neuropeptide-y and Cachexia

Chronic heart failure (CHF) is a major health problem that carries a devastating prognosis. The prognosis worsens considerably once cardiac cachexia has been diagnosed. Neurohormonal, metabolic, hemodynamic and immunological alterations are involved in the initiation and progression of cardiac cachexia. Cachexia is characterized by a hypothalamic inappropriate response to the mechanisms controlling energy homeostasis. Levels of the anorexigenic hormone leptin are decreased whereas the orexigenic gherlin hormone levels are normal or elevated. Nevertheless, energy intake is not increased as expected due to a persistent activation of the proopiomelanocortin (POMC) system (anorexigenic) paralleled by a decreased activity of the neuropeptide Y (NPY, orexigenic) neurons. Cachexia is also characterized by an imbalance in anabolic (impairment in the growth hormone/insulin-like growth factor-I axis, insulin resistance) and catabolic (increased levels of catecholamines, increased cortisol/dehydroepiandrosterone ratio and activation of proinflammatory cytokines such as tumor necrosis factor-alpha, interleuchin-6, interleuchin-1') at the basis of the wasting process. This review discusses the complex role of the endocrine system in modulating energy balance, appetite and metabolism in patients with chronic heart failure. A joint multidisciplinary effort of the cardiologists, immunologists and endocrinologists might be useful to identify the precise mechanisms involved in the neuroendocrine alteration and to develop therapeutic strategies able to improve the prognosis of CHF patients.

Topics: Appetite; Biomarkers; Cachexia; Chronic Disease; Cytokines; Endocrine System; Ghrelin; Heart Failure; Humans; Hypothalamus; Leptin; Neuropeptide Y; Pro-Opiomelanocortin; Prognosis

Ghrelin, a peptide hormone predominantly produced by the stomach, was isolated as the endogenous ligand for the growth hormone secretagogue receptor. Ghrelin is a potent stimulator of growth hormone (GH) secretion and is the only circulatory hormone known to potently enhance feeding and weight gain and to regulate energy homeostasis following central and systemic administration. Therapeutic intervention with ghrelin in catabolic situations may induce a combination of enhanced food intake, increased gastric emptying and nutrient storage, coupled with an increase in GH thereby linking nutrient partitioning with growth and repair processes. These qualities have fostered the idea that ghrelin-based compounds may have therapeutic utility in treating malnutrition and wasting induced by various sub-acute and chronic disorders. Conversely, compounds that inhibit ghrelin action may be useful for the prevention or treatment of metabolic syndrome components such as obesity, impaired lipid metabolism or insulin resistance. In recent years, the effects of ghrelin on glucose homeostasis, memory function and gastrointestinal motility have attracted considerable amount of attention and revealed novel therapeutic targets in treating a wide range of pathologic conditions. Furthermore, discovery of ghrelin O-acyltransferase has also opened new research opportunities that could lead to major understanding of ghrelin physiology. This review summarizes the current knowledge on ghrelin synthesis, secretion, mechanism of action and biological functions with an additional focus on potential for ghrelin-based pharmacotherapies.

Topics: Agouti-Related Protein; Amino Acid Sequence; Animals; Blood Glucose; Blood-Brain Barrier; Body Weight; Cachexia; Eating; Energy Metabolism; Gastrointestinal Motility; Ghrelin; Homeostasis; Human Growth Hormone; Humans; Insulin Resistance; Molecular Sequence Data; Neuropeptide Y; Obesity; Receptors, Ghrelin; Weight Gain

The role of nutrition and balanced metabolism in normal growth, development, and health maintenance is well known. Patients affected with either acute or chronic diseases often show disorders of nutrient balance. In some cases, a devastating state of malnutrition known as cachexia arises, brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. Other common features that are not required for the diagnosis include decreases in voluntary movement, insulin resistance, and anhedonia. This combination is found in a number of disorders including cancer, cystic fibrosis, AIDS, rheumatoid arthritis, renal failure, and Alzheimer's disease. The severity of cachexia in these illnesses is often the primary determining factor in both quality of life, and in eventual mortality. Indeed, body mass retention in AIDS patients has a stronger association with survival than any other current measure of the disease. This has led to intense investigation of cachexia and the proposal of numerous hypotheses regarding its etiology. Most authors suggest that cytokines released during inflammation and malignancy act on the central nervous system to alter the release and function of a number of neurotransmitters, thereby altering both appetite and metabolic rate. This review will discuss the salient features of cachexia in human diseases, and review the mechanisms whereby inflammation alters the function of key brain regions to produce stereotypical illness behavior. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.

