNF-α and IL-1β, on DBI mRNA levels in cultured rat astrocytes.. Studies were performed on Sprague-Dawley male rats and on cultures of rat cortical astrocytes. Sepsis was induced using the CLP method. Sham-operated control animals underwent the same procedure, but the cecum was neither ligated nor incised.. Sepsis caused by CLP evoked an increase of DBI mRNA levels in ependymal cells bordering the third ventricle and in tanycytes of the median eminence. CLP-induced sepsis was also associated with stimulated ODN-like immunoreactivity (ODN-LI) in the hypothalamus. In addition, TNF-α, but not IL-1β, induced a dose-dependent increase in DBI mRNA in cultured rat astrocytes. An increase in the mRNA encoding the precursor of the anorexigenic peptide α-melanocyte stimulating hormone, the pro-opiomelanocortin, and the corticotropin-releasing hormone was observed in the hypothalamus.. These results suggest that during sepsis, hypothalamic mRNA encoding endozepines, anorexigenic peptide as well as stress hormone could play a role in the anorexia/cachexia associated with inflammation due to sepsis and we suggest that this hypothalamic mRNA expression could involve TNF-α.

Topics: Animals; Anorexia; Corticotropin-Releasing Hormone; Diazepam Binding Inhibitor; Disease Models, Animal; Hypothalamus; In Vitro Techniques; Inflammation; Interleukin-18; Ligands; Male; Neuropeptide Y; Neuropeptides; Peptide Fragments; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Sepsis; Tumor Necrosis Factor-alpha

We hypothesize that anorexia nervosa (AN) poses a physiological stress. Therefore, the way an individual copes with stress may affect AN vulnerability. Since prenatal stress (PNS) exposure alters stress responsivity in offspring this may increase their risk of developing AN. We tested this hypothesis using the activity based anorexia (ABA) rat model in control and PNS rats that were characterized by either proactive or passive stress-coping behavior. We found that PNS passively coping rats ate less and lost more weight during the ABA paradigm. Exposure to ABA resulted in higher baseline corticosterone and lower insulin levels in all groups. However, leptin levels were only decreased in rats with a proactive stress-coping style. Similarly, ghrelin levels were increased only in proactively coping ABA rats. Neuropeptide Y (Npy) expression was increased and proopiomelanocortin (Pomc) expression was decreased in all rats exposed to ABA. In contrast, agouti-related peptide (Agrp) and orexin (Hctr) expression were increased in all but the PNS passively coping ABA rats. Furthermore, DNA methylation of the orexin gene was increased after ABA in proactive coping rats and not in passive coping rats. Overall our study suggests that passive PNS rats have innate impairments in leptin and ghrelin in responses to starvation combined with prenatal stress associated impairments in Agrp and orexin expression in response to starvation. These impairments may underlie decreased food intake and associated heightened body weight loss during ABA in the passively coping PNS rats.

Topics: Adaptation, Psychological; Agouti-Related Protein; Animals; Anorexia; Body Weight; DNA Methylation; Drinking; Eating; Female; Ghrelin; Leptin; Male; Motor Activity; Neuropeptide Y; Orexins; Pregnancy; Prenatal Exposure Delayed Effects; Pro-Opiomelanocortin; Rats; Up-Regulation

Chicken lines that have been divergently selected for either low (LWS) or high (HWS) body weight at 56 days of age for more than 57 generations have different feeding behaviours in response to a range of i.c.v. injected neurotransmitters. The LWS have different severities of anorexia, whereas the HWS become obese. Previously, we demonstrated that LWS chicks did not respond, whereas HWS chicks increased food intake, after central injection of neuropeptide Y (NPY). The present study aimed to determine the molecular mechanisms underlying the loss of orexigenic function of NPY in LWS. Chicks were divided into four groups: stressed LWS and HWS on day of hatch, and control LWS and HWS. The stressor was a combination of food deprivation and cold exposure. On day 5 post-hatch, each chick received an i.c.v. injection of vehicle or 0.2 nmol of NPY. Only the LWS stressed group did not increase food intake in response to i.c.v. NPY. Hypothalamic mRNA abundance of appetite-associated factors was measured at 1 h post-injection. Interactions of genetic line, stress and NPY treatment were observed for the mRNA abundance of agouti-related peptide (AgRP) and synaptotagmin 1 (SYT1). Intracerebroventricular injection of NPY decreased and increased AgRP and SYT1 mRNA, respectively, in the stressed LWS and increased AgRP mRNA in stressed HWS chicks. Stress was associated with increased NPY, orexin receptor 2, corticotrophin-releasing factor receptor 1, melanocortin receptor 3 (MC3R) and growth hormone secretagogue receptor expression. In conclusion, the loss of responsiveness to exogenous NPY in stressed LWS chicks may be a result of the decreased and increased hypothalamic expression of AgRP and MC3R, respectively. This may induce an intensification of anorexigenic melanocortin signalling pathways in LWS chicks that block the orexigenic effect of exogenous NPY. These results provide insights onto the anorexic condition across species, and especially for forms of inducible anorexia such as human anorexia nervosa.

Topics: Agouti-Related Protein; Animals; Anorexia; Avian Proteins; Chickens; Drinking; Eating; Female; Food Deprivation; Hypothalamic Hormones; Hypothalamus; Male; Neuropeptide Y; Receptor, Melanocortin, Type 3; RNA, Messenger; Stress, Psychological

This study examined the proteomic profile of the hypothalamus in mice exposed to a high-fat diet (HFD) or with the anorexia of acute illness. This comparison could provide insight on the effects of these two opposite states of energy balance on appetite regulation.. Four to six-week-old male C56BL/6J mice were fed a normal (control 1 group; n=7) or a HFD (HFD group; n=10) for 8 weeks. The control 2 (n=7) and lipopolysaccharide (LPS) groups (n=10) were fed a normal diet for 8 weeks before receiving an injection of saline and LPS, respectively. Hypothalamic regions were analysed using a quantitative proteomics method based on a combination of techniques including iTRAQ stable isotope labeling, orthogonal two-dimensional liquid chromatography hyphenated with nanospray ionization and high-resolution mass spectrometry. Key proteins were validated with quantitative PCR.. Quantitative proteomics of the hypothalamous regions profiled a total of 9249 protein groups (q<0.05). Of these, 7718 protein groups were profiled with a minimum of two unique peptides for each. Hierachical clustering of the differentiated proteome revealed distinct proteomic signatures for the hypothalamus under the HFD and LPS nutritional conditions. Literature research with in silico bioinformatics interpretation of the differentiated proteome identified key biological relevant proteins and implicated pathways. Furthermore, the study identified potential pharmacologic targets. In the LPS groups, the anorexigen pro-opiomelanocortin was downregulated. In mice with obesity, nuclear factor-κB, glycine receptor subunit alpha-4 (GlyR) and neuropeptide Y levels were elevated, whereas serotonin receptor 1B levels decreased.. High-precision quantitative proteomics revealed that under acute systemic inflammation in the hypothalamus as a response to LPS, homeostatic mechanisms mediating loss of appetite take effect. Conversely, under chronic inflammation in the hypothalamus as a response to HFD, mechanisms mediating a sustained 'perpetual cycle' of appetite enhancement were observed. The GlyR protein may constitute a novel treatment target for the reduction of central orexigenic signals in obesity.

Topics: Animals; Anorexia; Appetite Regulation; Computational Biology; Diet, High-Fat; Disease Models, Animal; Down-Regulation; Hypothalamus; Inflammation; Insulin; Insulin Resistance; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; NF-kappa B; Obesity; Pro-Opiomelanocortin; Proteome; Receptor, Serotonin, 5-HT1B; Receptors, Glycine; RNA, Messenger

We previously found that daidzein decreased food intake in female rats. The present study aimed to elucidate the relationship between dynamics of appetite-mediated neuropeptides and the anorectic effect of daidzein. We examined appetite-mediated gene expression in the hypothalamus and small intestine during the 3 meals per day feeding method. Daidzein had an anorectic effect specifically at the second feeding. Neuropeptide-Y (NPY) and galanin mRNA levels in the hypothalamus were significantly higher after feeding in the control but not in the daidzein group, suggesting that daidzein attenuated the postprandial increase in NPY and galanin expression. The daidzein group had higher corticotrophin-releasing hormone (CRH) mRNA levels in the hypothalamus after feeding, and increased cholelcystokinin (CCK) mRNA levels in the small intestine, suggesting that CCK is involved in the hypothalamic regulation of this　anorectic effect. Therefore, daidzein may induce anorexia by suppressing expression of NPY and galanin and increasing expression of CRH in the hypothalamus.

Topics: Animals; Anorexia; Appetite; Body Weight; Eating; Feeding Methods; Female; Galanin; Gene Expression Regulation; Humans; Hypothalamus; Isoflavones; Neuropeptide Y; Rats; Receptors, Cholecystokinin; Receptors, Corticotropin-Releasing Hormone; RNA, Messenger

Obesity and eating disorders are prevailing health concerns worldwide. It is important to understand the regulation of food intake and energy metabolism. Thiamine (vitamin B1) is an essential nutrient. Thiamine deficiency (TD) can cause a number of disorders in humans, such as Beriberi and Wernicke-Korsakoff syndrome. We demonstrated here that TD caused anorexia in C57BL/6 mice. After feeding a TD diet for 16days, the mice displayed a significant decrease in food intake and an increase in resting energy expenditure (REE), which resulted in a severe weight loss. At the 22nd day, the food intake was reduced by 69% and 74% for male and female mice, respectively in TD group. The REE increased by ninefolds in TD group. The loss of body weight (17-24%) was similar between male and female animals and mainly resulted from the reduction of fat mass (49% decrease). Re-supplementation of thiamine (benfotiamine) restored animal's appetite, leading to a total recovery of body weight. The hypothalamic adenosine monophosphate-activated protein kinase (AMPK) is a critical regulator of food intake. TD inhibited the phosphorylation of AMPK in the arcuate nucleus (ARN) and paraventricular nucleus (PVN) of the hypothalamus without affecting its expression. TD-induced inhibition of AMPK phosphorylation was reversed once thiamine was re-supplemented. In contrast, TD increased AMPK phosphorylation in the skeletal muscle and upregulated the uncoupling protein (UCP)-1 in brown adipose tissues which was consistent with increased basal energy expenditure. Re-administration of thiamine stabilized AMPK phosphorylation in the skeletal muscle as well as energy expenditure. Taken together, TD may induce anorexia by inhibiting hypothalamic AMPK activity. With a simultaneous increase in energy expenditure, TD caused an overall body weight loss. The results suggest that the status of thiamine levels in the body may affect food intake and body weight.

Topics: AMP-Activated Protein Kinases; Analysis of Variance; Animals; Anorexia; Body Composition; Body Weight; Calorimetry; Diet; Eating; Energy Metabolism; Female; Gene Expression Regulation; Hypothalamus; Ion Channels; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Neuropeptide Y; Thiamine Deficiency; Uncoupling Protein 1

Topics: Agouti-Related Protein; Animals; Anorexia; Appetite; Arcuate Nucleus of Hypothalamus; Calcitonin Gene-Related Peptide; Feeding Behavior; gamma-Aminobutyric Acid; Humans; Hunger; Mice; Neurons; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Prader-Willi Syndrome; Pro-Opiomelanocortin; Time Factors

Rheumatoid cachexia is associated with rheumatoid arthritis and it increases mortality and morbidity. Adjuvant-induced arthritis is an experimental model of rheumatoid arthritis that causes anorexia and muscle wasting. α-Melanocyte-stimulating hormone (α-MSH) has anti-inflammatory actions, and it is able to decrease inflammation in several inflammatory diseases including experimental arthritis. In this study we tested whether systemic α-MSH treatment is able to ameliorate cachexia in arthritic rats. On day 8 after adjuvant injection control and arthritic rats were treated with α-MSH (50 μg/rat ip) twice a day, until day 16 when all rats were euthanized. Arthritis decreased food intake, but it increased hypothalamic expression of neuropeptide Y (NPY) and Agouti-related peptides (AgRP) as well as interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2) mRNA. In arthritic rats, α-MSH decreased the external signs of arthritis and increased food intake (P < 0.01). In addition, α-MSH decreased hypothalamic expression of IL-1β, COX-2, proopiomelanocortin, and prohormone-converting (PC) enzymes PC1/3 and PC2 mRNA in arthritic rats. In control rats, α-MSH did not modify food intake or hypothalamic expression of aforementioned mRNA. α-MSH prevented arthritis-induced increase in gastrocnemius COX-2, muscle-specific RING-finger protein-1 (MuRF1), and atrogin-1 expression, and it increased fast myofiber size. In conclusion our data show that in arthritic rats peripheral α-MSH treatment has an anti-cachectic action increasing food intake and decreasing muscle wasting.

Topics: Agouti-Related Protein; alpha-MSH; Animals; Anorexia; Arthritis, Experimental; Cachexia; Cyclooxygenase 2; Hypothalamus; Interleukin-1beta; Male; Muscular Atrophy; Neuropeptide Y; Rats; Rats, Wistar

Aminoprocalcitonin (N-PCT), a neuroendocrine peptide encoded by the calcitonin-I (CALC-I) gene, suppresses food intake when administered centrally in rats. However, the neural pathways underlying this effect remain unclear. N-PCT and calcitonin receptors (CT-R) have been identified in hypothalamic regions involved in energy homeostasis, including the arcuate nucleus (ARC). Here, we hypothesized an involvement of the hypothalamic ARC in mediating the anorexic effects of central N-PCT based on its content of peptidergic neurons involved in feeding and its expression of N-PCT and CT-R. Fasting strongly reduced expression of the N-PCT precursor gene CALC-I in the ARC, and central immunoneutralization of endogenous N-PCT increased food intake. Intracerebroventricular administration of N-PCT reduced food intake in fed and fasted rats, and its effect was attenuated by a neutralizing anti-N-PCT antibody. Immunohistochemistry for N-PCT showed that it is expressed in astrocytes and neurons in the ARC and is colocalized with anorexigenic proopiomelanocortin (POMC) neurons. Fasting reduced coexpression of N-PCT and POMC, and N-PCT administration activated hypothalamic neurons, including rostral POMC neurons. We also found that N-PCT stimulates POMC mRNA expression in fed and fasted rats, whereas it reduced the expression of orexigenic peptides neuropeptide Y (NPY) and agouti-related peptide (AgRP) only in fasted rats in which those mRNAs are normally elevated. Finally, we showed that the melanocortin-3/4 receptor antagonist SHU 9119 attenuates the intake-suppressive effect of N-PCT. These data demonstrate that hypothalamic N-PCT is involved in control of energy balance and that its anorexigenic effects are mediated through the melanocortin system.

Topics: Agouti-Related Protein; Animals; Anorexia; Antibodies, Neutralizing; Arcuate Nucleus of Hypothalamus; Calcitonin; Calcitonin Gene-Related Peptide; Eating; Energy Metabolism; Feeding Behavior; Male; Melanocyte-Stimulating Hormones; Neuropeptide Y; Protein Precursors; Rats; Rats, Wistar; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Receptors, Melanocortin; Signal Transduction

Cisplatin has been widely used; however, various disadvantageous side effects afflict patients. Rikkunshito (RKT), a traditional Japanese herbal medicine, has been widely prescribed in Japan to improve anorexia; but the mechanisms are unknown. Here we studied whether RKT could improve anorexia induced by cisplatin and changes in feeding-regulating peptides in the hypothalamus in rats. Adult male rats were divided into 4 groups: water+saline (WS), water+cisplatin (WC), RKT+saline (RS), and RKT+cisplatin (RC) groups. Water or RKT (1g/kg) was intragastrically administered for 4 days, from day -1 to day 2, and saline or cisplatin (6mg/kg) was intraperitoneally (i.p.) administered at day 0. After i.p. administration, cumulative food intake, water intake, urine volume and body weight were measured. The rats were then decapitated, followed by removal of the brain, and feeding-regulating peptides in the hypothalamus were measured by in situ hybridization histochemistry. In the three-day measurements, there were no significant changes in cumulative water intake and urine volume. The body weight and cumulative food intake in WC significantly decreased compared to WS, whereas these were not observed in RC. Pro-opiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) in the arcuate nucleus (ARC) in WC significantly increased, and neuropeptide Y (NPY) in the ARC decreased compared to WS, whereas those in RS and RC were comparable to WS. These results suggest that RKT may have therapeutic potential for anorexia induced by cisplatin.

Topics: Animals; Anorexia; Blood Glucose; Body Weight; Cisplatin; Drugs, Chinese Herbal; Eating; Feeding Behavior; Ghrelin; Herbal Medicine; Hesperidin; Hypothalamus; Male; Nerve Tissue Proteins; Neuropeptide Y; Plant Extracts; Pro-Opiomelanocortin; Rats; Rats, Wistar

The "lethal yellow" mutation at the mouse agouti locus (A(y)) results in hyperphagia, obesity, and type 2 diabetes at rest, but helps to reduce food intake under stress. The aim of this work was to investigate mechanisms of exaggerated anorectic response to stress in A(y) mice. All parameters were measured in C57BL/6J male mice of a/a (control) and A(y)/a genotypes before, 0, 1, and 3h after a 1-h restraint. Baseline food intake and plasma insulin concentrations were higher in A(y)/a mice compared to a/a mice. Restraint reduced food intake and plasma insulin concentrations only in A(y)/a mice. Stress-induced anorexia in A(y)/a mice was independent of pathways involving hypothalamic-pituitary-adrenal axis activity and hypothalamic orexigenic neuropeptide (agouti-related peptide and neuropeptide Y) gene expressions and corticotrophin-releasing factor type 1 receptor (CRFR1). Gene expression of CRFR2 was elevated in A(y)/a mice with genotype differences particularly manifested immediately after the restraint. Hypothalamic CRFR2 is known to mediate anorectic signals from CRF-related peptides. Thus, our data suggest that stress-induced anorexia in A(y)/a mice may be associated with increased anorectic signals mediated by CRFR2 in the hypothalamus.

Topics: Agouti-Related Protein; Analysis of Variance; Animals; Anorexia; Blood Glucose; Eating; Female; Gene Expression; Hypothalamo-Hypophyseal System; Hypothalamus; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Real-Time Polymerase Chain Reaction; Receptors, Corticotropin-Releasing Hormone; Restraint, Physical; RNA, Messenger; Stress, Psychological

A small population of neurons in the hypothalamus is known to promote food intake by releasing inhibitory agouti‑related peptide (ARP) and neuropeptide Y to broad postsynaptic areas. Acute ablation of ARP neurons in adult mice leads to rapid loss of appetite and the development of an anorexic phenotype. Recent studies have suggested that ablation of ARP neurons removes critical inhibition of postsynaptic neurons, resulting in hyperexcitation of selected downstream neurons. Left uncontrolled, this neuronal hyperactivation is hypothesized to induce starvation. However, the cellular mechanism underlying the control of excitability of postsynaptic neurons in response to the ablation of ARP neurons is poorly understood. The present study aimed to determine the functional correlation between ARP neurons and an immediate early gene, early growth response factor‑1 (Egr1), in postsynaptic neurons in the context of energy homeostasis. Egr1 expression levels were analyzed in different postsynaptic areas upon acute ablation of ARP neurons. As ARP neurons increase appetite by inhibiting the pro‑opiomelanocortin pathway, it was also investigated whether blockade of melanocortin signaling affects Egr1 expression in ARP neuron‑ablated mice. The results suggested that ablation of ARP neurons induced robust expression of Egr1 in numerous common postsynaptic targets of ARP and pro‑opiomelanocortin neurons. When ARP neurons were acutely ablated, it was demonstrated that Egr1 induction was attenuated by chronic blockade of the melanocortin signaling pathway in the arcuate nucleus, but not in other downstream regions. Further analysis of the Egr1 signaling cascade may aid in differentiating the functional involvement of postsynaptic targets of ARP neurons in the control of energy metabolism.