Topics: Animals; Cachexia; Cytokines; Energy Metabolism; Feeding Behavior; Humans; Hypothalamus; Inflammation; Melanocortins; Models, Biological; 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

It is well established that disruptions in melanocortin signaling in the CNS result in morbid obesity, but only recently has evidence linked the activation of this system with the production of cachexia, also known as disease-associated wasting. Pro-opiomelanocortin-producing neurons, which express cytokine receptors, show increased activation in the presence of several cytokines that are increased in diseases that are associated with cachexia. Recent experiments show that blockade of melanocortin signaling using antagonists to the melanocortin MC(4) receptor attenuates disease-associated anorexia and wasting in rodent models of cancer and renal failure. This successful inhibition of cachexia is important because loss of appetite and lean body mass worsen the prognosis of many the diseases with which cachexia is associated.

Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Cachexia; Eating; Hormone Antagonists; Humans; Intercellular Signaling Peptides and Proteins; Models, Biological; Neurons; Neuropeptide Y; Pro-Opiomelanocortin; Proteins; Receptor, Melanocortin, Type 4; Receptors, Melanocortin

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

Recent advances in our understanding of the regulation of body weight, appetite, and metabolic rate have highlighted the role of the adipose-derived hormone leptin and its receptor as fundamental modulators of these processes. Investigations of the neural targets for leptin action--as well as characterization of the agouti obesity syndrome--have, in turn, led to the discovery of fundamental neural pathways involved in the central regulation of energy homeostasis. In particular, the central melanocortin system has been shown to regulate appetite and metabolic rate in rodents; mutations in this system have been demonstrated to result in obesity in humans. Overall, the melanocortin system appears to function as a bidirectional rheostat in the regulation of energy intake and expenditure in rodents and potentially in humans. The first section of this chapter will focus on the development of our understanding of melanocortin physiology in the context of obesity. In particular, recent data regarding the interplay between melanocortin and neuropeptide Y (NPY) signaling at a cellular level will be discussed. The following section will discuss the hypothesis that melanocortin signaling plays a role in pathological weight loss and hypermetabolism observed in murine cachexia models. The potential role of this system in integrating a variety of anorexic and cachexic signals, as well as the potential for its pharmacological manipulation in the treatment of human cachexia, will be discussed.

Topics: alpha-MSH; Animals; Cachexia; Cytokines; Humans; Mice; Models, Biological; Neuropeptide Y; Obesity; Protein Binding; Rats; Signal Transduction

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

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

Cancer cachexia (CC), a syndrome characterized by anorexia and body weight loss due to low fat-free mass levels, including reduced musculature, markedly worsens patient quality of life. Although stomach cancer patients have the highest incidence of cachexia, few experimental models for the study of stomach CC have been established. Herein, we developed stomach CC animal models using nude rats subcutaneously implanted with two novel cell lines, i.e., MKN45c185, established from the human stomach cancer cell line MKN-45, and 85As2, derived from peritoneal dissemination of orthotopically implanted MKN45c185 cells in mice. Both CC models showed marked weight loss, anorexia, reduced musculature and muscle strength, increased inflammatory markers, and low plasma albumin levels; however, CC developed earlier and was more severe in rats implanted with 85As2 than in those implanted with MKN45cl85. Moreover, human leukemia inhibitory factor (LIF), a known cachectic factor, and hypothalamic orexigenic peptide mRNA levels increased in the models, whereas hypothalamic anorexigenic peptide mRNA levels decreased. Surgical removal of the tumor not only abolished cachexia symptoms but also reduced plasma LIF levels to below detectable limits. Importantly, oral administration of rikkunshito, a traditional Japanese medicine, substantially ameliorated CC-related anorexia and body composition changes. In summary, our novel peritoneal dissemination-derived 85As2 rat model developed severe cachexia, possibly caused by LIF from cancer cells, that was ameliorated by rikkunshito. This model should provide a useful tool for further study into the mechanisms and treatment of stomach CC.

Topics: Agouti-Related Protein; Animals; Cachexia; Cell Line, Tumor; Corticotropin-Releasing Hormone; Cytokines; Disease Models, Animal; Drugs, Chinese Herbal; Humans; Hypothalamic Hormones; Hypothalamus; Leukemia Inhibitory Factor; Male; Melanins; Nerve Tissue Proteins; Neuropeptide Y; Oxygen Consumption; Pituitary Hormones; Pro-Opiomelanocortin; Rats; Rats, Nude; RNA, Messenger; Stomach Neoplasms

To study the leptin resistance mechanism of Xiaoyan Decoction (XD) in lung cancer cachexia (LCC) rats.. An LCC rat model was established. Totally 40 rats were randomly divided into the normal control group, the LCC model group, the XD group, and the positive control group, 10 in each group. After LCC model was set up, rats in the LCC model group were administered with normal saline, 2 mL each time. Rats in the XD group were administered with XD at the daily dose of 2 mL. Those in the positive control group were administered with Medroxyprogesterone Acetate suspension (20 mg/kg) by gastrogavage at the daily dose of 2 mL. All medication lasted for 14 days. The general condition and tumor growth were observed. Serum levels of leptin and leptin receptor in the hypothalamus were detected using enzyme-linked immunosorbent assay. Contents of neuropeptide Y (NPY) and anorexia for genomic POMC were detected using real-time PCR technique.. Serum leptin levels were lower in the LCC model group than in the normal control group with statistical significance (P < 0.05). Compared with the LCC model groups, serum leptin levels significantly increased in the XD group (P < 0.01). Leptin receptor levels in the hypothalamus increased significantly in the LCC model group (P < 0.01). Increased receptor levels in the LCC model group indicated that either XD or Medroxyprogesterone Acetate could effectively reduce levels of leptin receptor with statistical significance (P < 0.01). There was also statistical difference between the XD group and the positive control group (P < 0.05). Contents of NPY was higher in the LCC model group than in the other groups with statistical difference (P < 0.05). There was no statistical difference in NPY between the normal control group and the rest 2 treatment groups (P > 0.05). There was statistical difference in POMC between the normal control group and the LCC model group (P < 0.05). POMC could be decreased in the XD group and the positive control group with statistical significance (P < 0.05), and it was more obviously decreased in the XD group (P < 0.05).. Leptin resistance existed in LCC rats. XD could increase serum leptin levels and reduce leptin receptor levels in the hypothalamus. LCC could be improved by elevating NPY contents in the hypothalamus and reducing POMC contents, promoting the appetite, and increasing food intake from the periphery pathway and the central pathway.

Topics: Animals; Cachexia; Drugs, Chinese Herbal; Eating; Humans; Hypothalamus; Leptin; Lung Neoplasms; Neuropeptide Y; Random Allocation; Rats; Rats, Sprague-Dawley

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

Angiotensin II (Ang II), which is elevated in many chronic disease states such as end-stage renal disease and congestive heart failure, induces cachexia and skeletal muscle wasting by increasing muscle protein breakdown and reducing food intake. Neurohormonal mechanisms that mediate Ang II-induced appetite suppression are unknown. Consequently, we examined the effect of Ang II on expression of genes regulating appetite. Systemic Ang II (1 μg/kg · min) infusion in FVB mice rapidly reduced hypothalamic expression of neuropeptide Y (Npy) and orexin and decreased food intake at 6 h compared with sham-infused controls but did not change peripheral leptin, ghrelin, adiponectin, glucagon-like peptide, peptide YY, or cholecystokinin levels. These effects were completely blocked by the Ang II type I receptor antagonist candesartan or deletion of Ang II type 1a receptor. Ang II markedly reduced phosphorylation of AMP-activated protein kinase (AMPK), an enzyme that is known to regulate Npy expression. Intracerebroventricular Ang II infusion (50 ng/kg · min) caused a reduction of food intake, and Ang II dose dependently reduced Npy and orexin expression in the hypothalamus cultured ex vivo. The reduction of Npy and orexin in hypothalamic cultures was completely prevented by candesartan or the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside. Thus, Ang II type 1a receptor-dependent Ang II signaling reduces food intake by suppressing the hypothalamic expression of Npy and orexin, likely via AMPK dephosphorylation. These findings have major implications for understanding mechanisms of cachexia in chronic disease states such as congestive heart failure and end-stage renal disease, in which the renin-angiotensin system is activated.