Topics: Agouti-Related Protein; Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Brain; Cells, Cultured; Diphtheria Toxin; Disease Models, Animal; Early Growth Response Protein 1; Energy Metabolism; Heparin-binding EGF-like Growth Factor; Humans; In Situ Hybridization; Intercellular Signaling Peptides and Proteins; Mice; Neurons; Neuropeptide Y; Pro-Opiomelanocortin

While neuropeptide Y (NPY) has been studied extensively per its pronounced role in food intake stimulation as well as its role in central pathways governing eating disorders, it has to our knowledge not been studied in polygenic models of hypo- and hyperphagia. Thus, the present study was designed to measure central NPY-associated food intake in lines of chickens that have undergone long-term genetic selection for low (LWS) or high (HWS) body weight and exhibit hypo- and hyperphagia, respectively. LWS chicks did not respond with any magnitude of altered food intake to any dose of NPY tested, while HWS chicks responded to all doses of NPY at similar magnitudes throughout the duration of observation. Both lines responded with similar increases in c-Fos immunoreactivity in the lateral hypothalamus and both divisions of the paraventricular nucleus; there were no significant line or line by treatment interactions. These data support the hypothesis that differences exist in the central NPY system of chicks from LWS and HWS lines and may provide novel insight for understanding NPY control of appetite.

Topics: Animals; Anorexia; Appetite; Body Weight; Chickens; Eating; Hypothalamus; Immunohistochemistry; Injections, Intraventricular; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Proto-Oncogene Proteins c-fos

Hypothalamic neuropeptide Y (NPY) and superoxide dismutase (SOD) have been reported to participate in the regulation of appetite-suppressing effect of phenylpropanolamine (PPA), a sympathomimetic agent. This study explored whether Y1 receptor (Y1R) and/or Y5 receptor (Y5R) was involved in this regulation. Wistar rats were treated with PPA for 24 h. Changes in food intake and hypothalamic NPY, Y1R, Y5R, and SOD contents were assessed and compared. Results showed that food intake and NPY contents were decreased following PPA treatment, while Y1R and SOD contents were increased and Y5R contents remained unchanged. Moreover, although Y1R or Y5R knockdown by themselves could modify the food intake, Y1R but not Y5R knockdown could modify PPA-induced anorexia as well as NPY and SOD contents. In addition, selective inhibition of Y1R but not Y5R could modulate PPA-induced anorexia. It is suggested that Y1R but not Y5R participates in the anorectic response of PPA via the modulation of NPY and SOD. Results provide molecular mechanism of NPY-mediated PPA anorexia and may aid the understanding of the toxicology of PPA.

Topics: Animals; Anorexia; Appetite; Appetite Depressants; Gene Knockdown Techniques; Hypothalamus; Injections, Intraventricular; Male; Neuropeptide Y; Oligonucleotides, Antisense; Oxidative Stress; Phenylpropanolamine; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Receptors, Neuropeptide Y; Superoxide Dismutase; Sympathomimetics

It has been reported that oxidative stress, antioxidants, and neuropeptide Y (NPY) are involved in regulating the feeding behavior of phenylpropanolamine (PPA), a sympathomimetic drug. This study explored whether transcription factor NF-κB is involved in this effect. Rats were treated daily with PPA for 4 days. Changes in hypothalamic NF-κB, NPY, superoxide dismutase (SOD), and glutathione peroxidase (GPx) levels during PPA treatment were assessed and compared. Results showed that NF-κB, SOD, and GPx increased, with a maximal response on Day 2, while the food intake and NPY decreased with the biggest reduction on Day 2 during PPA treatment. To further determine whether NF-κB was involved, intracerebroventricular infusion of antisense oligonucleotide was performed at 1 h before daily PPA in free-moving rats. Cerebral NF-κB knockdown could modify PPA anorexia and the expressions of NPY, SOD, and GPx. It is suggested that hypothalamic NF-κB participates in the reciprocal regulation of NPY and antioxidants, which mediated the appetite-suppressing effect of PPA. Results may further the understanding of the molecular mechanisms of PPA.

Topics: Animals; Anorexia; Antioxidants; DNA; Feeding Behavior; Glutathione Peroxidase; Hypothalamus; Male; Neuropeptide Y; NF-kappa B; Phenylpropanolamine; Rats; Rats, Wistar; Superoxide Dismutase; Sympathomimetics

One common physiological phenomenon that is involved both in infectious and in malignant processes is the reduction in appetite: disease anorexia. An increase in plasma levels of leptin with inflammation is thought to be involved in this process. However, from an evolutionary perspective, in certain cases, it would be more adaptive for an internal parasite to stimulate the appetite of the host instead of causing its suppression. We tested whether a parasitic infection with the larvae of the helminth parasite Taenia taeniaformis affects the levels of appetite-regulating proteins, such as leptin, ghrelin and neuropeptide-Y (NPY) in wild yellow-necked mouse (Apodemus flavicollis). We found that infected mice had lower plasma levels of leptin and increased levels of NPY than the uninfected subjects. Ghrelin levels were not associated with the occurrence of the parasites; however, these levels strongly correlated with the levels of NPY. This study suggests a possible manipulation by parasitic larvae of appetite regulation in infected subjects.

Topics: Animals; Anorexia; Appetite; Appetite Regulation; Ghrelin; Host-Parasite Interactions; Hunger; Leptin; Male; Mice; Neuropeptide Y; Parasitic Diseases; Taenia

It has been reported that neuropeptide Y (NPY) contributes to the behavioral response of amphetamine (AMPH), a psychostimulant. The present study examined whether protein kinase C (PKC)-λ signaling was involved in this action. Moreover, possible roles of glutathione peroxidase (GP) and melanocortin receptor 4 (MC4R) were also examined. Rats were given AMPH daily for 4 days. Hypothalamic NPY, PKCλ, GP and MC4R were determined and compared. Pretreatment with α-methyl-para-tyrosine could block AMPH-induced anorexia, revealing that endogenous catecholamine was involved in regulating AMPH anorexia. PKCλ, GP and MC4R were increased with maximal response on Day 2 during AMPH treatment, which were concomitant with the decreases in NPY. cAMP response element binding protein (CREB) DNA binding activity was increased during AMPH treatment, revealing the involvement of CREB-dependent gene transcription. An interruption of cerebral PKCλ transcript could partly block AMPH-induced anorexia and partly reverse NPY, MC4R and GP mRNA levels to normal. These results suggest that PKCλ participates in regulating AMPH-induced anorexia via a modulation of hypothalamic NPY gene expression and that increases of GP and MC4R may contribute to this modulation. Our results provided molecular evidence for the regulation of AMPH-induced behavioral response.

Topics: alpha-Methyltyrosine; Amphetamine; Animals; Anorexia; Antisense Elements (Genetics); Appetite Depressants; Behavior, Animal; Binding Sites; Catecholamines; Central Nervous System Stimulants; Cyclic AMP Response Element-Binding Protein; Dose-Response Relationship, Drug; Eating; Enzyme Inhibitors; Gene Expression Regulation; Gene Knockdown Techniques; Glutathione Peroxidase; Hypothalamus; Injections, Intraventricular; Isoenzymes; Male; Neuropeptide Y; Protein Kinase C; Rats; Rats, Wistar; Receptor, Melanocortin, Type 4; RNA, Messenger; Time Factors; Tyrosine 3-Monooxygenase

To assess whether endocrine dysfunction may cause derangement in energy homeostasis in patients undergoing hemodialysis (HD), we profiled hormones, during a 3-day period, from the adipose tissue and the gut and the nervous system around the circadian clock in 10 otherwise healthy HD patients and 8 normal controls. The protocol included a 40-h fast. We also measured energy-protein intake and output and assessed appetite and body composition. We found many hormonal abnormalities in HD patients: 1) leptin levels were elevated, due, in part, to increased production, and nocturnal surge in response to daytime feeding, exaggerated. 2) Peptide YY (PYY), an anorexigenic gut hormone, was markedly elevated and displayed an augmented response to feeding. 3) Acylated ghrelin, an orexigenic gut hormone, was lower and did not exhibit the premeal spike as observed in the controls. 4) neuropeptide Y (NPY), a potent orexigenic peptide, was markedly elevated and did not display any circadian variation. 5) Norepinephrine, marginally elevated, did not exhibit the normal nocturnal dip. By contrast, α-melanocyte-stimulating hormone and glucagon-like peptide-1 were not different between the two groups. Despite these hormonal abnormalities, HD patients maintained a good appetite and had normal body lean and fat mass, and there was no evidence of increased energy expenditure or protein catabolism. We explain the hormonal abnormalities as well as the absence of anorexia on suppression of parasympathetic activity (vagus nerve dysfunction), a phenomenon well documented in dialysis patients. Unexpectedly, we noted that the combination of high leptin, PYY, and NPY with suppressed ghrelin may increase arterial blood pressure, impair vasodilatation, and induce cardiac hypertrophy, and thus could predispose to adverse cardiovascular events that are the major causes of morbidity and mortality in the HD population. This is the first report attempting to link hormonal abnormalities associated with energy homeostasis to adverse cardiovascular outcome in the HD patients.

Topics: Adult; Anorexia; Appetite; Body Composition; Cardiovascular Diseases; Circadian Rhythm; Endocrine System Diseases; Energy Metabolism; Fasting; Female; Ghrelin; Homeostasis; Humans; Leptin; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Peptide YY; Protein-Energy Malnutrition; Renal Dialysis; Renal Insufficiency; Risk Factors

Mice homozygous for the anorexia (anx) mutation are characterized by poor food intake and death by three to five weeks after birth. By P21 these mice display lower density of hypothalamic neuropeptides, including Agouti gene-related protein (AGRP). The AGRP/neuropeptide Y (NPY) system of the anx/anx mice develops normally until postnatal day (P) 12, then the normal increase in fiber density ceases, in some areas even distinctly decreases. This overlaps with activation of microglia, indicating an inflammatory and/or degenerative process. Here we studied, by in situ hybridization and immunohistochemistry (IHC), the expression of major histocompatibility complex (MHC) class I-related molecules and markers for cellular reactivity in hypothalamus of anx/anx mice. MHC class I transcript and -related proteins were found in arcuate nucleus (Arc), presumably both in neurons and glia, the latter also in areas innervated by AGRP (NPY) neurons. In the anx/anx hypothalamus, using TUNEL labeling, significantly higher number of apoptotic cells were found compared with +/+ mice, and active caspase 6 immunoreactivity was detected in degenerating NPY-fibers as well as signs of "microglia-associated cell death". In addition, Y1 receptor-labeled processes and soma of pro-opiomelanocortin (POMC) neurons, were markedly decreased at P21. These results support the hypothesis of degeneration of hypothalamic arcuate neuron populations in the anx/anx mice, whereby the AGRP system may be first affected, the changes in the POMC system being secondary in this process.

Topics: Animals; Anorexia; Apoptosis; Hypothalamus; Immunohistochemistry; In Situ Hybridization; In Situ Nick-End Labeling; Major Histocompatibility Complex; Mice; Mutation; Neurons; Neuropeptide Y; Pro-Opiomelanocortin

Food-restricted animals present metabolic adaptations that facilitate food-seeking behavior and decelerate energy utilization by reducing the hypothalamus-pituitary-thyroid (HPT) axis function. Stress by dehydration induces an anorexic behavior in rats, loss of weight and reduced food intake when compared to ad libitum fed animals, however these alterations are accompanied by HPT axis changes such as increased serum thyrotropin levels and enhanced expression of thyrotropin-releasing hormone (TRH) in the paraventricular nucleus of the hypothalamus, which is considered as anorexigenic peptide. In contrast, a pair-fed group conformed by forced-food-restricted animals (FFR) (eating the exact same amount of food as dehydration-induced anorexic rats--DIA rats) present decreased TRH mRNA levels. NPY synthesis in the arcuate nucleus and orexin-expressing neurons from the lateral hypothalamic area (LHA) are activated during food restriction. These brain structures project into PVN, suggesting that NPY and orexins are possible factors involved in TRHergic neuron activation in DIA rats. Leptin signaling is another likely factor to be involved in TRH differential expression. Therefore, to gain more insight into the regulation of the feeding behavior in the experimental models, we analyzed Y1, Y5, Ox1-R and Ob-R(b) mRNA levels in PVN and prepro-orexin in LHA, since their signaling to the PVN might be altering TRH synthesis and feeding in DIA animals. Prepro-orexinergic cells were activated in FFR animals; Ox1-R and Y1 expression was reduced in FFR vs. controls or DIA group. Compensatory changes in PVN receptor expression of some feeding-related peptides in anorexic rats may alter TRHergic neural response to energy demands.

Topics: Animals; Anorexia; Dehydration; Feeding Behavior; Gene Expression Regulation; Hypothalamo-Hypophyseal System; Intracellular Signaling Peptides and Proteins; Leptin; Male; Malnutrition; Neurons; Neuropeptide Y; Neuropeptides; Orexin Receptors; Orexins; Paraventricular Hypothalamic Nucleus; Pituitary-Adrenal System; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Receptors, Neuropeptide Y; Signal Transduction; Thyrotropin; Thyrotropin-Releasing Hormone

Aging is associated with decreased food intake, a phenomenon termed the anorexia of aging. In this study, we sought to clarify changes in peripheral and central appetite-related factors in aged mice. Furthermore, we investigated the effects of rikkunshito, a traditional Japanese medicine, on age-related anorexia. C57BL/6J mice that were 6 or 75 wk old were studied. We investigated changes in food intake, ghrelin and leptin levels, and the expression of appetite-related genes with age. In addition, we verified the effects of ghrelin, rikkunshito, phosphodiesterase 3 (PDE3), and phosphoinositide 3-kinase inhibitors on appetite. Food intake was significantly decreased in 75-wk-old mice compared with the 6-wk-old mice. In 75-wk-old mice, plasma acylated ghrelin levels under fasting conditions were lower than in 6-wk-old mice, whereas leptin levels under feeding conditions were substantially higher. The expression levels of hypothalamic preproghrelin under feeding conditions and the expression levels of neuropeptide Y and agouti-related protein under fasting conditions were lower compared with those of the 6-wk-old mice. Ghrelin supplementation (33 microg/kg) failed to increase food intake in 75-wk-old mice. Conversely, oral administration of LY294002, a phosphoinositide 3-kinase inhibitor, and cilostamide, a PDE3 inhibitor, increased food intake in 75-wk-old mice. Moreover, rikkunshito increased food intake in aged mice. The components of rikkunshito (nobiletin, isoliquiritigenin, and heptamethoxyflavone) had inhibitory effects on PDE3. These results suggest that dysregulation of ghrelin secretion and ghrelin resistance in the appetite control system occurred in aged mice and that rikkunshito ameliorated aging-associated anorexia via inhibition of PDE3.

Topics: Aging; Agouti-Related Protein; Animals; Anorexia; Drug Evaluation, Preclinical; Drugs, Chinese Herbal; Eating; Ghrelin; Growth Hormone; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Phosphodiesterase 3 Inhibitors; Phosphodiesterase Inhibitors; Receptors, Ghrelin

Rodents exhibit aversive behavior toward a diet that lacks at least one of the essential amino acids. We sought to determine whether the particular form of anorexia caused by such diets could be ameliorated by the administration of orexigenic peptides while simultaneously analyzing the neural mechanisms underlying anorexia. Rats were fed a valine-deficient diet, which induced severe anorexia (reducing food consumption by 80%). The severe anorexia was associated with a significant decrease in the cerebrospinal fluid valine concentration and hyper-ghrelinemia. Between 6 and 12 days after initiation of the valine-deficient diet, we injected rats twice daily with valine and/or an orexigenic peptide (ghrelin, neuropeptide Y, or agouti-related protein) either i.p. or i.c.v.. We then measured dietary intake. An i.c.v. valine injection allowed earlier food intake compared with an i.p valine injection and increased the density of c-Fos-positive ependymal cells lining the third ventricle. Whereas an i.c.v. injection of ghrelin or neuropeptide Y increased consumption of the valine-deficient diet, i.p injection of ghrelin or i.c.v. injection of agouti-related protein did not. Following i.c.v. administration of either valine or ghrelin, we did not observe complete recovery of consumption of the valine-deficient diet. This may be due to the ineffectiveness of peripheral ghrelin and central agouti-related protein and/or to conditioned aversion to the valine-deficient diet. Since ghrelin is known to be involved in food anticipatory activities, whether the hyper-ghrelinemia observed in valine-deficient rats play role in foraging behavior other than food intake is the future study to be investigated.

Topics: Agouti-Related Protein; Animals; Anorexia; Appetite; Appetite Regulation; Dietary Proteins; Disease Models, Animal; Ependyma; Exploratory Behavior; Feeding Behavior; Food, Formulated; Ghrelin; Hypothalamus; Male; Neuropeptide Y; Rats; Rats, Wistar; Third Ventricle; Valine

Neuropeptide W (NPW) is an anorectic peptide produced in the brain. Here, we showed that NPW was present in several hypothalamic nuclei, including the paraventricular hypothalamic nucleus, ventromedial hypothalamic nucleus, lateral hypothalamus, and hypothalamic arcuate nucleus. NPW expression was significantly up-regulated in leptin-deficient ob/ob and leptin receptor-deficient db/db mice. The increase in NPW expression in ob/ob mice was abrogated to control levels after leptin replacement. Leptin induced suppressors of cytokine signaling-3 after phosphorylation of signal transducer and activator of transcription-3 in NPW-expressing neurons. In addition, we demonstrated that NPW reduces feeding via the melanocortin-4-receptor signaling pathway. We also showed that NPW activates proopiomelanocortin and inhibits neuropeptide Y neurons using loose-patch extracellular recording of these neurons identified by promoter-driven green fluorescent protein expression. This study indicates that NPW may play an important role in the regulation of feeding and energy metabolism under the conditions of leptin insufficiency.

Topics: Animals; Anorexia; Basal Metabolism; Gene Expression; Hypothalamus; Immunohistochemistry; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Microscopy, Immunoelectron; Neurons; Neuropeptide Y; Neuropeptides; Patch-Clamp Techniques; Phosphorylation; Rats; Rats, Wistar; Receptor, Melanocortin, Type 4; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; STAT3 Transcription Factor

Hypothalamic neuropeptide Y (NPY) has been reported to involve in regulating behavioral response of phenylpropanolamine (PPA), a sympathomimetic agent. This study explored if protein kinase C (PKC)-delta signaling participated in this regulation. Moreover, possible roles of anti-free radical enzyme catalase (CAT) and nitrogen oxide synthase (NOS) were also examined. Rats were treated daily with PPA for 4 days. Changes in food intake and hypothalamic NPY, PKCdelta, CAT, and NOS contents were assessed and compared. Results showed that PKCdelta and CAT increased during PPA treatment, which were concomitant with decreases in NPY content and food intake, while the change of NOS was expressed differently. Moreover, PKCdelta knockdown could modify PPA anorexia as well as NPY and CAT expression, while NOS expression remained unchanged. Furthermore, pre-treatment with NOS inhibitor could modify both PPA anorexia and NPY content. It is suggested that PKCdelta participates in the anorectic response of PPA via the modulation of NPY and CAT, while NOS contribute to this modulation via a different mechanism during PPA treatment. Results provide molecular mechanism of NPY-mediated PPA anorexia and may aid the therapeutic research of PPA and other anti-obesity drugs.

Topics: Animals; Anorexia; Catalase; Disease Models, Animal; Eating; Free Radicals; Gene Expression Regulation; Hypothalamus; Male; Neuropeptide Y; Nitric Oxide; Nitric Oxide Synthase Type I; Oxidative Stress; Phenylpropanolamine; Protein Kinase C-delta; Rats; Rats, Wistar

Rheumatoid arthritis (RA) is associated with enhanced pro-inflammatory cytokine levels, pain, anorexia, and cognitive changes. The enhanced production of cytokines appears before the full manifestation of the disease. So far, any experimental data on behavioral effects of early arthritis are lacking. In the present series we describe anorexia early changes in, pain hyper-sensitivity and altered cognitive behavior during the first four days of adjuvant arthritis in rats (AA), when no clinical signs are yet apparent.. AA was induced to male Lewis rats by a single injection of complete Freund's adjuvant (cFA) at the base of the tail. Plasma leptin and ghrelin were measured using specific RIA methods. Gene expressions for food-regulatory peptides, neuropeptide-Y (NPY) and interleukin-1β (IL-1β) in the hypothalamic arcuate nuclei (nARC), were quantitated by TaqMan real-time PCR. Pain sensation was measured on all four limbs and tail by the plantar test. Cognitive functions were tested in the Morris water maze (MWM).. Levels of orexigenic ghrelin as well as mRNA expression of orexigenic NPY in nucleus arcuatus (nRC)re significantly enhanced on day 2 of AA only. Reduced body weight and food intake persisted by day 4 with the most profound reduction on day 2. The mRNA for anorexigenic IL-1β in the nARC was significantly enhanced on days 2 and 4. Enhanced pain sensitivity was observed on day 2, as was the cognitive impairment given by longer time to find the hidden platform, longer time spent in thigmotaxis zone, and longer trajectory. The less effective strategy used to find the hidden platform was observed up to the day 4 of AA.. Early stage of AA brings about reduced body weight, food intake, and activation of central orexigenic pathways. The observed anorexia could be ascribed to the over-expression of anorexigenic IL-1β which dominates over the NPY orexigenic effects. On day 2 of AA higher pain sensitivity and cognitive impairment appear. All the observed change tend to recover by day 4 of the disease.

Topics: Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Arthritis, Experimental; Cognition Disorders; Gene Expression; Ghrelin; Hyperalgesia; Interleukin-1beta; Leptin; Male; Neuropeptide Y; Rats; RNA, Messenger; Time Factors

Food intake is activated by hypothalamic orexigenic neuropeptide Y (NPY), which is mainly under the dual control of leptin and ghrelin. Rat adjuvant arthritis (AA), similarly as human rheumatoid arthritis, is associated with cachexia caused by yet unknown mechanisms. The aim of our study was to evaluate NPY expression in hypothalamic arcuate nuclei (nARC) under the conditions of AA-induced changes in leptin, ghrelin and adiponectin. Since IL-1beta is involved in the central induction of anorexia, we studied its expression in the nARC as well.. AA was induced to Lewis rats using complete Freund's adjuvant. On days 12, 15 and 18 after complete Freund's adjuvant injection, the levels of leptin, adiponectin, ghrelin and IL-1beta were determined by RIA or ELISA. The mRNA expressions for NPY, leptin receptor (OB-R), ghrelin receptor (Ghsr) and IL-1beta were determined by TaqMan RT-PCR from isolated nARC.. In AA rats, decreased appetite, body mass and epididymal fat stores positively correlated with reduced circulating and epididymal fat leptin and adiponectin. Ghrelin plasma levels were increased. In nARC, mRNA for OB-R, Ghsr and NPY were overexpressed in AA rats. AA rats showed overexpression of mRNA for IL-1beta in nARC while circulating, and spleen IL-1beta was unaltered.. During AA, overexpression of orexigenic NPY mRNA in nARC along with enhanced plasma ghrelin and lowered leptin levels occur. Decreased food intake indicates a predominant effect of the anorexigenic pathway. Activated expression of IL-1beta in nARC suggests its role in keeping AA-induced anorexia in progress. The reduction in adiponectin may also contribute to AA-induced anorexia.

Topics: Adiponectin; Animals; Anorexia; Appetite; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Arthritis; Disease Models, Animal; Gene Expression Regulation; Ghrelin; Hypothalamo-Hypophyseal System; Interleukin-1beta; Leptin; Male; Neuropeptide Y; Rats; Rats, Inbred Lew; RNA, Messenger; Signal Transduction; Up-Regulation

Anorexia that accompanies cellular dehydration in rats (DE-anorexia) offers a relatively simple model for investigating the functional organization of neural mechanisms that can suppress feeding during dehydration. Previous studies strongly suggest that the inputs that drive ingestive behavior control neurons in the paraventricular nucleus of the hypothalamus (PVH) and lateral hypothalamic area (LHA) remain active during DE-anorexia. Here we examine whether these two regions retain their sensitivity to neuropeptide Y (NPY). NPY is an important component in two major feeding-related inputs from the arcuate nucleus and the hindbrain. We found that intake responses to NPY injections in the LHA and PVH were suppressed in DE-anorexia, but the PVH remained less sensitive to the effects of NPY than the LHA in DE-anorexic animals. Indeed the higher dose of NPY (238 pmol) completely overcame shorter periods of DE-anorexia when injected into the LHA but not the PVH. However, the latency to eat after NPY injections remained unchanged from control animals, regardless of NPY dose, injection location, or intensity of anorexia. Furthermore, the onset and size of the strong and rapidly induced compensatory feeding that follows the return of water to DE-anorexic animals was also unaffected by any NPY injections. These data support the hypothesis that DE-anorexia develops as a consequence of the premature termination of regularly initiated meals, which perhaps involves processes that alter the sensitivity of satiety mechanisms downstream to the PVH and LHA.

Topics: Animals; Anorexia; Dehydration; Disease Models, Animal; Drinking; Drinking Behavior; Eating; Feeding Behavior; Hypothalamic Area, Lateral; Injections; Male; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Reaction Time; Satiety Response; Time Factors

In an attempt to gain better insight into the central effects of glucagon-like peptide (GLP-1), we studied the action of glucose and of regulatory peptides on the expression of its receptor (GLP-1R) in hypothalamic GT1-7 cells and in ventromedial (VMH) and lateral (LH) rat hypothalamus slices. The promoter activity of GLP-1R in transfected GT1-7 cells increased with leptin, whereas neuropeptide Y (NPY) did not modify it. Interestingly, when cells were incubated with both NPY and leptin, NPY blocked the stimulating effect of leptin. The effects of leptin and NPY were also confirmed at messenger RNA levels. In hypothalamic slices, GLP-1R messenger RNA levels increased at higher glucose concentrations in the VMH. In addition, leptin exerted a stimulating effect; and NPY did not modify receptor expression. By contrast, in the LH, the opposite effects were found for those parameters, except at 20 mmol/L glucose. These findings suggest that the stimulating effect of leptin on GLP-1R expression, with no changes in NPY-induced activity, could enhance the anorexic actions generated through this receptor. In addition, the different responses of the VMH and LH may be related to specific functions of these structures, as already known in vivo, highlighting the interest of hypothalamic slices for this kind of study.

Topics: Animals; Anorexia; Cell Line; Gene Expression Regulation; Glucagon-Like Peptide-1 Receptor; Glucose; Hypothalamus; Leptin; Male; Neuropeptide Y; Organ Culture Techniques; Promoter Regions, Genetic; Rats; Rats, Wistar; Receptors, Glucagon; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Agouti-related protein (AgRP) is a key orexigenic neuropeptide expressed in the hypothalamic arcuate nucleus and a marker for neurons conveying hormonal signals of hunger to the brain. Mice homozygous for the anorexia (anx) mutation are characterized by decreased food intake, starvation, and death by 3-5 weeks of age. At this stage immunoreactivity for AgRP is increased in cell bodies but decreased in the nerve terminals. We studied when during early postnatal development the aberrant phenotype of the AgRP system becomes apparent in anx/anx mice and possible underlying mechanisms. AgRP and ionized calcium binding adapter molecule (Iba1), a marker for activated microglia, as well as Toll-like receptor 2 (TLR-2), were studied by immunohistochemistry at postnatal days P1, P5, P10, P12, P15 and P21 in anx/anx and wild-type mice. We found that the AgRP system in the anx/anx mouse develops similarly to the wild type until P12, when AgRP fibers in anx/anx mice cease to increase in density in the main projection areas. At P21, AgRP fiber density in anx/anx mice was significantly reduced vs. P15, in certain regions. At P21, many strongly AgRP-positive cell bodies were observed in the anx/anx arcuate nucleus vs. only few and weakly fluorescent ones in the wild type. The decrease in AgRP fiber density in anx/anx mice overlapped with an increase in Iba1 and TLR-2 immunoreactivities. Thus, the aberrant appearance of the AgRP system in the anx/anx mouse in the early postnatal development could involve a microglia-associated process and the innate immune system.

Topics: Agouti-Related Protein; Animals; Anorexia; Antibodies; Arcuate Nucleus of Hypothalamus; Calcium-Binding Proteins; Eating; Female; Immunohistochemistry; Male; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Microfilament Proteins; Microglia; Mutation; Nerve Degeneration; Neuropeptide Y; Toll-Like Receptor 2

Nitric oxide (NO) is known as an orexigenic factor in the brain of mammals and mediates the feeding-stimulatory effect of other factors such as neuropeptide Y (NPY). In neonatal chicks, however, we recently reported that NO might have an anorexigenic effect and suggested that the feeding-regulatory mechanism in chicks might be different from that in mammals regarding NO. In the present study, we investigated the involvement of NO in the effect of other orexigenic and anorexigenic factors in neonatal chicks. Intracerebroventricular co-injection of N(G)-nitro-l-arginine methyl ester (l-NAME), a NO synthase inhibitor, did not affect NPY- and prolactin-releasing peptide-induced feeding behavior. On the other hand, the co-injection of l-NAME significantly attenuated the anorexigenic effect of corticotropin-releasing hormone (CRH). The anorexigenic effects of glucagon-like peptide-1, alpha-melanocyte-stimulating hormone and ghrelin were not affected by the l-NAME treatment. These results suggest that NO might mediate the anorexigenic effect of CRH in the brain of neonatal chicks.

Topics: alpha-MSH; Animals; Animals, Newborn; Anorexia; Chickens; Corticotropin-Releasing Hormone; Drug Combinations; Ghrelin; Glucagon-Like Peptide 1; Hypothalamic Hormones; Male; Neuropeptide Y; Neuropeptides; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Prolactin-Releasing Hormone

Although amphetamine (AMPH)-induced appetite suppression has been attributed to its inhibitory action on neuropeptide Y (NPY), an appetite neurotransmitter abundant in the brain, molecular mechanisms underlying this effect are not well known. This study examined the possible role of protein kinase A (PKA) and cAMP response element-binding protein (CREB) signaling in this anorectic effect, and the results showed that both PKA and CREB mRNA levels in hypothalamus were increased following AMPH treatment, which was relevant to a reduction of NPY mRNA level. To determine whether PKA or CREB was involved in the anorectic response, intracerebroventricular infusions of antisense oligonucleotide (or missense control) were performed 60 min before daily AMPH treatment in conscious rats, and results showed that either PKA or CREB knockdown could block AMPH-induced anorexia as well as restore NPY mRNA level, indicating the respective involvement of PKA and CREB signaling in the regulation of NPY gene expression. It is suggested that hypothalamic PKA and CREB signaling may involve the central regulation of AMPH-mediated feeding suppression via the modulation of NPY gene expression.

Topics: Amphetamine; Animals; Anorexia; Appetite Depressants; Appetite Regulation; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Feeding Behavior; Injections, Intraventricular; Male; Movement; Nerve Tissue Proteins; Neuropeptide Y; Oligonucleotides, Antisense; Rats; Rats, Wistar; RNA, Messenger

Anorexia is possibly one of the most important causes of malnutrition in uremic patients. The cause of this abnormality is still unknown. Considering that: (a) NPY is one of the most important stimulants of food intake; (b) eating is a central nervous system regulated process and (c) NPY is expressed in hypothalamus, we hypothesized that the decrease of NPY gene expression in the hypothalamus could be an important factor contributing to anorexia associated with uremic state. In contrast to the prediction, the results presented in this paper indicate that the NPY gene expression in the hypothalamus of chronic renal failure (CRF) rats was significantly higher than in the hypothalamus of control (pair-fed) rats. Moreover, we found that serum NPY concentration in CRF rats was higher than in control (pair-fed) animals. The increase of plasma NPY concentration in CRF rats may be due to the greater synthesis of the neuropeptide in liver, since higher level of NPY mRNA was found in liver of CRF rats. The results obtained revealed that experimental chronic renal failure is associated with the increase of NPY gene expression in hypothalamus and liver of rats.

Topics: Animals; Anorexia; Disease Models, Animal; Gene Expression Regulation; Hypothalamus; Kidney Failure, Chronic; Liver; Male; Neuropeptide Y; Rats; Rats, Wistar; RNA, Messenger; Up-Regulation

Although previous studies have implicated NPY in the etiology of experimental cancer anorexia, the results have been difficult to interpret. Studies have suggested that although NPY level and message were decreased in the dorsomedial hypothalamic area (DMA), they were elevated in the ventromedial hypothalamic area (VMA). To better assess specific intra-area alterations of NPY, Y(1) receptor (Y(1) R), and agouti-related peptide (AgRP) in TB rats, we used radioimmunoassay, quantitative real-time RT-PCR, and immunohistochemistry. We found that NPY and AgRP mRNA were elevated significantly in whole hypothalamus of anorectic TB rats, while Y(1) R mRNA was decreased. Based on two replicates of four pooled samples each, both NPY and AgRP mRNA appeared to be elevated in the VMA of anorectic TB rats, while only AgRP exhibited a similar increase in the DMA. Levels of NPY were elevated in the VMA of both TB and pair-fed (PF) rats, but in the DMA only PF rats exhibited a significant NPY increase. NPY and Y(1) R immunohistochemistry revealed reduced NPY staining in PVN and ARC nucleus of TB and PF rats. Y(1) R immunostaining was also reduced in the ARC and PVN of TB rats, while PF rats exhibited elevated immunostaining in the PVN. These results continue to implicate dysfunction of NPY feeding systems in experimental cancer anorexia and suggest down-regulation of Y(1) R receptors as well as possible problems in NPY translation.

Topics: Agouti-Related Protein; Animals; Anorexia; Hypothalamus; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Neoplasms, Experimental; Neuropeptide Y; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

We assessed the time course effects of lipopolysaccaride (LPS) on food intake, cytokines, and hormones in rats and evaluated the relation between LPS-induced anorexia and its possible causative factors. Food intake was reduced 2 h after LPS injection (500 microg/kg, intraperitoneally) and remained decreased for 24 h. Plasma TNF-alpha and IL-6 levels increased by LPS administration at 0.5 and 2 h, and at 2 and 4 h, respectively. Plasma leptin and glucose levels were elevated at 8 and 16 h, and insulin levels were elevated at 2, 4, 8, and 16 h in the LPS-injected group, as compared to the counterpart controls. IL-6 levels in the CSF were elevated at 2 and 4 h. Hypothalamic cytokines tended to increase as early as 0.5 h after LPS injection and remained increased until 16 h. LPS-induced anorexia was attenuated in insulin-deficient STZ rats and was abolished by insulin treatment. The hypothalamic expression of NPY, a target of insulin's anorexic effect, was decreased 2 h after LPS administration, and central NPY injection (3 nM) prevented LPS-induced anorexia. In conclusion, cytokines, insulin, and leptin levels evidence different time courses by LPS administration. In LPS-induced anorexia, insulin may constitute a newly found causative factor, whereas leptin appears to be uninvolved in an early period in rats.

Topics: Animals; Anorexia; Cytokines; Eating; Hypoglycemic Agents; Injections, Intraperitoneal; Insulin; Interleukin-6; Leptin; Lipopolysaccharides; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Time Factors; Tumor Necrosis Factor-alpha

Neuropeptide Y (NPY) is an appetite-controlling neuromodulator that contributes to the appetite-suppressing effect of phenylpropanolamine (PPA). Aims of this study were to investigate whether protein kinase A (PKA) signaling is involved in regulating NPY gene expression and PPA-induced anorexia. Rats were given daily with PPA for 5 days. Changes in daily food intake and hypothalamic NPY, PKA, cAMP response element binding protein (CREB), and pro-opiomelanocortin (POMC) gene expression were measured and compared. To further determine if PKA was involved, intracerebroventricular infusions of antisense oligodeoxynucleotide were performed at 60 min before daily PPA treatment in freely moving rats. Results showed that daily PKA, CREB, and POMC expression were increased following PPA treatment, which showed a closely reverse relationship with alterations of decreased feeding behaviors and NPY mRNA levels. Results also showed that PKA knock-down could block PPA-induced anorexia as well as restore NPY mRNA level, indicating the involvement of PKA signaling in the regulation of NPY gene expression. It is suggested that hypothalamic PKA signaling may participate in the central regulation of PPA-mediated appetite suppression via the modulation of hypothalamic NPY gene expression. The present findings reveal that manipulations at the molecular level of PKA or cAMP may allow the development of therapeutic agents to improve the undesirable properties of PPA or other amphetamine-like anorectic drugs.

Topics: Animals; Anorexia; Appetite Depressants; Body Weight; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Feeding Behavior; Gene Expression Regulation; Gene Targeting; Hypothalamus; Injections, Intraventricular; Male; Neuropeptide Y; Oligodeoxyribonucleotides, Antisense; Phenylpropanolamine; Pro-Opiomelanocortin; Protein Biosynthesis; Rats; RNA, Messenger; Transcription, Genetic

Hypermetabolism and anorexia are significant problems associated with major burn trauma. Recent studies have shown that hypothalamic corticotropin releasing factor (CRF) elevates metabolic rate, while neuropeptide Y (NPY) reduces it. CRF also elicits anorexia, while NPY stimulates feeding. We hypothesized that elevation of CRF and decrease of NPY may be mediators of these negative effects of burn trauma. Therefore, we assessed concentrations of CRF and NPY in hypothalamus of burned rats one, three, and twenty-one days after a 30% body surface area, full-thickness, open flame burn. In addition we determined whether a biochemical lesion of CRF receptors using 3rd ventricle injections of a saporin-CRF conjugated peptide would decrease resting energy expenditure (REE). We found a three-day period of anorexia, with REE significantly increasing three days after the burn trauma. Concentrations of NPY were increased in the PVN-containing dorsomedial region of the hypothalamus 1 and 3 days after burn trauma, but were increased further in the day 1 pair-fed rats suggesting this change was a consequence of the anorexia. Levels of CRF were decreased in the ventromedial region of the hypothalamus in day 1 and day 3 burned and PF rats. Treatment with the saporin-CRF conjugate normalized REE and reduced CRF receptor-2 density in the hypothalamus of burned rats, and blocked CRF-induced hypermetabolism in sham-burned rats. Although these results suggest a role of CRF receptors in mediating burn-induced hypermetabolism, CRF itself may not be the principle ligand, as suggested by the significant elevation of hypothalamic urocortin 15 days after burn injury.

Topics: Animals; Anorexia; Burns; Corticotropin-Releasing Hormone; Disease Models, Animal; Energy Metabolism; Hypothalamus; Immunotoxins; Male; N-Glycosyl Hydrolases; Neuropeptide Y; Plant Proteins; Rats; Rats, Sprague-Dawley; Ribosome Inactivating Proteins, Type 1; Saporins

Tumor growth leads to cancer anorexia that is ameliorated using omega-3 fatty acids (omega-3FA). We hypothesize that omega-3FA modulates up-regulation of hypothalamic orexigenic neuropeptide Y (NPY) and down-regulation of anorexigenic alpha melanocyte-stimulating hormone (alpha-MSH) and serotonin 1B receptors (5-HT(1B)-receptors) in tumor-bearing rats.. Twenty-eight tumor-bearing rats were fed either chow (TB-Control) or omega-3FA (TB-omega-3FA). When anorexia developed in TB-Control rats, they and a cohort of TB-omega-pi-3 rats were killed. The rest had their tumor resected (R-Control and R-omega-3FA), and when anorexic TB-Controls normalized their food intake, brains were removed for hypothalamic immunocytochemical study of NPY, alpha-MSH, and 5-HT(1B)-receptor antibodies concentrations. Comparison among slides were assessed by image analysis and analyzed by ANOVA and t test.. At anorexia, hypothalamic NPY in arcuate nucleus (ARC) increased by 38% in TB-omega3FA versus TB-Control, whereas alpha-MSH decreased 64% in ARC and 29% in paraventricular nucleus (PVN). Omega-3FA diet in anorexia (TB-omega-3FA vs R-omega-3FA) produced similar qualitative changes of NPY (22% increase) and alpha-MSH (31% decrease) in ARC, with concomitant decrease of 37% in 5-HT(1B)-receptors in PVN, confirming the influence of omega-3FA on the hypothalamic food intake modulators. However, after tumor resection (TB-Control vs R-Control) a 97% increase in NPY and a 62% decrease in alpha-MSH occurred that was significantly greater than in rats fed omega-3FA diet.. Tumor resection and omega-3FA modifies hypothalamic food intake activity, up-regulating NPY and down-regulating alpha-MSH and 5-HT(1B)-receptors. Tumor resection in anorexic rats on chow diet restored hypothalamic NPY, alpha-MSH, and food intake quantitatively more than in rats fed omega3FA diet.

Topics: Animal Feed; Animals; Anorexia; Appetite; Down-Regulation; Eating; Fatty Acids, Omega-3; Hypothalamus; Male; Neoplasms; Neuropeptide Y; Rats; Rats, Inbred F344; Receptor, Serotonin, 5-HT1B; Up-Regulation

Despite irrefutable epidemiologic evidence, cigarette smoking remains the major preventable cause of lung disease morbidity worldwide. The appetite-suppressing effect of tobacco is a major behavioral determinant of smoking, but the underlying molecular and neuronal mechanisms are not understood. Neuropeptide Y (NPY) is an orexigenic neuropeptide, whose activity in the hypothalamic paraventricular nucleus governs appetite.. To compare the effects of smoke exposure and equivalent food restriction on body weight, organ mass, cytokines, and brain NPY in Balb/c mice.. A pair-feeding study design compared smoke exposure (4 wk; 1 cigarette, 3 x /d, 5 d/wk) to equivalent food restriction (pair-fed) and sham-exposed control mice.. Smoke exposure rapidly induced mild anorexia. After 4 wk, smoke-exposed and pair-fed groups were lighter than control mice (22.0 +/- 0.2, 23.2 +/- 0.5, 24.9 +/- 0.4 g, respectively; p < 0.05). Brown and white fat masses were only reduced by smoke exposure, relative to control mice. NPY concentration in the paraventricular nucleus was significantly and paradoxically reduced by smoke exposure, despite lower plasma leptin concentrations; this was not observed in the pair-fed group experiencing 19% food restriction. Adipose mRNA expression of uncoupling proteins, inflammatory cytokines interleukin 6 and tumor necrosis factor alpha, and adipose triglyceride lipase was decreased by smoke exposure, and even lower in pair-fed mice.. In contrast to food restriction, smoke exposure caused a reduction in hypothalamic NPY and fat mass, and regulated adipose cytokines. These findings may contribute to understanding weight loss in smoking-related lung disease and in the design of more effective smoking cessation strategies.

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Anorexia; Appetite Regulation; Body Weight; Carrier Proteins; Hypothalamus; Interleukin-6; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Mitochondrial Proteins; Neuropeptide Y; RNA, Messenger; Smoking; Tumor Necrosis Factor-alpha; Uncoupling Protein 1; Uncoupling Protein 3; Weight Loss

It is known that, in rats, central and peripheral ghrelin increases food intake mainly through activation of neuropeptide Y (NPY) neurons. In contrast, intracerebroventricular (ICV) injection of ghrelin inhibits food intake in neonatal chicks. We examined the mechanism governing this inhibitory effect in chicks. The ICV injection of ghrelin or corticotropin-releasing factor (CRF), which also inhibits feeding and causes hyperactivity in chicks. Thus, we examined the interaction of ghrelin with CRF and the hypothalamo-pituitary-adrenal (HPA) axis. The ICV injection of ghrelin increased plasma corticosterone levels in a dose-dependent or a time-dependent manner. Co-injection of a CRF receptor antagonist, astressin, attenuated ghrelin-induced plasma corticosterone increase and anorexia. In addition, we also investigated the effect of ghrelin on NPY-induced food intake and on expression of hypothalamic NPY mRNA. Co-injection of ghrelin with NPY inhibited NPY-induced increase in food intake, and the ICV injection of ghrelin did not change NPY mRNA expression. These results indicate that central ghrelin does not interact with NPY as seen in rodents, but instead inhibits food intake by interacting with the endogenous CRF and its receptor.

Topics: Animals; Animals, Newborn; Anorexia; Brain; Chickens; Corticosterone; Corticotropin-Releasing Hormone; Feeding Behavior; Ghrelin; Hypothalamus; Male; Neuropeptide Y; Peptide Hormones; Peptides; Pituitary-Adrenal System; Protein Binding; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors

This study investigated leptin and neuropeptide Y levels in children with cancer, the relationship of those levels to cachexia, and their usefulness as prognostic indicators. Twenty-three newly diagnosed children with cancer were included in the study. The median age at diagnosis was 8 years (range 1.5-14), and the male to female ratio was 13:10. Body mass index, serum leptin and neuropeptide Y levels were measured at diagnosis and at each cycle of chemotherapy. The mean neuropeptide Y level was 211.1 pmol/l at diagnosis and decreased to 92.8 pmol/l at the fifth cycle of chemotherapy. In contrast, the mean leptin level was 3.9 ng/ml at diagnosis and increased to 13.0 ng/ml at the fifth cycle of chemotherapy. Thus, levels of these factors are influenced by treatment status and disease progression. The mean neuropeptide Y level at diagnosis was 82.32 pmol/l in children with complete remission and 430.16 pmol/l in those who died with disease during the follow-up period. The mean leptin level at diagnosis was 6.60 ng/ml in children with complete remission and 0.192 ng/ml in patients who died with disease during the follow-up period. The neuropeptide Y and leptin levels seem to be related to prognosis and could be used as prognostic indicators in the follow-up of children with cancer.

Topics: Adolescent; Anorexia; Biomarkers; Cachexia; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Leptin; Male; Neoplasms; Neuropeptide Y; Prognosis; Weight Loss

In cancer anorexia, a decrease in food intake (FI) occurs concomitant with changes in orexigenic peptides such as neuropeptide Y (NPY) and anorexigenic peptides such as alpha-melanocyte-stimulating hormone (alpha-MSH) and anorexigenic neurotransmitter serotonin. omega-3 Fatty acid (omega-3FA) inhibits cytokine synthesis, and delays tumor appearance, tumor growth, and onset of anorexia in tumor-bearing rats. We hypothesize that, in cancer anorexia, omega-3FA is associated with quantitative reversal of hypothalamic NPY, alpha-MSH, and serotonin receptor (5-HT(1B)-receptor) enhancing FI. Fischer rats were divided into: MCA tumor bearing fed chow (TB-Chow) or omega-3FA diet (TB-omega-3FA) and controls: non-tumor bearing fed chow (NTB-Chow) or omega-3FA diet (NTB-omega-3FA). Rats were euthanized at anorexia and brains were removed for hypothalamic immunohistochemical study, using NPY, alpha-MSH, and 5-HT(1B)-receptor-specific antibodies and slides assessed by image analysis. Immunostaining specificity was controlled by omission of primary or secondary antibodies and pre-absorption test. At anorexia, FI decreased (P < 0.05) in TB-Chow but did not change in TB-omega-3FA rats. In TB-omega-3FA vs. TB-Chow, NPY immunoreactivity increased 38% in arcuate nucleus (ARC; P < 0.05), and 50% in magnocellular paraventricular nucleus (mPVN; P < 0.05). alpha-MSH decreased 64% in ARC and 29% in mPVN (P < 0.05). 5-HT(1B)-receptor immunoreactivity decreased 13% only in supraoptic nucleus (P < 0.05). No immunoreactivity was found in the control sections. omega-3FA modified hypothalamic peptides and 5-HT-(1B)-receptor immunoreactivity at anorexia, concomitant with an increase in FI, were probably mediated by omega-3FA inhibition of tumor-induced cytokines.

Topics: alpha-MSH; Analysis of Variance; Animals; Anorexia; Appetite Regulation; Dietary Fats; Fatty Acids, Omega-3; Hypothalamus; Immunohistochemistry; Male; Neuropeptide Y; Rats; Rats, Inbred F344; Receptor, Serotonin, 5-HT1B; Sarcoma, Experimental; Serotonin; Soft Tissue Neoplasms

Tumor growth leads to anorexia and decreased food intake, the regulation of which is via the integrated hypothalamic peptidergic and monoaminergic system. Serotonin (5-HT), an anorectic monoamine acts primarily via 5-HT 1B-receptors in hypothalamic nuclei while neuropeptide Y (NPY) acts an orexigenic peptide. We previously reported that 5-HT 1B-receptors are up regulated while NPY is down regulated in tumor-bearing (TB)-related anorexia, contributing to food intake reduction. In anorectic TB rats we hypothesize that after tumor resection when food intake has reverted to normal, normalization of 5-HT 1B-receptor and NPY will occur. The aim of this study was to demonstrate normalization of these hypothalamic changes compared to Controls. In anorectic tumor-bearing rats after tumor resection (TB-R) and in sham-operated (Control) rats, distribution of 5-HT 1B-receptors and NPY in hypothalamic nuclei was analyzed using peroxidase antiperoxidase immunocytochemical methods. Image analysis of immunostaining was performed and the data were statistically analyzed. Immunostaining specificity was controlled by omission of primary or secondary antibodies and pre-absorption test. Our results show that after TB-R versus Controls a normalization of food intake, 5-H-1B-receptor and NPY expression in the hypothalamus occurs. These data, discussed in context with our previous studies, support the hypothesis that tumor resection results not only in normalization of food intake but also in reversible changes of anorectic and orexigenic hypothalamic modulators.

Topics: Animals; Anorexia; Body Weight; Diagnostic Imaging; Eating; Hypothalamus; Immunohistochemistry; Male; Methylcholanthrene; Neuropeptide Y; Rats; Rats, Inbred F344; Receptor, Serotonin, 5-HT1B; Recovery of Function; Sarcoma, Experimental; Time Factors

Anorexia (anx) is a recessive mutation that causes lethal starvation in homozygous mice. Studies of anx/anx mice hypothalamus have shown abnormalities in the orexigenic (NPY/AGRP neurons) and the anorexigenic (POMC/CART neurons) pathways. By gene expression profiling using cDNA and oligonucleotide microarrays, we have shown that a surexpression of genes involved in inflammatory process occurred in anx mice hypothalamus. This inflammatory process could be the cause of the anorexia phenotype observed in these mice.

Topics: Animals; Anorexia; Gene Expression; Gene Expression Profiling; Hypothalamus; Inflammation; Mice; Mice, Neurologic Mutants; Neuropeptide Y; Oligonucleotide Array Sequence Analysis; Pro-Opiomelanocortin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Fasting attenuates disease-associated anorexia, but the mechanisms underlying this effect are not well understood. In the present study, we investigated the extent to which a 48 h fast alters hypothalamic neuronal activity in response to the anorectic effects of lipopolysaccharide in rats. Male rats were fed ad libitum or fasted, and were injected with i.p. saline or lipopolysaccharide (250 microg/kg). Immunohistochemistry for Fos protein was used to visualize neuronal activity in response to lipopolysaccharide within selected hypothalamic feeding regulatory nuclei. Additionally, food intake, body weight, plasma interleukin-1 and leptin levels, and the expression of mRNA for appetite-related neuropeptides (neuropeptide Y, proopiomelanocortin and cocaine-amphetamine-regulated transcript) were measured in a time-related manner. Our data show that the pattern of lipopolysaccharide-induced Fos expression was similar in most hypothalamic nuclei whatever the feeding status. However, we observed that fasting significantly reduced lipopolysaccharide-induced Fos expression in the paraventricular nucleus, in association with an attenuated lipopolysaccharide-induced anorexia and body weight loss. Moreover, lipopolysaccharide reduced fasting-induced Fos expression in the perifornical area of the lateral hypothalamus. Lipopolysaccharide-induced circulating levels of interleukin-1 were similar across feeding status. Finally, fasting, but not lipopolysaccharide, affected circulating level of leptin and appetite-related neuropeptides expression in the arcuate nucleus. Together, our data show that fasting modulates lipopolysaccharide-induced anorexia and body weight loss in association with neural changes in specific hypothalamic nuclei.

Topics: Animals; Anorexia; Behavior, Animal; beta-Endorphin; Body Weight; Cell Count; DNA-Binding Proteins; Eating; Enzyme-Linked Immunosorbent Assay; Feeding Behavior; Food Deprivation; Gene Expression Regulation; Hypothalamus; Immunohistochemistry; In Situ Hybridization; Interleukin-1; Interleukin-1beta; Leptin; Lipopolysaccharides; Male; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Oncogene Proteins v-fos; Peptide Fragments; Pro-Opiomelanocortin; Rats; Rats, Wistar; STAT3 Transcription Factor; Time Factors; Trans-Activators

Fluoxetine is an anorexic agent known to reduce food intake and weight gain. However, the molecular mechanism by which fluoxetine induces anorexia has not been well-established. We examined mRNA expression levels of neuropeptide Y (NPY) and proopiomelanocortin (POMC) in the brain regions of rats using RT-PCR and in situ hybridization techniques after 2 weeks of administering fluoxetine daily. Fluoxetine persistently suppressed food intake and weight gain during the experimental period. The pair-fed group confirmed that the reduction in body weight in the fluoxetine treated rats resulted primarily from decreased food intake. RT-PCR analyses showed that mRNA expression levels of both NPY and POMC were markedly reduced by fluoxetine treatment in all parts of the brain examined, including the hypothalamus. POMC mRNA in situ signals were significantly decreased, NPY levels tended to increase in the arcuate nucleus (ARC) of fluoxetine treated rats (compared to the vehicle controls). In the pair-fed group, NPY mRNA levels did not change, but the POMC levels decreased (compared with the vehicle controls). These results reveal that the chronic administration of fluoxetine decreases expression levels in both NPY and POMC in the brain, and suggests that fluoxetine-induced anorexia may not be mediated by changes in the ARC expression of either NPY or POMC. It is possible that a fluoxetine raised level of 5-HT play an inhibitory role in the orectic action caused by a reduced expression of ARC POMC (alpha-MSH).

Topics: Animals; Anorexia; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Autoradiography; Body Weight; Brain Chemistry; Eating; Fluoxetine; Gene Expression Regulation; Male; Neuropeptide Y; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Selective Serotonin Reuptake Inhibitors

Multiple hormones controlling energy homeostasis regulate the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus. Nevertheless, inactivation of the genes encoding NPY and/or AgRP has no impact on food intake in mice. Here we demonstrate that induced selective ablation of AgRP-expressing neurons in adult mice results in acute reduction of feeding, demonstrating direct evidence for a critical role of these neurons in the regulation of energy homeostasis.

Topics: Agouti-Related Protein; Animals; Anorexia; Arcuate Nucleus of Hypothalamus; beta-Galactosidase; Body Weight; Cell Count; Diphtheria Toxin; Eating; Feeding Behavior; Gene Expression Regulation; Intercellular Signaling Peptides and Proteins; Mice; Mice, Knockout; Neurons; Neuropeptide Y; Pro-Opiomelanocortin; Proteins; Time Factors

A mutation in the Contactin-1 gene results in an ataxic and anorectic phenotype that is apparent by postnatal day 10 and lethal by postnatal day 19 [Berglund et al. (1999) Neuron 24, 739-750]. The resemblance of this phenotype with the anorexia (anx/anx) mouse mutation prompted us to investigate the hypothalamic neurochemistry of Contactin knock-out (KO) mice. Contactin was expressed in the hypothalamic neuropil of wild-type (WT) but not Contactin KO mice. In the KO condition, neuropeptide Y (NPY) and agouti-related protein (AgRP) immunoreactivity (IR) accumulated in the somata of arcuate nucleus neurons, whereas IR for these neuropeptides as well as for alpha-melanocyte-stimulating hormone (alpha-MSH) decreased in the corresponding axon projections. These changes in the pattern of neuropeptide expression in the Contactin-deficient hypothalamus were similar but more pronounced than those found in anx/anx mice. Increased levels of NPY and AgRP and decreased concentrations of pro-opiomelanocortin mRNA in arcuate neurons accompanied these changes. In relating these alterations a 24-h food deprivation period, we observed in 3-week-old WT mice an elevation of NPY- and AgRP-IR in the perikarya of arcuate neurons without notable reduction of NPY- or AgRP-IR in nerve fibers, suggesting that the decrease of arcuate projections can be associated with postnatal anorectic phenotype. Our data implicate Contactin in the postnatal development of the NPY/AgRP and alpha-MSH arcuate neurons and suggest that similar to anx/anx mutant mice, compromised orexigenic signaling via NPY/AgRP neurons may contribute to reduced food intake by the Contactin-mutant animals.

Topics: Agouti-Related Protein; alpha-MSH; Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Cell Adhesion Molecules, Neuronal; Contactin 1; Contactins; Food Deprivation; Gene Expression Regulation; Hypothalamic Hormones; Immunohistochemistry; In Situ Hybridization; Intercellular Signaling Peptides and Proteins; Melanins; Mice; Mice, Knockout; Neuropeptide Y; Pituitary Hormones; Pro-Opiomelanocortin; Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Paraventricular (PVN) concentrations of neuropeptide Y (NPY), serotonin (5-HT) and dopamine (DA) in anorectic tumor-bearing (TB) rats were measured before and after tumor resection. At onset of anorexia in TB versus non-tumor bearing (NTB) Controls 5-HT increased from 12.19+/-0.49 pg/microg to 14.89+/-0.81 pg/microg ( P<0.05 ) while DA and NPY decreased from 7.34+/-0.42 pg/microg to 4.97+/-0.56 pg/microg and 23.47+/-4.27 pg/microg to 13.64+/-1.44 pg/microg, respectively ( P<0.05 ). After tumor resection, these neuromediators normalized when compared to sham-operated NTB rats. NTB pair-fed Controls were also studied. We conclude that the increased 5-HT and the decreased DA and NPY concentrations in PVN are associated with cancer anorexia and that the NPY food stimulatory effect is linked to serotoninergic and dopaminergic systems in hypothalamus.

Topics: Animals; Anorexia; Dopamine; Hypothalamus; Male; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Rats; Sarcoma, Experimental; Serotonin

Tumor-bearing (TB) rats exhibit elevated concentrations of lactate in blood contiguous with the development of anorexia. Continuous intravenous infusion of lactate into non-TB rats reduced food intake at plasma concentrations lower than those observed in anorectic TB rats. Levels of neuropeptide Y (NPY) were elevated in the ventromedial (VMH) and dorsomedial hypothalamic regions of lactate-infused rats. The addition of the enhancer of pyruvate dehydrogenase activity, dichloroacetate (DCA), to the drinking water of TB rats (0.1-0.4%) normalized blood lactate concentration but had no significant effect on anorexia. However, the elevated concentration of NPY in the VMH of anorectic TB rats was also normalized by the DCA treatment. No alterations in regional hypothalamic levels of corticotropin-releasing factor were observed within any treatment conditions. These results suggest that, although hyperlactatemia may be involved in maintaining elevated NPY concentrations in anorectic TB rats, it does not appear to be a significant factor in the etiology of experimental cancer anorexia.

Topics: Animals; Anorexia; Dichloroacetic Acid; Hypothalamus, Middle; Lactates; Male; Neoplasms, Experimental; Neuropeptide Y; Random Allocation; Rats; Rats, Inbred F344

Anorexia-associated malnutrition is a severe complication that increases mortality in peritoneal dialysis (PD) patients. Ghrelin is a recently-discovered orexigenic hormone with actions in brain and stomach. We analyzed, in 42 PD patients, the possible relationship between ghrelin and appetite regulation with regard to other orexigens [neuropeptide Y (NPY), NO3] and anorexigens [cholecystokinin (CCK), leptin, glucose-dependent insulinotropic peptide (GIP), tumor necrosis factor alpha (TNFalpha)]. All orexigens and anorexigens were determined in plasma. Eating motivation was evaluated using a visual analog scale (VAS). The patients were divided into three groups: those with anorexia (n = 12), those with obesity associated with high intake (n = 12), and those with no eating behavior disorders (n = 18). A control group of 10 healthy volunteers was also evaluated. Mean plasma levels of ghrelin were high (3618.6 +/- 1533 mg/mL), with 36 patients showing values above the normal range (< 2600 mg/mL). Patients with anorexia had lower ghrelin and NPY levels and higher peptide-C, CCK, interleukin-1 (IL-1), TNFalpha, and GIP levels than did the other patients. Patients with anorexia also had an early satiety score and low desire and pleasure in eating on the VAS and diet survey. We observed significant positive linear correlations between ghrelin and albumin (r = 0.43, p < 0.05), prealbumin (r = 0.51, p < 0.05), transferrin (r = 0.4, p < 0.05), growth hormone (r = 0.66, p < 0.01), NO3 (r = 0.36, p < 0.05), and eating motivation (VAS). At the same time, negative relationships were observed between blood ghrelin and GIP (r = -0.42, p < 0.05), insulin (r = -0.4, p < 0.05), leptin (r = -0.45, p < 0.05), and creatinine clearance [r = -0.33, p = 0.08 (nonsignificant)]. Ghrelin levels were not related to Kt/V or to levels of CCK and cytokines. Ghrelin plasma levels are elevated in PD patients. Uremic patients with anorexia show relatively lower ghrelin plasma levels than the levels seen in obese patients or in patients with normal appetite. The role of ghrelin in appetite modulation is altered in uremic PD patients, and that alteration is possibly associated with disorders in insulin and growth hormone metabolism.

Topics: Adult; Aged; Anorexia; Appetite Regulation; Blood Proteins; Cholecystokinin; Cytokines; Eating; Female; Gastric Inhibitory Polypeptide; Ghrelin; Humans; Leptin; Male; Middle Aged; Neuropeptide Y; Nitric Oxide; Nutritional Status; Obesity; Peptide Hormones; Peritoneal Dialysis

We examined gene expression of corticotropin-releasing hormone and neuropeptide Y level in the hypothalamic paraventricular nucleus of mouse bearing a human oral squamous cell carcinoma. A cell line derived from a human oral squamous cell carcinoma was inoculated into the lower dorsal area of nude mice. Body weight, tumor size and daily food intake were recorded every morning. Mice were sacrificed for corticotropin-releasing hormone mRNA in situ hybridization and neuropeptide Y immunohistochemistry, when the tumor ratio reached to 11-13% of real body weight. The results were compared with the age-matching non-tumor controls injected with saline instead of carcinoma cell. Body weight gain was significantly reduced in tumor bearing mice, however, no compensatory hyperphagia was found, i.e. daily food intake of the tumor mice did not differ from the non-tumor mice. Both neuropeptide Y immunoreactivity and corticotropin-releasing hormone mRNA level were significantly increased in the hypothalamic paraventricular nucleus of tumor mice. These results suggest that a human oral squamous cell carcinoma may induce anorexia, at least partly, via increasing the hypothalamic expression of corticotropin-releasing hormone in the tumor subjects. Additionally, neuropeptide Y-induced feeding appears to be inhibited in this tumor anorexia model, and this may correlate with increased expression of corticotropin-releasing hormone.

Topics: Animals; Anorexia; Antibodies; Carcinoma, Squamous Cell; Corticotropin-Releasing Hormone; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Male; Mice; Mice, Inbred BALB C; Mouth Neoplasms; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; RNA, Messenger

Whether the decrease in food intake that occurs at the onset of anorexia in tumor bearing (TB) rats is related to a change in the hypothalamic neuropeptide Y (NPY) system was tested by comparing NPY expression in sham operated Fischer Control and anorectic TB rats. Coronal cryocut sections of their fixed brain were processed by the peroxidase-antiperoxidase method with NPY polyclonal antibodies. NPY-immunoreactive fibers were widely distributed throughout the forebrain, but were most prominent in the hypothalamic paraventricular, suprachiasmatic, arcuate and periventricular nuclei. NPY-immunoreactive neurons were visualized in Control and anorectic TB rats in the preoptic region, the arcuate nucleus, and occasionally in the lateral hypothalamus. Semiquantitative image analysis showed a significant decrease in the NPY immunostaining in some hypothalamic nuclei of the anorectic TB rats, most prominently in the supraoptic nucleus, the parvocellular portion of the paraventricular nucleus, and, to a lesser extent, the suprachiasmatic and arcuate nuclei. No changes in NPY innervation were seen in the ventromedial nucleus and the lateral hypothalamus. The data support the hypothesis of an altered hypothalamic NPY system at the onset of anorexia in TB rats and also reveal the hypothalamic nuclei through which NPY influences food intake.

Topics: Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Hypothalamus; Immunohistochemistry; Male; Neoplasm Transplantation; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Rats; Rats, Inbred F344; Reference Values; Sarcoma; Suprachiasmatic Nucleus; Supraoptic Nucleus; Tissue Distribution

The preset study examined the hypothesis that an increase of brain neuropeptide Y (NPY), an orexigenic peptide, might decrease the action of amphetamine (AMPH), a well-known anorectic agent. Transgenic mice overexpressing the NPY gene were used to compare with the wild-type control. AMPH-induced anorexia is documented to mediate through the release of dopamine (DA), via an activation of D(1)- and D(2)-subtype receptors, to affect the hypothalamic NPY. Thus, co-administration of D(1)/D(2) agonists was also performed to mimic the action of AMPH. The mice of NPY-overexpressing (NPY-OX) and wild-type groups were administered with AMPH or a combination of D(1)/D(2) agonists repeatedly for 5 days. We found that repeated AMPH administration-induced anorexia in wild-type mice was longer (at the initial 3 days) than that in NPY-OX mice (only at the first day). Moreover, repeated co-administration of D(1)/D(2) agonists significantly exerted a continuous anorectic effect in wild-type mice, but exerted a significant effect only at the first day in NPY-OX mice. These results indicated that the anorectic effect of AMPH decayed faster in NPY-OX mice and suggested that NPY expression by the stimuli could counteract the anorectic effect of AMPH. Thus, NPY can be considered to play a functional role in the regulation of AMPH-induced anorexia in mice.

Topics: Amphetamine; Animals; Anorexia; Central Nervous System Stimulants; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Eating; Feeding Behavior; Gene Expression; Homozygote; Male; Mice; Mice, Transgenic; Neuropeptide Y; Receptors, Dopamine D1; Receptors, Dopamine D2

On low-fat chow diet, rats prone to diet-induced obesity (DIO) have increased arcuate nucleus neuropeptide Y (NPY) expression but similar leptin levels compared with diet-resistant (DR) rats (19). Here, body weight and leptin levels rose in DIO rats, and they defended their higher body weight after only 1 wk on a 31% fat high-energy (HE) diet. However, DIO NPY expression did not fall to DR levels until 4 wk when plasma leptin was 168% of DR levels. When switched to chow, DIO rats lost carcass fat (18). By 10 wk, leptin levels fell to 148% and NPY expression again rose to 150% of DR levels. During 4 wk of food restriction, DIO leptin fell by approximately 50% while NPY increased by 30%. While both returned to control levels by 8 wk, DIO rats still regained all lost weight when fed ad libitum. Finally, the anorexic effect of intracerebroventricular leptin (10 microg) was inversely correlated with subsequent 3-wk weight gain on HE diet. Thus NPY expression and food intake are less sensitive to the leptin's suppressive effects in DIO rats. While this may predispose them to develop DIO, it does not fully explain their defense of a higher body weight on HE diet.

Topics: Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Body Weight; Brain; Dietary Fats; Energy Intake; Food Deprivation; Injections, Intraventricular; Leptin; Male; Neuropeptide Y; Obesity; Rats; Rats, Sprague-Dawley; RNA, Messenger

As in Prader-Willi syndrome (PWS) infants, mouse models of PWS display failure-to-thrive during the neonatal period. In rodents, the hypothalamic neuropeptide, Neuropeptide Y (NPY) and Agouti-related peptide (AgrP) stimulate while alpha-melanocyte stimulating hormone (alpha-MSH) inhibits appetite. We hypothesized that altered expression of these neuropeptides in the hypothalamus may underlie the failure-to-thrive in PWS neonatal mice. To test this hypothesis we evaluated mRNA expression of Npy, Agrp, and Pomc by in situ hybridization in the hypothalamic arcuate nucleus (ARC) of 3-day-old female and male PWS neonates. The results showed that Agrp mRNA expression was decreased relative to wild-type (WT) controls in neonates of both sexes, while mRNA expression of Pomc was upregulated in PWS neonates. Since AgrP and the Pomc-derived peptide, alpha-MSH, are functional antagonists at melanocortin 4 receptors in the hypothalamic regulation of appetitive behavior, these results show that robust anorexigenic melanocortin signaling, may contribute to the failure-to-thrive in PWS neonatal mice.

Topics: Agouti-Related Protein; Animals; Animals, Newborn; Anorexia; Arcuate Nucleus of Hypothalamus; Disease Models, Animal; Female; In Situ Hybridization; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, Transgenic; Neuropeptide Y; Prader-Willi Syndrome; Pro-Opiomelanocortin; Proteins; RNA, Messenger; Signal Transduction; Up-Regulation

Anorexia and weight loss are frequent complications of acute and chronic infections and result from induction of cytokines, prostaglandins, and other inflammatory mediators that are critical for pathogen elimination. Selective attenuation of the hypophagic response to infection and maintenance of the production of factors essential for infection control would be a useful addition to antimicrobial therapy in the treatment of human disease. Here, we evaluate the relative contribution of cyclooxygenase (COX)-1- and COX-2-derived prostaglandins to anorexia and weight loss precipitated by systemic immune activation by lipopolysaccharide (LPS). Using COX isoform-selective pharmacological inhibitors and gene knockout mice, we found that COX-2 inhibition during LPS-induced inflammation results in preserved food intake and maintenance of body weight, whereas COX-1 inhibition results in augmented and prolonged weight loss. Regulation of neuropeptide Y, corticotropin-releasing hormone, leptin, and interleukin-6 does not change as a function of COX-2 inhibition after LPS administration. Our data implicate COX-2 inhibition as a therapeutic target to maintain nutritional status while still allowing a normal cytokine response during infection.

Topics: Animals; Anorexia; Corticotropin-Releasing Hormone; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Cytokines; Energy Intake; Energy Metabolism; Hypothalamus; Immunity; Inflammation; Isoenzymes; Lipopolysaccharides; Male; Membrane Proteins; Mice; Mice, Inbred C3H; Mice, Knockout; Neuropeptide Y; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pyrazoles; RNA, Messenger; Sulfonamides; Weight Loss

Neuropeptide Y (NPY) is thought to play a crucial role in the normal hypothalamic response to starvation. After a period of food restriction, increased release of NPY induces hunger and hyperphagia, and helps to restore body weight to its set point. Persistent anorexia in rats with experimental colitis implies failure of this adaptive feeding response. In vivo NPY release and regional hypothalamic NPY concentrations were measured in rats with trinitrobenzenesulphonic acid (TNBS)-induced colitis, healthy controls and animals pair-fed to match the food intake of the colitic group. Food intake in the colitic group was assessed after administration of NPY and two other potent orexigenic peptides: melanin-concentrating hormone (MCH) and hypocretin (orexin-A). Food intake was decreased by 30-80% below control values for 5 days in the colitic rats. In both the pair-fed and colitic groups, release of NPY in the paraventricular nucleus was significantly increased compared with free-feeding controls. Intraventricular or intrahypothalamic administration of NPY, MCH or hypocretin elicited a feeding response in healthy controls, but not in the colitic group. In summary, animals with TNBS-colitis and anorexia show an appropriate increase in hypothalamic NPYergic activity. However, the failure of NPY and other orexigenic peptides to increase feeding in the colitic group indicates suppression of feeding, either by inhibition of a common downstream hypothalamic neuronal pathway or by induction of one or more potent anorexigenic agents.

Topics: Adaptation, Physiological; Animals; Anorexia; Blood Glucose; Body Weight; Carrier Proteins; Colitis; Corticosterone; Eating; Hypothalamic Hormones; Hypothalamus; Insulin; Intracellular Signaling Peptides and Proteins; Male; Melanins; Neuropeptide Y; Neuropeptides; Orexins; Pituitary Hormones; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid

The administration of leptin to leptin-deficient humans, and the analogous Lepob/Lepob mice, effectively reduces hyperphagia and obesity. But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone. In addition to regulating long-term energy balance, leptin also rapidly affects neuronal activity. Proopiomelanocortin (POMC) and neuropeptide-Y types of neurons in the arcuate nucleus of the hypothalamus are both principal sites of leptin receptor expression and the source of potent neuropeptide modulators, melanocortins and neuropeptide Y, which exert opposing effects on feeding and metabolism. These neurons are therefore ideal for characterizing leptin action and the mechanism of leptin resistance; however, their diffuse distribution makes them difficult to study. Here we report electrophysiological recordings on POMC neurons, which we identified by targeted expression of green fluorescent protein in transgenic mice. Leptin increases the frequency of action potentials in the anorexigenic POMC neurons by two mechanisms: depolarization through a nonspecific cation channel; and reduced inhibition by local orexigenic neuropeptide-Y/GABA (gamma-aminobutyric acid) neurons. Furthermore, we show that melanocortin peptides have an autoinhibitory effect on this circuit. On the basis of our results, we propose an integrated model of leptin action and neuronal architecture in the arcuate nucleus of the hypothalamus.

Topics: Action Potentials; Animals; Animals, Genetically Modified; Anorexia; Arcuate Nucleus of Hypothalamus; Electrophysiology; Evoked Potentials; gamma-Aminobutyric Acid; Green Fluorescent Proteins; Leptin; Luminescent Proteins; Male; Mice; Mice, Inbred C57BL; Nerve Net; Neural Inhibition; Neurons; Neuropeptide Y; Pro-Opiomelanocortin

Anorexia and weight loss are manifestations of inflammation seen both in patients and in experimental animal models such as the lipopolysaccharide (LPS)-treated rat. Using in situ hybridization, the levels of mRNAs encoding proopiomelanocortin (POMC), neuropeptide Y (NPY), galanin, melanin-concentrating hormone (MCH) and cocaine- and amphetamine-regulated transcript (CART) were investigated in the rat hypothalamus after a single intraperitoneal dose (125 microg/kg) of LPS. Four hours after LPS injection the food intake was significantly decreased. POMC and CART mRNA levels were increased in the arcuate nucleus, and MCH, CART and galanin mRNAs were all decreased in the lateral hypothalamic area in LPS-treated rats. Levels of mRNAs for NPY and galanin in the arcuate nucleus, and for MCH and CART in the zona incerta did not change significantly after LPS treatment. These findings support the hypothesis that LPS-induced factors mediate signalling to the POMC/CART neurons in the arcuate nucleus which could lead to reduced food intake by decreasing MCH, CART and galanin synthesis in target lateral hypothalamic neurons.

Topics: Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Eating; Galanin; Gene Expression; Hypothalamic Area, Lateral; Hypothalamic Hormones; In Situ Hybridization; Lipopolysaccharides; Male; Melanins; Nerve Tissue Proteins; Neuropeptide Y; Pituitary Hormones; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; RNA, Messenger

Anorexia is a debilitating manifestation of many malignancies. The etiology of cancer anorexia is poorly understood, and effective treatment options are limited. To investigate the role of central melanocortin receptor signaling in the pathogenesis of cancer anorexia, we assessed the effects on food intake of the melanocortin receptor antagonist SHU9119 administered into the third cerebral ventricle of Lobund-Wistar rats that were anorexic from prostate cancer. In anorexic tumor-bearing rats, daily treatment with SHU9119 (0.35 nmol, intracerebroventricularly) increased food intake from 71 +/- 3% to 110 +/- 6% of preanorectic baseline and caused significant weight gain (13 +/- 5 vs. 5 +/- 1 g/3 d, SHU9119 vs. baseline in tumor-bearing rats). In control rats pair-fed to the intake of tumor-bearing animals, SHU9119 was ineffective at increasing food intake. The specificity of the SHU9119 feeding response was assessed using two other orexigenic peptides, NPY and the novel hormone ghrelin. Treatment of tumor-bearing rats with intracerebroventricular ghrelin (10 microg) increased food intake, but the effect was blunted relative to that in controls. Intracerebroventricular injections of NPY (1 microg) also failed to reverse anorexia in tumor-bearing rats. Because SHU9119 completely reverses cancer anorexia in this model, whereas ghrelin and NPY do not, increased central nervous system melanocortin signaling is implicated in the pathogenesis of this disorder. This suggests that new targets for the treatment of cancer anorexia may be found in the melanocortin pathways.

Topics: Adenocarcinoma; Animals; Anorexia; Body Weight; Brain; Eating; Ghrelin; Injections, Intraventricular; Male; Melanocyte-Stimulating Hormones; Neuropeptide Y; Peptide Hormones; Peptides; Prostatic Neoplasms; Rats; Rats, Wistar; Receptors, Corticotropin; Receptors, Melanocortin; Reference Values; Third Ventricle

Anorexia is a noxious symptom, and over half of patients with advanced cancer experience it. Neuropeptide Y (NPY), leptin, and cholecystokinin 8 (CCK8) have been implicated.. This exploratory study 1) compared circulating concentrations of NPY and leptin between anorectic cancer patients and historic controls and 2) explored whether NPY, leptin, or CCK8 may serve as correlates of anorexia severity. Cancer patients met predefined eligibility criteria: 1) weight loss > or = 2.3 kg over the preceding 2 months and/or a physician-estimated caloric intake of < 20 calories per kilogram of body weight per day and 2) patient acknowledgment that appetite or weight loss was an ongoing problem.. Seventy-three cancer patients were studied, and > 90% reported a > or = 50% decline in appetite from baseline in the preceding 2 months. NPY levels were lower than control values: mean +/- standard deviation, 466 pg/mL +/- 161 pg/mL versus 560 pg/mL +/- 151 pg/mL, respectively (P = 0.004). Because a few (but not all) earlier studies suggested an age-related decline in NPY levels, a subgroup analysis was performed and found no age-adjusted difference in NPY levels between groups. Similarly, leptin concentrations were not different between groups. Significant correlations were not observed between anorexia severity and NPY, leptin, or CCK8 levels.. There were no differences in leptin and CCK8 levels between anorectic cancer patients and historic controls. Circulating concentrations of NPY, leptin, and CCK8 did not correlate with anorexia severity. However, the current results suggest a need for further examination of NPY in cancer-associated anorexia.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Cholecystokinin; Female; Humans; Leptin; Male; Middle Aged; Neoplasms; Neuropeptide Y; Peptide Fragments

Anorexia causing weight loss at high altitude (HA) is a major problem. Neuropeptide Y (NPY) and galanin are considered to have appetite regulatory function. The present study was therefore undertaken to investigate the changes in these two peptides at simulated HA and its possible role in anorexia. Male Sprague-Dawley rats (n = 8 in each group) were exposed to simulated HA (7620 m) for 1, 7, 14 and 21 days for 6 h a day and to an altitude of 6,096 m for 72 h to study the effect of intermittent and continuous exposure, respectively. NPY and galanin levels were estimated in different brain parts and plasma of exposed and unexposed control animals. Significant reduction in food intake was observed in rats during both intermittent as well as continuous exposure. In case of 72 h continuous exposure severe reduction in food intake was observed (73.2%) with reduction in body mass (approximately 29.7g/rat in 48h). Hypothalamic NPY levels were decreased by 54.7, 35.0 and 15.4% in 1, 7, and 14 days, respectively, in case of intermittent exposure to HA. However in case of 72 h HA exposure no significant change in hypothalamic and circulating NPY levels were observed. Plasma galanin levels were decreased in both intermittent and 72 h continuous HA exposed rats. Hypothalamic galanin levels were also decreased in 72h exposed rats. The changes in levels of these peptides may be responsible for anorexia at HA.

Topics: Altitude; Animals; Anorexia; Body Weight; Brain; Eating; Galanin; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley

Nippostrongylus brasiliensis induces a biphasic anorexia in laboratory rats, the first phase coincident with lung invasion (ca day 2) and the second when the worms mature in the intestine (ca day 8). Using the anthelminthic, mebendazole (MBZ), N. brasiliensis infections of the rat were eliminated between the first and second anorexic episodes. This intervention prevented the expression of the second phase of anorexia. Rats exposed to a second infection with N. brasiliensis, 3 weeks after the primary infection, exhibited only a first phase anorexic response which was not influenced by MBZ termination of the primary infection. The lower cumulative food intake and weight gain of all infected rats after 8 days of infection were accompanied by elevated plasma insulin and, in some individuals, by elevated plasma leptin, compared with uninfected controls and previously-infected MBZ-treated rats. Messenger RNA levels for neuropeptide Y were higher in the hypothalamic arcuate nucleus of 8-day infected rats than in recovering MBZ-treated animals. Inoculation of rats with heat-killed N. brasiliensis larvae failed to induce anorexia and did not alter the severity of biphasic anorexia on subsequent injection of viable larvae. The first anorexic episode is therefore dependent upon viable migrating larvae. The second phase of anorexia clearly requires the continuing presence of the parasite beyond the lung phase. Viable migrating larvae are also required to confer 'resistance' to reinfection.

Topics: Animals; Anorexia; Anthelmintics; Body Weight; Corticosterone; Corticotropin-Releasing Hormone; DNA Primers; DNA, Helminth; Eating; Galanin; Host-Parasite Interactions; Image Processing, Computer-Assisted; Insulin; Leptin; Mebendazole; Neuropeptide Y; Nippostrongylus; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Helminth; Strongylida Infections

Ciliary neurotrophic factor (CNTF), a cytokine of the interleukin-6 superfamily, has been shown to induce hypophagia and weight loss. Neuropeptide Y (NPY) and orexin are potent orexigenic signals in the hypothalamus. Anorexia, normally seen in response to infection, injury and inflammation, may result from diminished hypothalamic orexigenic signalling caused by persistently elevated cytokines, including CNTF. To test this hypothesis, we first examined the effects of chronic intracerebroventricular (i.c.v.) infusion of CNTF for 6-7 days on food intake and body weight as well as hypothalamic NPY and orexin gene expression in male rats. Subsequently, the effectiveness of NPY replacement to counteract the effects of CNTF by coinfusion of NPY and CNTF was evaluated. Chronic i.c.v. infusion of CNTF (2.5 microg/day) reduced body weight (14.3% vs control) at the end of 7 days. Food intake remained suppressed for 5 days postinfusion and subsequently gradually returned to the control range by day 7. Serum leptin concentrations in these rats were in the same range seen in control rats. Chronic i.c.v. infusion of higher doses of CNTF (5.0 microg/day) produced sustained anorexia and body weight loss (29% vs controls) through the entire duration of the experiment. This severe anorexia was accompanied by markedly suppressed serum leptin concentrations. Furthermore, CNTF infusion alone significantly reduced hypothalamic NPY gene expression (P < 0. 05) without affecting orexin gene expression. As expected, in fusion of NPY alone (18 microg/day) augmented food intake (191.6% over the initial control, P < 0.05) and produced a 25.1% weight gain in conjunction with a 10-fold increase in serum leptin concentrations at the end of the 7-day period. Interestingly, coinfusion of this regimen of NPY with the highly effective anorectic and body reducing effects of CNTF (5.0 microg/day) not only prevented the CNTF-induced anorexia and weight loss, but also normalized serum leptin concentrations and hypothalamic NPY gene expression. These results demonstrate that chronic central infusion to produce a persistent elevation of the cytokine at pathophysiological levels (a situation that may normally manifest during infection, injury and inflammation) produced severe anorexia and weight loss in conjunction with reduction in both serum leptin concentrations and hypothalamic NPY gene expression. Reinstatement of hypothalamic NPY signalling by coinfusion of NPY counteracted these CNTF-induced

Topics: Animals; Anorexia; Brain; Ciliary Neurotrophic Factor; Eating; Gene Expression; Hypothalamus; Leptin; Male; Neuropeptide Y; Neuropeptides; Rats; Rats, Sprague-Dawley; RNA, Messenger; Weight Loss

The aim of the present study was to determine whether the anorexic and thermogenic effects of leptin were attenuated in overweight aged rats following intracerebroventricular (i.c.v.) injection of murine leptin. Male F344/BN rats of two ages (6 months: young (n=20) and 24 months: old (n=18)) were divided into three groups (control, pair-fed and leptin) and were treated with either vehicle (artificial cerebrospinal fluid) or leptin (15.6 microgram/day) for 3 days. There was an age-related increase in basal food intake (20+/-2%), serum leptin levels (363+/-106%) and leptin (OB) mRNA (72+/-16%) in perirenal white adipose tissue (PWAT). In contrast, basal expression of hypothalamic NPY mRNA and brown adipose tissue (BAT) uncoupling protein 1 (UCP1) mRNA was reduced significantly (-35+/-4% and -51+/-5%, respectively) with age. I.c.v. leptin treatment had a significantly greater effect in reducing food intake (-42+/-5% vs. -23+/-4%), serum leptin levels (-55+/-7% vs. 10+/-2%) and PWAT OB mRNA (-46+/-2% vs. 10+/-5%) in young than in old rats. Similarly, central leptin treatment also had a greater effect in suppressing hypothalamic NPY mRNA expression in young (-23+/-4%) than in old (-8+/-4%) rats compared with their age-matched pair-fed treated rats. The stimulatory effect of i.c.v. leptin treatment on BAT UCP1 mRNA expression was also significantly greater in young rats (45+/-8%) than in old rats (10+/-6%) compared with age-matched pair-fed rats. Our previous report indicated that these overweight aged rats were resistant to peripheral administered leptin. The present data extend those findings and demonstrate that the impaired anorexic and metabolic effects of leptin are centrally mediated. This leptin resistance may be due to either the elevated obesity and serum leptin with age or due to age itself or both. The development of leptin resistance with age may contribute to the hyperphagia, hyperleptinemia and impaired energy balance with age.

Topics: Adipose Tissue, Brown; Aging; Animals; Anorexia; Body Weight; Carrier Proteins; Eating; Gene Expression Regulation; Hypothalamus; Injections, Intraventricular; Ion Channels; Leptin; Male; Membrane Proteins; Membrane Transport Proteins; Mice; Mitochondrial Proteins; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Inbred BN; Rats, Inbred F344; RNA, Messenger; Thermogenesis; Uncoupling Protein 1; Uncoupling Protein 2; Uncoupling Protein 3

Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide produced by neurons of the lateral hypothalamic area (LHA). Because genetic MCH deficiency induces hypophagia and loss of body fat, we hypothesized that MCH neurons may represent a specific LHA pathway that, when inhibited, contributes to the pathogenesis of certain anorexia syndromes. To test this hypothesis, we measured behavioral, hormonal, and hypothalamic neuropeptide responses in two models of hyperestrogenemia in male rats, a highly reproducible anorexia paradigm. Whereas estrogen-induced weight loss engaged multiple systems that normally favor recovery of lost weight, the expected increase of MCH mRNA expression induced by energy restriction was selectively and completely abolished. These findings identify MCH neurons as specific targets of estrogen action and suggest that inhibition of these neurons may contribute to the hypophagic effect of estrogen.

Topics: Agouti-Related Protein; Animals; Anorexia; Corticotropin-Releasing Hormone; Disease Models, Animal; Drug Implants; Eating; Energy Metabolism; Estrogens; Hormones; Hypothalamic Hormones; Hypothalamus; Intercellular Signaling Peptides and Proteins; Leydig Cell Tumor; Male; Melanins; Neoplasm Transplantation; Neuropeptide Y; Pituitary Hormones; Pro-Opiomelanocortin; Proteins; Rats; Rats, Wistar; RNA, Messenger; Weight Loss

Topics: Adult; Aged; Aged, 80 and over; Aging; Anorexia; Humans; Leptin; Male; Middle Aged; Neuropeptide Y; Reference Values

Cocaine- and amphetamine-regulated transcript (CART) is expressed in the hypothalamus, and putative peptides encoded by CART potently inhibit feeding when administered centrally. CART is strongly down-regulated in the lateral hypothalamic area and the arcuate nucleus in animal models of obesity with disrupted leptin signaling. Here we have used in situ hybridization and immunohistochemistry to study CART expression in mice homozygous for the anorexia (anx) mutation which are characterized by a much reduced food intake and premature death. anx/anx mice had significantly decreased levels of CART mRNA label and peptide-immunoreactive cell bodies and fibers in the arcuate nucleus and a lower number of detectable CART-expressing cells in the dorsomedial hypothalamic nucleus/lateral hypothalamic area. Moreover, serum leptin levels were significantly lower in anx/anx mice compared to normal littermates, most likely due to the prominent depletion of body fat in these animals. The decrease in the anorexigenic agents leptin and CART, may reflect a compensatory down-regulation in response to the energy-deprived state of anx/anx mice. Alternatively, the reduced arcuate CART expression may be a consequence of a molecular defect in the arcuate nucleus of these animals.

Topics: Aging; Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Eating; Enzyme-Linked Immunosorbent Assay; Gene Deletion; Homozygote; Hypothalamus; Immunohistochemistry; In Situ Hybridization; Leptin; Mice; Mice, Knockout; Mice, Mutant Strains; Nerve Tissue Proteins; Neuropeptide Y; Pro-Opiomelanocortin; RNA, Messenger

Islet amyloid polypeptide (IAPP or amylin) potently reduces food intake in rats at or near physiological concentrations. Although the mechanisms of action of IAPP are not understood, the brain is a suggested site. Changes in hypothalamic and striatal neurotransmission have been reported following acute systemic administration of a pharmacological concentration of IAPP. In the current study, we evaluated the effects of chronic administration of low doses of IAPP on satiety-related neurotransmitters and neuropeptides in the hypothalamus, hippocampus, striatum, left cortex, and right cortex of the rat. Doses of 0, 5 and 25 pmol IAPP/kg-min were administered subcutaneously for 2 or 5 days. Food intake was reduced by 27 and 44% (both P<0.001) for the 5 and 25 pmol/kg-min groups, respectively, in the 2-day experiment and was decreased by 14% (P<0.01) and 24% (P<0.001), respectively, in the 5-day experiment. Body weight was significantly decreased in a dose-dependent fashion. In the 2-day experiment, norepinephrine increased in the hypothalamus in the 5 pmol IAPP/kg-min group, and neurotensin increased in the hippocampus in the 25 pmol/kg-min rats (both P<0.05). In the 5-day, 5 pmol/kg-min rats, 5-hydroxyindoleacetic acid (5-HIAA) increased in the hypothalmus and cholecystokinin (CCK) increased in the striatum (both P<0.05). In the 5-day, 25 pmol/kg-min group, neuropeptide Y (NPY) increased in the hypothalamus (P<0.01) and CCK increased in the hypothalmus and striatum (both P<0.05). The present study confirms that IAPP is a potent anorectic peptide at low doses and suggests that IAPP not only affects classical neurotransmitters in the brain but also alters concentrations of neuropeptides known to be involved in food intake.

Topics: 3,4-Dihydroxyphenylacetic Acid; Amyloid; Animals; Anorexia; Biogenic Monoamines; Blood Glucose; Brain; Cholecystokinin; Chromatography, High Pressure Liquid; Dopamine; Dose-Response Relationship, Drug; Homovanillic Acid; Hydroxyindoleacetic Acid; Infusions, Parenteral; Insulin; Islet Amyloid Polypeptide; Male; Methoxyhydroxyphenylglycol; Neuropeptide Y; Neuropeptides; Neurotensin; Norepinephrine; Rats; Rats, Wistar; Serotonin

We have investigated the hormonal and hypothalamic neuropeptidergic substrates of dehydration-associated anorexia. In situ hybridization and hormone analyses of anorexic and paired food-restricted rats revealed two distinct profiles. First, both groups had the characteristic gene expression and endocrine signatures usually associated with starvation: increased neuropeptide Y and decreased proopiomelanocortin and neurotensin mRNAs in the arcuate nucleus (ARH); increased circulating glucocorticoid but reduced leptin and insulin. Dehydrated animals are strongly anorexic despite these attributes, showing that the output of leptin- and insulin-sensitive ARH neurons that ordinarily stimulate eating must be inhibited. The second pattern occurred only in anorexic animals and had two components: (1) reduced corticotropin-releasing hormone (CRH) mRNA in the neuroendocrine paraventricular nucleus (PVH) and (2) increased CRH and neurotensin mRNAs in the lateral hypothalamic (LHA) and retrochiasmatic areas. However, neither corticosterone nor suppressed PVH CRH gene expression is required for anorexia after dehydration because PVH CRH mRNA in dehydrated adrenalectomized animals is unchanged from euhydrated adrenalectomized controls. We also showed that LHA CRH mRNA was strongly correlated with the intensity of anorexia, increased LHA CRH gene expression preceded the onset of anorexia, and dehydrated adrenalectomized animals (which also develop anorexia) had elevated LHA CRH gene expression with a distribution pattern similar to intact animals. Finally, we identified specific efferents from the CRH-containing region of the LHA to the PVH, thereby providing a neuroanatomical framework for the integration by the PVH of neuropeptidergic signals from the ARH and the LHA. Together, these observations suggest that CRH and neurotensin neurons in the LHA constitute a novel anatomical substrate for their well known anorexic effects.

Topics: Adrenalectomy; Adrenocorticotropic Hormone; Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Axonal Transport; Body Weight; Corticosterone; Corticotropin-Releasing Hormone; Dehydration; Food Deprivation; Gene Expression Regulation; Hypothalamic Area, Lateral; Insulin; Leptin; Male; Neuropeptide Y; Neuropeptides; Neurotensin; Paraventricular Hypothalamic Nucleus; Phytohemagglutinins; Pro-Opiomelanocortin; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thymus Gland; Time Factors; Transcription, Genetic

We have isolated a stable, transplantable, and small glucagonoma (MSL-G-AN) associated with abrupt onset of severe anorexia occurring 2-3 wk after subcutaneous transplantation. Before onset of anorexia, food consumption is comparable to untreated controls. Anorexia is followed by adipsia and weight loss, and progresses rapidly in severity, eventually resulting in reduction of food and water intake of 100 and 80%, respectively. During the anorectic phase, the rats eventually become hypoglycemic and hypothermic. The tumor-associated anorexia shows no sex difference, and is not affected by bilateral abdominal vagotomy, indicating a direct central effect. The adipose satiety factor leptin, known to suppress food intake by reducing hypothalamic neuropeptide Y (NPY) levels, was not found to be expressed by the tumor, and circulating leptin levels were reduced twofold in the anorectic phase. A highly significant increase in hypothalamic (arcuate nucleus) NPY mRNA levels was found in anorectic rats compared with control animals. Since elevated hypothalamic NPY is among the most potent stimulators of feeding and a characteristic of most animal models of hyperphagia, we conclude that the MSL-G-AN glucagonoma releases circulating factor(s) that overrides the hypothalamic NPY-ergic system, thereby eliminating the orexigenic effect of NPY. We hypothesize a possible central role of proglucagon-derived peptides in the observed anorexia.

Topics: Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Drinking; Female; Glucagon; Glucagon-Like Peptide 1; Glucagonoma; Male; Neoplasm Transplantation; Neuropeptide Y; Pancreatic Neoplasms; Peptide Fragments; Protein Precursors; Rats; RNA, Messenger; Weight Loss

Although ciliary neurotropic factor (CNTF) is a tropic factor in nervous system development and maintenance, peripheral administration of this cytokine also causes severe anorexia and weight loss. The neural mechanism(s) mediating the loss of appetite is not known. As hypothalamic neuropeptide Y (NPY) is a potent orexigenic signal, we tested the hypothesis that CNTF may adversely affect NPYergic signaling in the hypothalamus. Intraperitoneal administration of CNTF (250 microg/kg) daily for 4 days significantly suppressed 24-h food intake in a time-dependent manner and decreased body weight. The loss in body weight was similar to that which occurred in pair-fed (PF) rats. As expected, hypothalamic NPY gene expression, determined by measurement of steady state prepro-NPY messenger RNA by ribonuclease protection assay, significantly increased in PF rats in response to energy imbalance. However, despite a similar loss in body weight, there was no increase in NPY gene expression in CNTF-treated rats. Daily administration of CNTF intracerebroventricularly (0.5 or 5.0 microg/rat) also produced anorexia and body weight loss. In this experiment, negative energy balance produced by both PF and food deprivation augmented hypothalamic NPY gene expression. However, despite reduced intake and loss of body weight, no similar increment in hypothalamic NPY gene expression was observed in CNTF-treated rats. In fact, in rats treated with higher doses of CNTF (5.0 microg/rat), NPY gene expression was reduced below the levels seen in control, freely fed rats. Furthermore, CNTF treatment also markedly decreased NPY-induced feeding. These results suggested that anorexia in CNTF-treated rats may be due to a deficit in NPY supply and possibly in the release and suppression of NPY-induced feeding. The possibility that CNTF-induced anorexia may be caused by increased leptin was next examined. Daily intracerebroventricular injections of leptin (7 microg/rat) decreased food intake, body weight, and hypothalamic NPY gene expression in a manner similar to that seen after CNTF treatment. Leptin administration also suppressed NPY-induced feeding. However, peripheral and central CNTF injections markedly decreased leptin messenger RNA in lipocytes, indicating a deficiency of leptin in these rats; thus, leptin was unlikely to be involved in appetite suppression. Thus, these results show that a two-pronged central action of CNTF, causing diminution in both NPY availability and the NPY-induce

Topics: Adipocytes; Animals; Anorexia; Body Weight; Ciliary Neurotrophic Factor; Cytokines; Eating; Gene Expression; Hypothalamus; Injections, Intraperitoneal; Injections, Intraventricular; Leptin; Male; Nerve Tissue Proteins; Neuropeptide Y; Proteins; Rats; Rats, Sprague-Dawley

Bacterial lipopolysaccharide (LPS) or endotoxin induces neurological manifestations including anorexia. It is proposed that LPS-induced cytokine production is involved in the generation of neurological manifestations and in neuroinflammatory/immunological responses during gram-negative infections. For example, LPS-induced effects can be blocked or ameliorated by the interleukin-1 receptor antagonist (IL-1Ra). Here, sensitive and specific RNase protection assays were used to investigate the effects of the intracerebroventricular (i.c.v.) administration of LPS on mRNA levels of interleukin-1beta (IL-1beta) system components, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, and neuropeptide Y (NPY) in the cerebellum, hippocampus, and hypothalamus. The same brain region sample was analyzed with all of the antisense probes. The data show simultaneous local induction of multiple cytokine components messenger ribonucleic acids (mRNAs) within specific brain regions in anorectic rats responding to i.c.v. administered LPS (500 ng/rat). Interleukin-1beta and IL-1Ra had a similar mRNA induction profile (hypothalamus > cerebellum > hippocampus). Interleukin-1 receptor type I (IL-1RI) mRNA also increased in all three brain regions examined, and the soluble form of IL-1 receptor accessory protein (IL-1R AcP II) mRNA was induced in the hypothalamus. Tumor necrosis factor-alpha mRNA levels increased in the hypothalamus > hippocampus > cerebellum. Levels of membrane bound IL-1R AcP, TGF-beta1, and NPY mRNAs did not change significantly in any brain region. The results suggest that: (1) endogenous up-regulation of IL-1beta and TNF-alpha in the hypothalamus contribute to LPS-induced anorexia; and (2) the ratio IL-1Ra/IL-1beta, and IL-1beta <--> TNF-alpha interactions may have implications for gram-negative infections associated with high levels of LPS in the brain-cerebrospinal fluid.

Topics: Animals; Anorexia; Brain; Cerebral Ventricles; Escherichia coli; Infusions, Parenteral; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-1 Receptor Accessory Protein; Lipopolysaccharides; Neuropeptide Y; Organ Specificity; Protein Biosynthesis; Proteins; Rats; Rats, Wistar; Receptors, Interleukin-1; RNA, Messenger; Sialoglycoproteins; Transcription, Genetic; Transforming Growth Factor beta

The mammalian hypothalamus strongly influences ingestive behaviour through several different signalling molecules and receptor systems. Here we show that CART (cocaine- and amphetamine-regulated transcript), a brain-located peptide, is a satiety factor and is closely associated with the actions of two important regulators of food intake, leptin and neuropeptide Y. Food-deprived animals show a pronounced decrease in expression of CART messenger RNA in the arcuate nucleus. In animal models of obesity with disrupted leptin signalling, CART mRNA is almost absent from the arcuate nucleus. Peripheral administration of leptin to obese mice stimulates CART mRNA expression. When injected intracerebroventricularly into rats, recombinant CART peptide inhibits both normal and starvation-induced feeding, and completely blocks the feeding response induced by neuropeptide Y. An antiserum against CART increases feeding in normal rats, indicating that CART may be an endogenous inhibitor of food intake in normal animals.

Topics: Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Cloning, Molecular; Escherichia coli; Fasting; Feeding Behavior; Gene Expression Regulation; Hypothalamus; Immunoenzyme Techniques; Leptin; Mice; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Proteins; Rats; Rats, Wistar; Rats, Zucker; Recombinant Fusion Proteins; RNA, Messenger; Signal Transduction

The anorexia (anx) mutation causes reduced food intake in preweanling mice, resulting in death from starvation within 3-4 weeks. In wild-type rodents, starvation induces increased neuropeptide Y (NPY) mRNA levels in the arcuate nucleus that promotes compensatory hyperphagia. Despite severely decreased body weight and food intake at 3-weeks age, anx/anx mice do not show elevated NPY mRNA levels in the hypothalamic arcuate nucleus compared to wild-type/heterozygous littermates. The NPY mRNA levels can be upregulated in normal mice at this chronological age, because 24-h food deprivation increased arcuate NPY mRNA in wild-type littermates. The unresponsiveness of NPY expression in the arcuate of anx/anx mice was paralleled by serotonergic hyperinnervation of the arcuate nucleus, comparable to the serotonergic hyperinnervation previously reported in the rest of the anx/anx brain. This result is consistent with the hypothesis that wasting disorders are accompanied by disregulation of NPY mRNA expression in the arcuate nucleus, and suggests that reduced food intake, the primary behavioral phenotype of the anx/anx mouse, may be the result of altered hypothalamic mechanisms that normally regulate feeding.

Topics: Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Body Weight; DNA, Complementary; Eating; Failure to Thrive; Female; Food Deprivation; Gene Expression Regulation, Developmental; In Situ Hybridization; Male; Mice; Mice, Mutant Strains; Nerve Fibers; Neuropeptide Y; RNA, Messenger; Serotonin; Weaning

Leptin, ob gene product, inhibits feeding behavior and stimulates energy expenditure in rodents. Corticotropin-releasing hormone (CRH) and neuropeptide Y (NPY), which act in the hypothalamus to influence energy homeostasis, may mediate the anorexic effect of leptin. The present studies were undertaken to examine the possible involvement of hypothalamic CRH in the anorexigenic action of leptin in male Wistar rats. Recombinant leptin (2 microg/rat), microinjected into the third ventricle, inhibited food intake at 2 h by 33.3% (P < 0.01) in rats that were deprived of food for 18 h. The intracerebroventricular injection of 2 microg leptin also increased hypothalamic CRH content (P < 0.05) at 2 h after its administration. Simultaneous intracerebroventricular administration of 5 microg/rat alpha-helical CRH 9-41 (alpha-hCRH), a CRH antagonist, with 2 microg/rat leptin attenuated the anorexic effect of leptin by 2 h. In contrast, single intracerebroventricular injection of alpha-hCRH did not affect food consumption in food-deprived rats. These results implicate hypothalamic CRH as an important mediator of the anorexic effect of leptin in food-deprived rats.

Topics: Animals; Anorexia; Blood Glucose; Cerebral Ventricles; Corticosterone; Corticotropin-Releasing Hormone; Energy Intake; Food Deprivation; Hypothalamus; Injections, Intraventricular; Leptin; Male; Neuropeptide Y; Proteins; Rats; Rats, Wistar; Recombinant Proteins

We investigated the effectiveness of lipopolysaccharide (LPS) and muramyl dipeptide (MDP) administered into the brain to induce anorexia in acutely fasted Wistar rats allowed to refeed. We also assayed for changes in mRNA levels of IL-1 system components, TNF-alpha, TGF-beta1, glycoprotein 130 (gp 130), leptin receptor (OB-R), pro-opiomelanocortin (POMC), neuropeptide Y (NPY), glucocorticoid receptor (GR), and CRF receptor (CRF-R) in selected brain regions. The data show that LPS and MDP induced anorexia differentially during refeeding. LPS-induced anorexia was of a stronger magnitude and duration than that of MDP. RNase protection assays showed that LPS and MDP significantly increased the expression of IL-1beta, IL-1 receptor type I, and TNF-alpha mRNAs in the cerebellum, hippocampus, and hypothalamus; LPS was more potent in all cases. MDP treatment, on the other hand, induced a stronger increase in hypothalamic levels of IL-1 receptor antagonist (IL-1Ra) and TGF-beta1 mRNAs relative to LPS. In addition, competitive RT-PCR analysis showed that LPS induced an eleven-fold increase in IL-1alpha mRNA in the hypothalamus relative to vehicle. These findings suggest that LPS and MDP mediate anorexia through different cytokine mechanisms. A stronger up-regulation of anti-inflammatory cytokines (IL-1Ra and TGF-beta1) mRNA expression by MDP may be involved in the weaker MDP-induced anorexia relative to LPS. No significant changes were observed in the peptide components examined except for an up-regulation in cerebellar gp 130 mRNA and down-regulation of hypothalamic GR mRNA expression in response to LPS or MDP. This study shows that LPS and MDP induce anorexia in fasted rats allowed to refeed, and suggests an important role for endogenous cytokine-cytokine interactions.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adjuvants, Immunologic; Adrenocorticotropic Hormone; Animals; Anorexia; Behavior, Animal; Brain Chemistry; Carrier Proteins; Cerebellum; Cytokines; Eating; Fasting; Hippocampus; Hypothalamus; Interleukin-1; Lipopolysaccharides; Lysosomal Membrane Proteins; Male; Membrane Glycoproteins; Neuropeptide Y; Neuropeptides; Opioid Peptides; Polymerase Chain Reaction; Pro-Opiomelanocortin; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Corticotropin-Releasing Hormone; Receptors, Glucocorticoid; Receptors, Leptin; Ribonucleases; RNA, Messenger; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Malnutrition has definitely been related to mortality among dialysis patients. Persistent loss of appetite is one of the major symptoms found in these patients. It is also well recognized that several substances produce anorexia or disorders of the hunger-satiety cycle in several diseases. The aim of this study was to identify the role of anorexigen substances (TNF-alpha and cholecystokinin or CCK) and an orexigen substance (neuropeptide Y or NPY) in anorexia and malnutrition among 55 clinically stable peritoneal dialysis (PD) patients.. High TNF-alpha plasma levels were found in 41 of 42 patients (97.6%) with a mean of 70.5+/-32.3 pg/ml. Patients with anorexia (n=11) or anorexia with nausea or vomiting (n=5) had higher TNF-alpha values than patients without these symptoms (75.9+/-34 vs 52.1 +/-24.5 pg/ml, P<0.05). Eight patients with a prior diagnosis of acid pylori disease showed higher TNF-alpha values (87.2+/-24.3) than 30 unaffected patients (63.6+/-30.5, P<0.05). TNF-alpha showed a significant negative linear correlation with retinol binding protein (RBP) (r=-0.37, n=34, P<0.05), and venous pH (r=-0.4, n=42, P<0.01); also, TNF-alpha values higher than 65 pg/ml were inversely associated with transferrin, cholesterol, blood urea nitrogen (BUN) and CCK. Patients with prealbumin levels lower than 30 mg/dl, a BMI lower than 30 kg/m2, nPCR lower than 1.1 g/kg/day and urea KT/V lower than 2.2 showed higher serum TNF-alpha levels. Patients who had been on CAPD treatment for longer periods showed higher TNF-alpha values. High plasma CCK levels were found in 38 of 45 patients (84%), mean 45.9+/-32.3 pg/ml. Patients with anorexia had no difference in CCK values compared with those without. A direct association was found between CCK levels and some nutritional markers (albumin, fibronectin, triglycerides, folic acid and nPCR in non diabetic patients). Although CCK has a recognized anorectic effect, this direct association might be because of an abnormal stimulation of CCK glucose feedback (trypsin) due to continuous peritoneal glucose absorption. This suggests that CCK could be an immediate food intake marker in PD patients. The NPY plasma levels were normal in 33 patients, high in 6 and low in 11. Patients with anorexia showed lower NPY levels than those without. NPY values greater than 50 pg/ml were directly associated with higher transferrin, prealbumin, RBP, nPCR and urea KT/V values. Importantly, a negative linear correlation between NPY and TNF-alpha was found (r=-0.42, n= 41, P<0.01). There was no significant relationship between residual renal clearance and the serum levels of the three peptides.. In conclusion, our data suggest that high TNF-alpha and low NPY serum levels are associated with anorexia. High TNF-alpha, low CCK and low NPY serum levels are also related to a poor nutritional status. Further research on these circulating substances is required.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Biomarkers; Cholecystokinin; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Neuropeptide Y; Nutrition Disorders; Nutritional Status; Peritoneal Dialysis; Protein-Energy Malnutrition; Tumor Necrosis Factor-alpha

Zinc deficiency reduces intake and produces an unusual approximately 3.5-d cycle of intake in rats. The mechanism underlying the anorexia and cycling has not yet been defined; current hypotheses suggest that alterations in amino acid metabolism and neurotransmitter concentrations may be a part of this anorexia. Recent reports indicate that appetite-stimulating neuropeptide Y (NPY) may be elevated during zinc deficiency. This suggests that a resistance to NPY may exist during zinc deficiency because NPY levels are high, yet appetite is low. The purpose of this study was to measure NPY peptide and mRNA concentrations during zinc deficiency in specific nuclei of the hypothalamus in which peptide and mRNA for NPY are known to be associated with appetite, and also to determine whether zinc-deficient rats are responsive to central infusions of NPY. Both NPY peptide levels in the paraventricular nucleus and NPY mRNA levels in the arcuate nucleus were higher (P < 0.05) in zinc-deficient rats than in zinc-adequate rats. When rats were administered exogenous NPY to the paraventricular nucleus, both zinc-deficient and zinc-adequate rats responded similarly by increasing food intake. These results suggest that NPY is elevated during zinc deficiency in an attempt to restore normal food intake levels, rather than being reduced and thereby contributing to the anorexia associated with zinc deficiency. During zinc deficiency, NPY receptors are able to bind NPY and initiate an orexigenic response.

Topics: Animals; Anorexia; Appetite; Arcuate Nucleus of Hypothalamus; Eating; Energy Intake; Hypothalamus; Male; Metallothionein; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; RNA, Messenger; Zinc

Cancer is consistently associated with anorexia. The Lobund-Wistar rat model of prostate cancer exhibits clinical manifestations (including anorexia) that resemble many aspects of the human disease. Cytokines are proposed to be involved in cancer-associated anorexia. Here we investigated mRNA profiles of feeding-modulatory cytokines and neuropeptides in specific brain regions of anorectic Lobund-Wistar rats bearing prostate adenocarcinoma tumor cells. Interleukin (IL)-1beta system components (ligand, signaling receptor, receptor accessory proteins, receptor antagonist), tumor necrosis factor-alpha, transforming growth factor-beta1, glycoprotein 130 (IL-6 receptor signal transducer), proopiomelanocortin (POMC, opioid peptide precursor), and neuropeptide Y (NPY) mRNAs were analyzed with sensitive and specific RNase protection assays. The same brain region sample was assayed for all components. The data show that early anorexia in tumor-bearing rats was associated with an upregulation of IL-1beta mRNA in the brain regions examined (cerebellum, cortex, and hypothalamus). IL-1 receptor antagonist (IL-1Ra) mRNA and IL-1 receptor type I mRNA levels were also significantly increased in the cortex and hypothalamus. All other cytokine components, POMC, or NPY mRNA levels were not significantly different between tumor-bearing and pair-fed (control) rats. IL-1beta mRNA and IL-1Ra mRNA were also significantly upregulated in the spleen of tumor-bearing rats. These data suggest that 1) IL-1beta mRNA upregulation in the brain may be relevant to the anorexia exhibited by the tumor-bearing Lobund-Wistar rat and 2) in vivo characterization of cytokine components in discrete brain regions during cancer is necessary to understand underlying molecular mechanisms responsible for cancer-associated neurological manifestations.

Topics: Adenocarcinoma; Analysis of Variance; Animals; Anorexia; Brain; Cytokines; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Male; Neuropeptide Y; Neuropeptides; Organ Specificity; Pro-Opiomelanocortin; Prostatic Neoplasms; Rats; Rats, Wistar; Receptors, Interleukin-1; RNA, Messenger; Sialoglycoproteins; Transcription, Genetic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Previous investigations suggest that neuropeptide Y (NPY) feeding mechanisms and corticotropin releasing factor (CRF) are altered in anorectic tumor-bearing (TB) rats. To better determine the relationship of NPY and CRF synthesis to cancer anorexia we measured mRNA for these peptides in medial and lateral hypothalamus of TB and control rats. NPY and CRF mRNA were reliably detected by Northern blot analysis only in medial hypothalamus, where NPY message was elevated significantly in TB rats. CRF mRNA tended to be reduced in both pair-fed (PF) and TB rats, but did not reach statistical significance. Concentrations of NPY or CRF were not altered significantly in either the lateral or medial hypothalamus of TB or PF rats. These results suggest that the transcription of NPY is elevated in PF rats and is increased further in anorectic TB rats. The lack of significant increases in levels of peptides may be related to dilution, due to measuring a relatively large block of hypothalamic tissue. Alternatively, translation of the signal for NPY production may be inhibited, or degradation of peptide levels may be increased.

Topics: Animals; Anorexia; Corticotropin-Releasing Hormone; Hypothalamus, Middle; Male; Neuropeptide Y; Rats; RNA, Messenger; RNA, Neoplasm; Sarcoma, Experimental; Time Factors

Neuropeptide Y (NPY) and the endogenous melanocortin receptor antagonist, agouti gene-related protein (AGRP), coexist in the arcuate nucleus, and both exert orexigenic effects. The present study aimed primarily at determining the brain distribution of AGRP. AGRP mRNA-expressing cells were limited to the arcuate nucleus, representing a major subpopulation (95%) of the NPY neurons, which also was confirmed with immunohistochemistry. AGRP-immunoreactive (-ir) terminals all contained NPY and were observed in many brain regions extending from the rostral telencephalon to the pons, including the parabrachial nucleus. NPY-positive, AGRP-negative terminals were observed in many areas. AGRP-ir terminals were reduced dramatically in all brain regions of mice treated neonatally with monosodium glutamate as well as of mice homozygous for the anorexia mutation. Terminals immunoreactive for the melanocortin peptide alpha-melanocyte-stimulating hormone formed a population separate from, but parallel to, the AGRP-ir terminals. Our results show that arcuate NPY neurons, identified by the presence of AGRP, project more extensively in the brain than previously known and indicate that the feeding regulatory actions of NPY may extend beyond the hypothalamus.

Topics: Animals; Anorexia; Brain; Food Additives; In Situ Hybridization; Mice; Mice, Inbred C57BL; Neuropeptide Y; RNA, Messenger; Sodium Glutamate

Interleukin-1 beta (IL-1 beta) induces anorexia and neuropeptide Y (NPY) increases feeding by direct action in the central nervous system (CNS). IL-1 beta, depending on the dose, attenuates or blocks NPY-induced feeding. This suggests that IL-1 beta-NPY interactions may be involved in IL-1 beta-induced anorexia. Here, RNase protection assays were used to investigate the effects of the chronic intracerebroventricular (ICV) administration of IL-1 beta (at a dose that yields estimated pathophysiological concentrations in the cerebrospinal fluid) on mRNA levels of IL-1 beta system components and NPY in the cerebellum, parietofrontal cortex, hippocampus, hypothalamus, and midbrain. The results show that the chronic ICV administration of IL-1 beta (8.0 ng/24 h for 72 h) differentially induced IL-1 beta system components across brain regions in anorectic rats. IL-1 beta mRNA and IL-1 receptor antagonist (IL-1Ra) mRNA were induced similarly, exhibiting highest and lowest expression levels in the hypothalamus and hippocampus, respectively. IL-1 receptor type I (IL-1RI) mRNA and the soluble form of IL-1 receptor accessory protein (IL-1R AcP II) mRNA were also induced in the hypothalamus and cerebellum. NPY mRNA expression showed a small, but significant decrease in the hypothalamus. Heat-inactivated IL-1 beta (8.0 ng/24 h for 72 h) had no effect on the behavioral or molecular profiles. The results suggest that endogenous upregulation of IL-1 beta contributes to IL-1 beta-induced anorexia, and that modification of NPY mechanisms also may be involved.

Topics: Animals; Anorexia; Body Weight; Cerebellum; Cerebral Cortex; Dose-Response Relationship, Drug; Drinking; Eating; Gene Expression; Hippocampus; Hypothalamus; Injections, Intraventricular; Interleukin-1; Male; Mesencephalon; Neuroimmunomodulation; Neuropeptide Y; Proteins; Rats; Rats, Wistar; Receptors, Interleukin; Receptors, Interleukin-1; Receptors, Interleukin-1 Type I; RNA, Messenger

Neuropeptide Y is one of the most powerful neurochemical stimulants of food intake known. The neuronal substrate for this action is believed to be the neuropeptide Y-expressing cell population in the hypothalamic arcuate nucleus. In this study, mice homozygous for the anorexia mutation (anx) were investigated histochemically; anx is a recessive mutation that causes decreased food intake and starvation, leading to death 22 days after birth. We were interested to see whether any hypothalamic neurochemical abnormalities could be detected in this genetic model of starvation. By using immunohistochemistry and in situ hybridization, the hypothalamic distributions of neuropeptide Y, cholecystokinin, galanin, and serotonin, all messenger molecules postulated to be involved in the regulation of food intake and energy metabolism, were investigated. Immunoreactivities for somatostatin, the excitatory amino acid aspartate, and acetylcholinesterase were also studied. Neuropeptide Y-like immunoreactivity was increased markedly in arcuate cell bodies and decreased in terminals in the arcuate nucleus and other hypothalamic regions of anx/anx mice compared with normal litter mates. In situ hybridization for neuropeptide Y mRNA, however, showed no significant difference in gene expression in the arcuate nucleus. In addition, immunoreactivities for aspartate, acetylcholinesterase, and somatostatin in the arcuate nucleus were decreased in anx/anx mice. For cholecystokinin, galanin, and serotonin, no certain differences in hypothalamic immunoreactivity could be seen. These data suggest that a defect in neuropeptide Y-ergic signalling in the arcuate neurons may contribute to the failure to thrive in anx/anx mice.

Topics: Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Cholecystokinin; Energy Metabolism; Food Deprivation; Galanin; Hypothalamus; Immunohistochemistry; Mice; Models, Genetic; Mutation; Neural Pathways; Neuropeptide Y; Phenotype; Serotonin

Neuropeptide Y (NPY) increases feeding by direct action in the central nervous system (CNS). Interleukin-1 beta (IL-1 beta), on the other hand, induces anorexia when administered ICV at estimated pathophysiological (e.g., yielded by 1.0 ng/rat dose) and pharmacological (> or = 4.0 ng) concentrations in the cerebrospinal fluid (CSF). In the present study, we investigated NPY/IL-1 beta interactions using the ICV administration. ICV microinfusion of NPY (5.0 micrograms) significantly increased 2-h food intake (by 89%), whereas IL-1 beta decreased 2-h food intake (32% decrease with 1.0 ng/rat; 53% with 4.0 ng/rat; and 51% with 8.0 ng/rat). NPY (5.0 micrograms) blocked the anorexic effect induced by all doses of IL-1 beta when both compounds were administered concomitantly. Central infusion of NPY was also able to induce feeding in IL-1 beta-pretreated rats exhibiting marked anorexia. The results show that ICV-administered NPY blocks and reverses the anorexia induced by estimated pathophysiological and pharmacological concentrations of IL-1 beta in rats. A second interpretation of a data subset is that IL-1 beta attenuates or blocks NPY-induced increase in feeding depending on the IL-1 beta dose used. Blockage and reversal of IL-1 beta-induced anorexia by NPY suggest the importance in studying cytokine-peptide interactions in the regulation of feeding behavior. Understanding these endogenous interactions may produce strategies with potential therapeutic implications for chronic diseases associated with long-term anorexia.

Topics: Animals; Anorexia; Cerebral Ventricles; Drug Administration Routes; Drug Interactions; Eating; Interleukin-1; Male; Neuropeptide Y; Rats; Rats, Wistar

Modulation of feeding behavior by neuropeptide Y (NPY) and opioids is well established, but the possibility that these neural influences provoke specific appetites, NPY for carbohydrate and opioids for fat, has also been considered. In other studies, intake of standard chow after NPY stimulation can be blocked by naloxone, indicating an interaction between these systems in the regulation of feeding. The present experiments examined the nature of NPY-opioid interactions in diet selection. Rats were administered NPY and naloxone concurrently, then chose between high-fat and high-carbohydrate diets. Subcutaneous administration of naloxone (0.01-0.3 mg/kg) potently reduced intake of the preferred diet, but not the nonpreferred diet. A similar pattern of selection was seen in a separate experiment where the same doses of naloxone were administered after 24-h food deprivation. These data support the idea that the opioid system mediates the "rewarding" aspects of feeding.

Topics: Animals; Anorexia; Dietary Carbohydrates; Dietary Fats; Eating; Food Deprivation; Food Preferences; Male; Naloxone; Neuropeptide Y; Rats; Rats, Sprague-Dawley

Tumor-bearing rats exhibited significant decreases in 1- to 4-h intake of rat chow following the intrahypothalamic injection of 2 micrograms neuropeptide Y (NPY). This refractory feeding response was present prior to the onset of anorexia and became more severe as anorexia worsened. The constant infusion of NPY (125 ng/h) into the perifornical hypothalamus of TB and control rats elicited increased feeding for only 2 days. Because chromatography revealed minipump NPY to be intact after 10 infusion days, downregulation of NPY receptors may have occurred. Daily injection of increasing doses of NPY stimulated ad lib feeding in non-TB rats, while having no effect on TB rats. Desensitization to NPY-induced feeding following daily injections of the peptide was suggested by the loss of feeding response to a dose (500 ng) of NPY that increased food intake prior to the daily NPY treatments. These results suggest that hypothalamic NPY feeding systems are refractory in TB rats, even before they exhibit anorexia. In addition, a rapid loss of the feeding response occurred in rats with constant infusion of NPY into hypothalamic tissue or with daily intrahypothalamic injections of the peptide, suggesting possible NPY receptor-mediated alterations. Therefore, control of obesity or anorexia through NPY feeding mechanisms may prove difficult due to rapid compensatory receptor changes.

Topics: Animals; Anorexia; Appetite Stimulants; Carcinogens; Feeding Behavior; Hypothalamus; Infusion Pumps, Implantable; Injections; Male; Methylcholanthrene; Neuropeptide Y; Rats; Rats, Inbred F344; Sarcoma, Experimental; Time Factors

We investigated the effect of recombinant human interleukin-1 beta (rhIL-1 beta)-induced anorexia and pyrexia on the hypothalamic neuropeptide Y (NPY)-ergic system, which stimulates feeding and reduces thermogenesis. In meal-fed rats, food intake decreased by 83%, 90 min after IL-1 beta treatment (1.3 micrograms/100 g ip; n - 8) vs. controls. NPY concentrations were significantly higher in the medial preoptic area (MPO), paraventricular (PVN), ventromedial (VMN), and dorsomedial (DMN) nuclei but unchanged in the arcuate nucleus (ARC) in both IL-1 beta-treated and pair-fed groups. Indomethacin (0.25 mg/100 g ip) reduced IL-1 beta-induced anorexia and tended to normalize NPY concentrations. In study 2, IL-1 beta increased core temperature by 1.1 degrees C above preinjection values (P < 0.001) and significantly raised NPY concentrations in the MPO, PVN, VMN, and DMN compared with controls, 60 min postinjection. Indomethacin prevented the pyrexia and normalized hypothalamic NPY levels. As NPY concentrations were not increased in the ARC (the hypothalamic site of synthesis), we suggest that the increased NPY levels may result from blocked release, which would be in accord with the known experimental effects of NPY.

Topics: Animals; Anorexia; Body Temperature; Eating; Fever; Humans; Hypothalamus; Interleukin-1; Male; Neuropeptide Y; Rats; Rats, Wistar; Recombinant Proteins

The authors determined whether radioligand binding of neuropeptide Y (NPY) to hypothalamus taken from nonanorectic and anorectic tumor-bearing rats was altered as compared with similar tissue taken from freely-feeding and food-restricted control rats.. Previous results indicate that tumor-bearing rats exhibit a refractory feeding response to NPY, the most potent feeding stimulus known. Additional studies indicate that the concentration of NPY in the hypothalamus of anorectic tumor-bearing rats is decreased as compared with freely-feeding or food-restricted control rats.. Because these observations of decreased response to exogenous peptide in the presence of decreased endogenous levels suggest an alteration in hypothalamic NPY receptors, this study investigated binding of 125I-NPY to hypothalamic membranes of tumor-bearing and control rats.. Determinations of receptor affinity for NPY (half maximal concentration for displacement) indicated a 20-fold decrease in affinity with the development of anorexia, which changed to an 80-fold decrease during severe anorexia. Receptor density, as indicated by specific binding, exhibited only a 30% decrease, even during severe anorexia.. These results suggest major alterations in NPY receptor mechanisms in experimental cancer anorexia, with receptor affinity being decreased progressively as the rats become more anorectic. The absence of a compensatory up-regulation in receptor density in the presence of decreased endogenous NPY concentrations indicate dysfunction in receptor regulatory mechanisms. This receptor aberration may be the central nervous system basis for the etiology of cancer anorexia.

Topics: Animals; Anorexia; Hypothalamus; Male; Neoplasms, Experimental; Neuropeptide Y; Radioligand Assay; Rats; Rats, Inbred F344; Receptors, Neuropeptide Y

The role of neuropeptide Y (NPY) in the central control of appetite and energy balance is now established, but its involvement in the control of drinking and fluid homeostasis is less well characterized. Central administration of NPY stimulates drinking in rats, an effect believed to be independent of its orexigenic effects. Recent studies have demonstrated increased preproneuropeptide Y (preproNPY) mRNA in the arcuate nucleus (ARC) of the rat following food deprivation (FD) or water deprivation (WD). Because WD also suppresses food intake, it was not clear whether the osmotic or the anorectic effects of this stimulus were responsible for increased ARC preproNPY mRNA. In an attempt to distinguish between these possibilities, the present study further examined the effects of hyperosmotic stimuli on preproNPY mRNA in the ARC. Salt loading (4 or 7 days) and WD (4 days) both increased the abundance of preproNPY mRNA in the ARC. These increases were proportional to the severity and duration of treatment and were related to the degree of anorexia and weight loss. In a separate study WD, FD, or combined food and water deprivation (4 days) all produced similar decreases in body weight, but WD produced a smaller increase in ARC preproNPY mRNA. All of these treatments resulted in the appearance of NPY-like immunoreactivity in ARC neuronal perikarya. Together these findings suggest that NPY neuron activity in the ARC may be regulated by decreases in food intake rather than changes in body weight per se or increased osmolarity and support other data implicating NPY in the central regulation of energy homeostasis.

Topics: Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Dehydration; Food Deprivation; Immunohistochemistry; In Situ Hybridization; Male; Neuropeptide Y; Osmosis; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Water Deprivation

Although isoproterenol stimulated adenylate cyclase activity in hypothalamic membranes taken from freely-feeding, food-restricted or nonanorectic tumor-bearing rats, the response was greatly reduced in anorectic tumor-bearing rats. The addition of NPY to the membrane preparation inhibited adenylate cyclase activity in hypothalamus taken from freely-feeding and food-restricted rats, but NPY-inhibitory activity was significantly reduced in both groups of tumor-bearing rats. These results suggest that cyclic AMP formation is refractory in anorectic tumor-bearing rats, and that NPY-induced inhibition of hypothalamic adenylate cyclase is reduced in tumor-bearing rats prior to the onset of significant anorexia. Therefore, NPY-induced feeding may be reduced in tumor-bearing organisms due to a dysfunction in the cyclic AMP second messenger system.

Topics: Adenylyl Cyclases; Analysis of Variance; Animals; Anorexia; Cyclic AMP; Feeding Behavior; Hypothalamus; Isoproterenol; Male; Neuropeptide Y; Rats; Rats, Inbred F344; Sarcoma, Experimental

Pretreatment of rats with intrahypothalamic injections of pituitary adenylate cyclase activating peptide (PACAP) 10 min prior to the injection of neuropeptide Y (NPY) significantly reduced food and water intake during the 4-h measurement period. Intrahypothalamic injection of PACAP in schedule-fed rats also reduced food and water intake for 2 h. A smaller 1-h reduction of water intake was observed in water-deprived rats, suggesting that the anticonsummatory effects of PACAP were primarily against food intake. PACAP treatment did not alter hypothalamic concentration of NPY, nor were neurotransmitters, precursors, or metabolites altered substantially in corpus striatum or nucleus accumbens regions. These results demonstrate primary anorectic effects of intrahypothalamic injection of PACAP. The demonstration of these anorectic effects may suggest a role of cyclic AMP activation and inhibition in the control of satiety and hunger.

Topics: Adenylyl Cyclases; Animals; Anorexia; Cyclic AMP; Drinking; Eating; Hunger; Hypothalamus; Male; Neuropeptide Y; Neuropeptides; Neurotransmitter Agents; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Rats, Sprague-Dawley; Satiation; Second Messenger Systems

Infections of the gastrointestinal nematode, Nippostrongylus brasiliensis, in the laboratory rat result in a characteristic biphasic anorexia which is followed by hyperphagia once the worm burden has been cleared. Despite the importance of parasite-induced anorexia, relatively little is known of the underlying mechanisms. We have investigated the involvement of the central appetite drive in this anorexia by studying the gene expression of two neuropeptides with opposing actions on energy balance, NPY and CRF. Gene expression was assessed by in situ hybridization at 2, 8 and 16 days post-infection (p.i.) in infected rats, in uninfected controls, and in a group with food intake restricted to match that taken voluntarily by the parasitize animals. The sampling intervals corresponded to each of the two phases of maximum anorexia and the period of compensatory hyperphagia. Surprisingly, we found that increases in NPY gene expression in the hypothalamic arcuate nucleus (ARC) accompany anorexia in rats infected with N. brasiliensis; there was a significant relationship between degree of anorexia and induction of NPY mRNA after 8 days of infection. Furthermore, ARC NPY mRNA levels in parasitized animals were similar to those in pair-fed individuals with food intake restricted to match the infected rats. The number of larvae used to establish the infection affected both the degree of anorexia and the level of NPY mRNA at 8 days p.i. in a dose-dependent manner. NPY gene expression remained elevated in infected rats during at least the initial stages of compensatory hyperphagia. This suggests that animals detect a state of energy deficit during the early stages of the infection, yet do not feed, but become hyperphagic coincident with worm loss. The failure of anorectic parasitized animals to feed in response to activation of the NPYergic system makes this a novel system in which to study the regulation of hypothalamic NPY by physiological challenge. There were no significant differences in CRF gene expression between the groups at any of the sampling intervals.

Topics: Animals; Anorexia; Body Weight; Corticotropin-Releasing Hormone; Eating; Feeding Behavior; Gene Expression; Hypothalamus; In Situ Hybridization; Male; Neuropeptide Y; Nippostrongylus; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors

We measured neuropeptide Y (NPY) concentration in microdissected hypothalamic nuclei, by radioimmunoassay, and NPY mRNA in the hypothalamus in rats treated systemically with the nonspecific opioid antagonist, naloxone, to produce mild anorexia. Twenty rats were treated with daily SC injections of naloxone (7.5 mg/kg); 20 were treated with vehicle alone. Naloxone produced a 7% reduction in food intake (p < 0.01) and a reduction in weight gain (p < 0.002). Neuropeptide Y concentrations were increased specifically in the dorsomedial nucleus of the hypothalamus (DMN) in rats treated with naloxone (6.8 +/- 0.7 fmol/micrograms protein vs. 3.1 +/- 1.0 fmol/micrograms protein, p < 0.05, n = 10 per group). Total hypothalamic NPY mRNA was unchanged. Neuropeptide Y-opioid interactions may be important in the control of food intake.

Topics: Animals; Anorexia; Body Weight; Eating; Feedback; Hypothalamus, Middle; Insulin; Male; Naloxone; Neuropeptide Y; Opioid Peptides; Random Allocation; Rats; Rats, Wistar; RNA, Messenger

The efficacy of NPY to elicit feeding in TB rats was reduced prior to the onset of overt anorexia, with the feeding response decreasing further as anorexia developed. Hypothalamic concentration of NPY was reduced in TB rats, with the magnitude of the decrease paralleling the degree of anorexia. Binding affinity of NPY to hypothalamic membranes taken from TB rats suggested decreased binding affinity with no change in receptor number. Infusing ammonium salts at a concentration and rate necessary to increase blood ammonia levels to the degree observed in TB rats, produced anorexia and decreased NPY feeding. These results suggest that NPY feeding systems are abnormal in TB rats and that hyperammonemia may be of primary importance in this dysfunction.

Topics: Ammonia; Animals; Anorexia; Brain; Eating; Hypothalamus; Male; Methylcholanthrene; Neoplasm Transplantation; Neuropeptide Y; Rats; Rats, Inbred F344; Receptors, Neuropeptide Y; Sarcoma, Experimental; Time Factors

Hypothalamic concentration of neuropeptide Y was decreased significantly in anorectic tumor-bearing rats, while NPY level was increased significantly in matched carcass weight control rats as compared with freely-feeding controls. In vivo microdialysis of the perifornical hypothalamic area of tumor-bearing rats prior to the development of anorexia revealed no alteration in NPY in dialysates. Following the development of anorexia, however, tumor-bearing rats exhibited significant reduction in NPY concentration in dialysates as compared with either matched carcass weight or freely-feeding control group. These results suggest that hypothalamic NPY concentration and release are decreased selectively in anorectic tumor-bearing rats. Since NPY also elicits less feeding in tumor-bearing rats, dysfunction of hypothalamic NPY feeding mechanisms may be of primary importance in cancer anorexia.

Topics: Animals; Anorexia; Hypothalamus; Male; Microdialysis; Neoplasms, Experimental; Neuropeptide Y; Rats; Rats, Inbred F344

Plasma and cerebrospinal fluid (CSF) concentrations of three well-known satiety neuropeptides, cholecystokinin (CCK), somatostatin and calcitonin gene-related peptide (CGRP), along with two powerful orexigenic neuropeptides, neuropeptide Y (NPY) and beta-endorphin have been measured in elderly persons with idiopathic anorexia and normal weight healthy subjects in a similar age range. Plasma and CSF immunoreactivity levels of the two main fractions of CCK (CCK8s and CCK33) after being separated by HPLC were measured by a radioimmunoassay (RIA) developed in our laboratory, whereas the other neuropeptides were assayed by commercially available RIA kits. Elderly underweight anorectic patients had significantly lower levels of beta-endorphin but increased concentrations of NPY in both plasma and CSF when compared to controls. In addition to significantly higher levels of CCK8s but not CCK33 in plasma, we found a trend to higher CSF concentrations of CCK8s and a positive correlation between the body mass index and either beta-endorphin (r = 0.58, P < 0.05) or CCK8s (r = 0.69, P < 0.01) concentrations in CSF in the anorectic group. CSF somatostatin concentrations were decreased significantly, but plasma somatostatin levels and plasma and CSF concentrations of CGRP were similar in senile anorectics and controls. Treatment of five anorectic patients with megestrol acetate, 480 mg daily for 6 months, reversed only the decrease in CSF beta-endorphin levels but did not normalize the body weight or the fat body mass. On the basis of our findings, we hypothesize that a decrease in CSF beta-endorphin concentration along with a rise in plasma levels of CCK8s might be accounted for the primary anorexia of aging.

Topics: Aged; Aged, 80 and over; Aging; Anorexia; beta-Endorphin; Calcitonin Gene-Related Peptide; Cholecystokinin; Female; Humans; Male; Middle Aged; Neuropeptide Y; Neuropeptides; Somatostatin

Mapping studies have revealed that the perifornical hypothalamus (PFH) is a primary locus for both the feeding-stimulatory effect of neuropeptide Y (NPY) and the anorectic effect of catecholamines (CAs), suggesting that NPY and CAs may interact antagonistically there. To investigate this, the CA-releasing agent amphetamine (AMPH) was injected through indwelling guide cannulas into the PFH of satiated adult male rats 5 min prior to injection of NPY (78 pmol/0.3 microliters) and food intake was measured 1, 2, and 4 h later. Amphetamine (50-200 nmol) dose-dependently reduced NPY feeding, usually eliminating it at the higher doses. The receptors mediating this effect were investigated by sequential injection of various CA antagonists, AMPH, and NPY into the PFH. Neither the alpha- nor beta-adrenergic receptor antagonists phentolamine (100 nmol) or propranolol (200 nmol) significantly affected AMPH suppression of NPY feeding. In contrast, the dopamine receptor antagonist haloperidol (5 nmol) abolished AMPH suppression of NPY feeding, suggesting that dopamine (DA) mediates the AMPH effect. To examine this, epinephrine (EPI, 50-200 nmol) and DA (25-200 nmol) were tested for suppression of NPY-induced feeding. While EPI had no significant effect, DA at the maximally effective dose (50 nmol) reduced the NPY feeding response by 36% or more. These findings provide convergent evidence for antagonistic interactions between endogenous DA and NPY in the control of eating behavior.

Topics: Amphetamine; Animals; Anorexia; Catecholamines; Dopamine; Eating; Epinephrine; Hypothalamus; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley

Regional hypothalamic concentrations of neuropeptide Y (NPY) and corticotropin-releasing factor (CRF), respectively a stimulant and an inhibitor of feeding behavior, were investigated in hypothalamic nuclei in rats carrying the Yoshida sarcoma. Tumor-bearing rats (n = 10), non-tumor-bearing controls (n = 10), and food-restricted rats (n = 10), which did not carry tumors but were pair-fed to match the reduced food intake of the tumor-bearing group, were studied after 10 days. NPY concentrations in the arcuate nucleus (ARC, the main site of NPY synthesis) were significantly increased above controls (P < 0.01) in both tumor-bearing and food-restricted groups. However, NPY concentrations in the paraventricular nucleus (PVN, an NPY-sensitive site of NPY release) showed opposing changes, with a 25% decrease (P = 0.052) in the tumor-bearing but a 48% increase (P < 0.01) in the food-restricted group. CRF concentrations in both the PVN and the ARC were significantly reduced (P < 0.01) in the food-restricted group, but remained close to control values in the tumor-bearing group (P not significant). Changes in hypothalamic appetite-regulating neuropeptides in cancer anorexia, which may result from the action of cytokines produced by a host defense response or the tumor itself, may account for reduced feeding. Such changes may include impaired activity of NPY or failure of CRF activity to be suppressed after underfeeding and weight loss.

Topics: Adipose Tissue; Animals; Anorexia; Blood Glucose; Body Weight; Corticotropin-Releasing Hormone; Energy Intake; Female; Hypothalamus; Insulin; Muscles; Neuropeptide Y; Organ Size; Organ Specificity; Rats; Rats, Wistar; Reference Values; Sarcoma, Yoshida