Topics: Angiotensin II; Animals; Cachexia; Cholecystokinin; Eating; Feeding Behavior; Gene Expression Regulation; Hypothalamus; Infusions, Intraventricular; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuropeptide Y; Neuropeptides; Orexins; Phosphorylation; Time Factors

Parathyroid hormone-related protein (PTHrP) is a causative factor of humoral hypercalcemia in malignancy. However, it is difficult to explain the mechanism of anorexia/cachexia with PTHrP secretion in detail. Previously, we demonstrated that the expressions of orexigenic peptides increased and anorexigenic peptides decreased under cachectic conditions in rats carrying tumors secreting PTHrP. In this study, we investigated whether such changes in the expression of hypothalamic feeding-regulating peptides can be solely attributed to PTHrP or are a general response under cachectic conditions. Cachectic syndromes were induced in rats by: (i) inoculation of human lung cancer LC-6 cells that secreted PTHrP, (ii) inoculation of human melanoma SEKI cells that secrete not PTHrP but LIF1, (iii) injection of heat-killed Mycobacterium leading to arthritis (AA) and (iv) oral administration of a high dose of 1α,25(OH)(2)D(3) that resulted in hypercalcemia. The LC-6-bearing rats and AA rats were treated with or without anti-PTHrP antibody and indomethacin, respectively, and the expression of the hypothalamic feeding-regulating peptide mRNAs were examined by in situ hybridization histochemistry. The orexigenic peptide mRNAs, such as neuropeptide Y and agouti-related protein, were significantly increased, and that of anorexigenic peptide mRNAs, such as proopiomelanocortin, cocaine- and amphetamine-regulated transcript and corticotropin-releasing hormone were significantly decreased when they developed cachectic syndromes and AA. A high dose of 1α,25(OH)(2)D(3) caused hypercalcemia and body weight loss but did not affect the expression of hypothalamic feeding-regulating peptide mRNAs. The expressions of the hypothalamic feeding-regulating peptides change commonly in different chronic cachectic models without relating to serum calcium levels.

Topics: Agouti-Related Protein; Animals; Arthritis, Experimental; Cachexia; Cell Line, Tumor; Corticotropin-Releasing Hormone; Humans; Hypercalcemia; Hypothalamus; In Situ Hybridization; Intracellular Signaling Peptides and Proteins; Leptin; Leukemia Inhibitory Factor; Male; Neoplasms, Experimental; Nerve Tissue Proteins; Neuropeptide Y; Neuropeptides; Orexins; Parathyroid Hormone-Related Protein; Pro-Opiomelanocortin; Rats; Rats, Nude; Rats, Wistar; RNA, Messenger

The development of anorexia continues to be a serious treatment issue for cancer patients. Because the orexigenic peptide, ghrelin, is active through systemic routes and activates hypothalamic neuropeptide systems known to be refractory in anorectic tumor-bearing (TB) rats, we investigated whether it would prevent the development of cancer anorexia when infused continuously intravenously. The 24-h food intake was increased in nontumor-bearing (NTB) rats at a dose of 288 microg/day ghrelin. However, no tested dose of ghrelin, up to 576 microg/day, elicited increased feeding in TB rats prior to or subsequent to the development of anorexia. In hypothalamus, ghrelin-infused TB rats exhibited significantly increased concentration of neuropeptide Y (NPY) as compared to saline-infused TB rats. Hypothalamic expression of NPY and agouti-related protein (AgRP) messenger RNA were elevated in ghrelin-infused TB rats as compared to NTB rats, but saline-infused TB rats also exhibited increased expression of AgRP. Proopiomelanocortin message was reduced in ghrelin-infused and saline-infused TB rats as compared to noninfused TB control rats. Although ghrelin infusion did not preserve muscle protein, a significant saving in body fat was observed in TB rats. Thus, the adiposity effects of ghrelin did not require an orexigenic response to the peptide. These results suggest that continuous ghrelin infusion may not be an effective treatment for cancer anorexia.

Topics: Agouti-Related Protein; Animals; Area Under Curve; Base Sequence; Cachexia; Dose-Response Relationship, Drug; Feeding Behavior; Ghrelin; Infusions, Intravenous; Male; Neoplasms, Experimental; Neuropeptide Y; Random Allocation; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction

Parathyroid hormone-related protein (PTHrP) is a causative factor of humoral hypercalcemia of malignancy (HHM) and concurrent anorexia and wasting. Because changes in the expression of hypothalamic feeding-regulating peptides can directly affect appetites and thereby can cause anorexia and wasting, we addressed whether the cachectic syndromes induced by PTHrP rely on the action of hypothalamic feeding-regulating peptides.. Rats were inoculated with a LC-6 human cancer xenograft that secreted PTHrP, and the mRNA levels of the hypothalamic feeding-regulating peptide genes and serum leptin levels were examined before and after the development of HHM by in situ hybridization histochemistry and ELISA, respectively. Some rats were given the anti-PTHrP antibody.. The mRNA levels for the orexigenic peptides, such as the agouti-related protein and the neuropeptide Y in the arcuate nucleus (Arc), were significantly increased after the development of HHM, whereas the mRNA levels for the anorexigenic peptides, such as the proopiomelanocortin in the Arc, the cocaine and amphetamine-regulated transcript in the Arc, and the corticotropin-releasing factor in the paraventricular nucleus, were significantly decreased after the development of HHM. Plasma leptin levels were also reduced in cachectic rats, and the administration of anti-PTHrP antibody to the cachectic rats not only improved the cachectic symptoms but also restored the mRNA levels of these orexigenic and anorexigenic peptides, except for orexin. Thus, PTHrP induces HHM and concurrent cachectic syndromes by mechanisms other than directly modulating the leptin or hypothalamic feeding-regulated peptides.

Topics: Animals; Cachexia; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Hypothalamus; In Situ Hybridization; Leptin; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neuropeptide Y; Parathyroid Hormone-Related Protein; Peptides; Rats; Rats, Nude

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

We previously reported that the human melanoma cell line, SEKI, induces severe weight loss in nude mice. In the present study, we examined the expression of weight-regulating neuropeptide mRNAs in the hypothalamus of this cancer cachectic model by using a sensitive quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method and in situ hybridization. mRNA levels of neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) in the whole hypothalamus were elevated significantly in the SEKI mice as compared with control mice. In situ hybridization showed that NPY and CRH mRNA were upregulated in the arcuate nucleus and the paraventricular nucleus, respectively. There were no significant differences in melanin-concentrating hormone (MCH), orexin (OX), and cholecystokinin mRNA levels between the SEKI and control mice. These results suggest that the NPYergic system is functioning in the rodent model of cancer cachexia; however, the role of the CRHergic system in energy homeostasis remains to be elucidated. This is the first report of the hypothalamic neuropeptide response to cachexia-inducing human cells.

Topics: Animals; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Body Weight; Cachexia; Corticotropin-Releasing Hormone; DNA Primers; Female; Histocytochemistry; Humans; Hypothalamus; In Situ Hybridization; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Neuropeptide Y; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors

Weight loss normally stimulates hunger, through mechanisms that include falls in circulating leptin and insulin, leading to stimulation of hypothalamic neuropeptide Y (NPY). Here, we investigated the leptin, insulin and NPY to clarify why hunger is suppressed in mice with severe cachexia due to the MAC16 adenocarcinoma. MAC16-bearing mice progressively lost weight (19% below controls) and fat (- 61%) over 16 days after tumour transplantation, while total food intake fell by 10%. Pair-fed mice showed less wasting, with final weight being 9% and fat mass 25% below controls. Plasma leptin fell by 85% in MAC16 and 51% in pair-fed mice, in proportion to loss of fat. Plasma insulin was also reduced by 49% in MAC16 and 53% in pair-fed groups. Hypothalamic leptin receptor (OB-Rb) mRNA was significantly increased in both MAC16 (+ 223%) and pair-fed (+192%) mice. Hypothalamic NPY mRNA was also significantly raised in MAC16 (+152%) and pair-fed (+ 99%) groups, showing negative correlations with plasma leptin and insulin, and a positive association with OB-Rb mRNA. In MAC16-induced cachexia, leptin production and hypothalamic OB-Rb and NPY expression are regulated appropriately in response to fat depletion. Therefore, suppression of hunger is probably due to tumour products that inhibit NPY transport or release, or that interfere with neuronal targets downstream of NPY.

Topics: Adenocarcinoma; Adipose Tissue; Animals; Blotting, Northern; Cachexia; Carrier Proteins; Eating; Female; Gene Expression Regulation; Hunger; Hypothalamus; Insulin; Leptin; Mice; Neoplasm Transplantation; Neuropeptide Y; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

In patients with cancers progressive reduction of body mass is frequently recent. Pathogenesis of cachexia in patients with cancer is multifactorial. Such factors as cytokines, peptides relieved by tumor mass and different forms of treatment as radio or chemotherapy may play a major role in the pathogenesis of cachexia in patients with cancer. The aim of this study was to assess the relationship between body fat and lean mass and plasma leptin, NPY and TNF concentrations in patients with cancer of oral cavity and pharynx, cancer of larynx and non-Hodgkin lymphoma (NIL). 30 patients (10 with cancer of oral cavity and pharynx, 10 with cancer of larynx and 10 with non-Hodgkin lymphoma) were enrolled into this study. Mean age of all cancer patients was 50 +/- 2.9 years (from 18 to 76 years). The control group consisted of 29 healthy subjects with a means age 48 +/- 3.5 years (from 18 to 75 years), properly chosen according to the body weight, BMI, gender and age as above mentioned groups of patients with cancer. In control and study groups body fat and not-fat mass was assessed before and after treatment using the bioelectrical impedance method. Before oncological therapy patients with cancer did not differ from healthy subject with regard to body weight and body mass index. After treatment significant: decrease of body weight, body fat mass and BMI was observed. Serum leptin, NPY and TNF concentrations were analysed in healthy subjects and patients with cancer before and after treatment. Before oncological treatment significantly lower serum leptin concentration in comparison to leptinaemia in control group was found. In contrast to serum leptin, NPY serum concentration was similar in patients with cancer and in control subjects. Serum concentration of TNF was significantly higher in patients with cancer in comparison to subjects of control group. After oncological treatment, serum leptin and NPY concentration did not change significantly. In contrast, serum TNF concentration decreased significantly after oncological therapy. From the results obtained in this study we can conclude, that in patients with cancer secretion of leptin is decreased in relation to body fat mass. However, contribution of this hormone to pathogenesis of cancer induced anorexia seems not to proven. From the other side, the role of TNF in pathogenesis of disregulation of leptin secretion seems to be very likely. After chemo or radiotherapy, serum NPY concentration did not change signif

Topics: Adult; Aged; Body Mass Index; Cachexia; Case-Control Studies; Chemotherapy, Adjuvant; Female; Head and Neck Neoplasms; Humans; Leptin; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neuropeptide Y; Radiotherapy, Adjuvant; Tumor Necrosis Factor-alpha

We selected three human cancer cell lines [human melanoma (SEKI), human melanoma (G361), and human neuroepithelioma (NAGAI)] that have an ability to develop cancer cachexia syndrome with and without accompanying anorexia and examined the hypothalamic levels of mRNAs for neuropeptide Y (NPY), melanin-concentrating hormone, and orexin. The body weight of sham-operated mice continued to increase, while mice of all tumor-bearing groups lost weight. Competitive reverse transcription-polymerase chain reaction analysis showed that, regardless of feeding status, NPY mRNA levels were elevated in all tumor-bearing mice compared with sham-operated mice, although to a lesser degree than weight-matched pair-weight mice. Melanin-concentrating hormone and orexin mRNA in the hypothalamus followed the same pattern as NPY, although most of the differences did not reach statistical significance. These results support the notion that the response of NPY mRNA to a negative energy balance is less sensitive in these rodent models of cancer cachexia.

Topics: Animals; Cachexia; Carrier Proteins; Eating; Energy Metabolism; Female; Gene Expression; Growth Inhibitors; Humans; Hypothalamic Hormones; Hypothalamus; Interleukin-6; Intracellular Signaling Peptides and Proteins; Leukemia Inhibitory Factor; Lymphokines; Melanins; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Neuroectodermal Tumors, Primitive, Peripheral; Neuropeptide Y; Neuropeptides; Orexins; Organ Size; Pituitary Hormones; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured; Weight Loss

Studies involving altered energy balance states in rodents have demonstrated that hypothalamic neuropeptide Y (NPY) activity is strongly activated in states of negative energy balance, such as periods of dietary restriction or starvation. However, in cancer cachexia, when there is a significant reduction in body weight as a result of appetite loss, leading to loss in fat and lean tissue mass, there is no augmentation in the activity of the hypothalamic NPY system. Therefore, we have examined whether cytokines, interleukin (IL)-1, IL-1beta, IL-6, and tumor-necrosis factor-alpha (TNF-alpha; cachectin), which are elevated in cancer patients, can attenuate NPY release from hypothalamic slices in vitro. None of the cytokines altered either the basal or stimulated NPY release from the hypothalamic slices. However, we were able to measure a significant reduction in potassium-stimulated NPY release (-60%) by using the nonselective voltage-dependent calcium channel blocker NiCl (30 microM) without any effect on basal release, as a positive control. Therefore, we suggest that the failure to activate the hypothalamic NPY system in states of cancer cachexia cannot be attributed to a cytokine-induced reduction in neurotransmitter release.

Topics: Animals; Cachexia; Cytokines; Hypothalamus; In Vitro Techniques; Interleukin-1; Interleukin-6; Male; Neuropeptide Y; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha