neuropeptide-y and Weight-Loss

The clinical outcomes achieved by bariatric surgery have been impressive. However, the physiologic mechanisms and complex metabolic effects of bariatric surgery are only now beginning to be understood. Ongoing research has contributed a large amount of data and shed new light on the science behind obesity and its treatment, and this article reviews the current understanding of metabolic and bariatric surgery physiology.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Gastric Bypass; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Leptin; Neuropeptide Y; Obesity, Morbid; Peptide YY; Weight Loss

Acute or long-term energy deficit in lean or obese rodents or humans stimulates food intake or appetite and reduces metabolic rate or energy expenditure. These changes contribute to weight regain in post-obese animals and humans. Some studies show that the reduction in metabolic rate with energy deficit in overweight people is transient. Energy restriction has been shown in some but not all studies to reduce physical activity, and this may represent an additional energy-conserving adaptation. Energy restriction up-regulates expression of the orexigenic neuropeptide Y, agouti related peptide and opioids and down-regulates that of the anorexigenic alpha-melanocyte stimulating hormone or its precursor pro-opioomelanocortin and the co-expressed cocaine and amphetamine-regulated transcript in the arcuate nucleus of the hypothalamus. Recapitulating these hypothalamic changes in sated animals mimics the effects of energy deficit, namely increased food intake, reduced physical activity and reduced metabolic rate, suggesting that these energy-conserving adaptations are at least partially mediated by the hypothalamus.

Topics: Agouti-Related Protein; Animals; Appetite; Arcuate Nucleus of Hypothalamus; Body Weight; Eating; Energy Metabolism; Fasting; Humans; Leptin; Motor Activity; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Oxygen Consumption; Pro-Opiomelanocortin; Signal Transduction; Weight Loss

Topics: 4-Butyrolactone; Acetyl-CoA Carboxylase; Animals; Eating; Enzyme Inhibitors; Fatty Acid Synthases; Humans; Mice; Neuropeptide Y; Obesity; Triglycerides; Weight Loss

Topics: Adipose Tissue; Animals; Body Weight; Endocrine System Diseases; Homeostasis; Humans; Hypothalamo-Hypophyseal System; Leptin; Neuropeptide Y; Pituitary-Adrenal System; Proteins; Starvation; Wasting Syndrome; Weight Loss

Leptin, the protein encoded by the recently cloned obese gene, has the properties of a hormone released by adipose tissue, regulating appetite and energy expenditure. Injected leptin reduces body weight and food intake in mice, and in obese, diabetic mice (with a mutated obese gene), it also reduces plasma insulin and glucose. Leptin release is stimulated by insulin; leptin appears to act on the hypothalamus by inhibiting the release of the neuropeptide Y.

Topics: Adipose Tissue; Animals; Appetite; Blood Glucose; Energy Metabolism; Humans; Hypothalamus; Insulin; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Neuropeptide Y; Obesity; Proteins; Weight Loss

Background and aims: intervention studies that evaluate the effect of rs16147 on metabolic response and weight change after dietary intervention are scarce. We propose to evaluate the role of the rs16147 genetic variant in the metabolic effects produced by a hypocaloric Mediterranean-pattern diet with high content of omega-9. Material and methods: a sample of 363 obese subjects was recruited. At the baseline visit the patients were randomly assigned to one of two hypocaloric diets for 12 weeks (diet M, Mediterranean pattern; diet C, standard hypocaloric). All patients, at baseline and at 12 weeks, had biochemical and anthropometric variables measured, and genotyping performed for the rs16147 variant. Results: in all subjects, and with both diets, the parameters of adiposity, blood pressure, and circulating leptin improved. In obese subjects with allele (A) insulin levels (GG vs. GA + AA) (-0.9 ± 1.1 IU/L vs. -4.4 ± 1.0 IU/L; p = 0.01) and HOMA-IR (-0.3 ± 0.1 units vs. -1.2 ± 0.3 units; p = 0.02) decreased significantly with diet M. Subjects carrying the minor allele showed a significant decrease in basal insulin levels (GG vs. GA + AA) (0.7 ± 0.3 IU/L vs. -2.2 ± 0.9 IU/L: p = 0.02) and HOMA-IR (-0.3 ± 0.2 units vs. -0.7 ± 0.1 units: p = 0.01) after diet C. This decrease in circulating insulin and HOMA-IR levels in patients with allele A was significantly higher with diet M than with diet C. Conclusions: the A allele of the rs16147 variant produces a better metabolic response in terms of insulin resistance and basal insulin secondary to weight loss with two different hypocaloric diets in obese subjects, with improvement being higher with the Mediterranean diet.. Introducción y objetivos: los estudios de intervención que evalúan el efecto del rs16147 sobre la respuesta metabólica y el cambio de peso después de una intervención dietética son escasos. Evaluamos el papel de la variante genética rs16147 en los efectos metabólicos que produce una dieta hipocalórica de patrón mediterráneo y alto contenido en omega-9. Material y métodos: se reclutó una muestra de 363 sujetos obesos. En visita basal, los pacientes se asignaron aleatoriamente, durante 12 semanas, a recibir una de dos dietas: dieta M, de patrón mediterráneo, o dieta C, hipocalórica estándar. Se determinaron momento basal y a las 12 semanas, una serie de variables bioquímicas y antropométricas, realizándose el genotipado de la variante rs16147. Resultados: en todos los sujetos con ambas dietas mejoraron los parámetros de adiposidad, tensión arterial y leptina circulante. En sujetos obesos con el alelo menor (A), los niveles de insulina (GG vs. GA + AA) (-0,9 ± 1,1 UI/L vs. -4,4 ± 1,0 UI/L; p = 0,01) y HOMA-IR (-0,3 ± 0,1 unidades vs. -1,2 ± 0,3 unidades; p = 0,02) disminuyeron significativamente con dieta M. Los sujetos portadores del alelo menor tras dieta C mostraron disminución significativa de niveles de insulina basal (GG vs. GA + AA) (0,7 ± 0,3 UI/L vs. -2,2 ± 0,9 UI/L: p = 0,02) y HOMA-IR (-0,3 ± 0,2 unidades vs. -0,7 ± 0,1 unidades: p = 0,01). Esta disminución de los niveles de insulina circulante y HOMA-IR en los pacientes con alelo A fue significativamente superior con la dieta M que con la dieta S. Conclusiones: el alelo A de la variante rs16147 se relaciona con mejor respuesta metabólica, en términos de resistencia a insulina e insulina basal secundaria a pérdida de peso, a dos dietas hipocalóricas, siendo superior el efecto obtenido con una dieta de patrón mediterráneo.

Topics: Adult; Diet, Mediterranean; Female; Humans; Male; Middle Aged; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Weight Loss

Our aim was to evaluate the relationship of weight loss and changes in adipokine levels after two hypocaloric diets in obese subjects with polymorphism rs16147 of the neuropeptide Y gene.. A population of 283 obese patients was analyzed. At the basal visit, patients were randomly allocated to one of two diets for a period of 3 months (diet I, low in carbohydrates; diet II, low in fat).. With diet I and in both genotype groups (major versus minor allele), body mass index (BMI), weight, fat mass, waist circumference, and leptin decreased. With diet II and in all genotypes, BMI, weight, fat mass, waist circumference, and leptin decreased. With both diets and in subjects with the minor allele, insulin levels (diet I: major allele -1.7 ± 7.8 IU/L versus minor allele -4.2 ± 6.1 IU/L, p = 0.01; diet II: major allele -2.3 ± 6.1 IU/L versus minor allele -4.0 ± 5.2 IU/L, p = 0.02) and insulin resistance (diet I: major allele -0.2 ± 3.1 units versus minor allele -1.7 ± 3.0 units, p = 0.03; diet II: major allele -0.9 ± 2.0 units versus minor allele -1.7 ± 1.3 units, p = 0.01) decreased.. The rs16147 genotype affected the reduction in insulin resistance and insulin levels in response to two different hypocaloric diets in obese subjects, with a lack of response in subjects with the major allele.

Topics: Adipokines; Adult; Cardiovascular Diseases; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Diet, Reducing; Female; Genetic Markers; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Neuropeptide Y; Nutrigenomics; Obesity; Polymorphism, Single Nucleotide; Prospective Studies; Risk Factors; Weight Loss

Neuropeptide Y is a key peptide affecting adiposity and has been related to obesity risk. However, little is known about the role of NPY variations in diet-induced change in adiposity.. The objective was to examine the effects of NPY variant rs16147 on central obesity and abdominal fat distribution in response to dietary interventions.. We genotyped a functional NPY variant rs16147 among 723 participants in the Preventing Overweight Using Novel Dietary Strategies trial. Changes in waist circumference (WC), total abdominal adipose tissue, visceral adipose tissue, and subcutaneous adipose tissue (SAT) from baseline to 6 and 24 mo were evaluated with respect to the rs16147 genotypes. Genotype-dietary fat interaction was also examined.. The rs16147 C allele was associated with a greater reduction in WC at 6 mo (P < 0.001). In addition, the genotypes showed a statistically significant interaction with dietary fat in relation to WC and SAT (P-interaction = 0.01 and 0.04): the association was stronger in individuals with high-fat intake than in those with low-fat intake. At 24 mo, the association remained statistically significant for WC in the high-fat diet group (P = 0.02), although the gene-dietary fat interaction became nonsignificant (P = 0.30). In addition, we found statistically significant genotype-dietary fat interaction on the change in total abdominal adipose tissue, visceral adipose tissue, and SAT at 24 mo (P = 0.01, 0.05, and 0.04): the rs16147 T allele appeared to associate with more adverse change in the abdominal fat deposition in the high-fat diet group than in the low-fat diet group.. Our data indicate that the NPY rs16147 genotypes affect the change in abdominal adiposity in response to dietary interventions, and the effects of the rs16147 single-nucleotide polymorphism on central obesity and abdominal fat distribution were modified by dietary fat.

Topics: Abdominal Fat; Adiposity; Adult; Body Mass Index; Diet, Fat-Restricted; Diet, High-Fat; Diet, Reducing; Female; Genetic Association Studies; Humans; Intra-Abdominal Fat; Male; Middle Aged; Neuropeptide Y; Obesity, Abdominal; Polymorphism, Single Nucleotide; Subcutaneous Fat, Abdominal; Waist Circumference; Weight Gain; Weight Loss

The aim of this study was to verify the effects of a multidisciplinary therapy (24 weeks) on neurohormonal control of food intake, specifically in orexigenic (total ghrelin, agouti-related protein [AgRP], neuropeptide Y [NPY], and melanin-concentrating hormone) and anorexigenic factors (leptin, insulin, and alpha-melanocyte stimulating hormone [α-MSH]), in obese adolescents.. A total of 88 adolescents (38 boys and 50 girls), including 62 obese and 26 normal-weight, aged 15-19 years were recruited. Obese adolescents were submitted to a 24-week multidisciplinary therapy. AgRP, NPY, melanin-concentrating hormone, leptin, insulin, glucose, α-MSH, total ghrelin, and food intake were measured at three stages (at baseline, after 12 weeks, and after 24 weeks).. At baseline, obese adolescents showed hyperleptinemia (circulating leptin levels, which were, in boys and girls, 40 and 35 times higher than in normal-weight subjects, respectively). After 24 weeks, these values decreased in all obese patients. Our results showed no differences in ghrelin levels between obese and normal-weight adolescents, in both genders. However, obese boys reduced their plasma ghrelin concentration after 24 weeks of therapy (p < .05). The multidisciplinary therapy decreased NPY and AgRP values and increased α-MSH; simultaneously with these changes there was a decrease in total food intake after 24 weeks of therapy.. We can conclude that the multidisciplinary therapy was efficient to modulate neurohormonal control of food intake in obese adolescents.

Topics: Adolescent; Adolescent Health Services; Agouti-Related Protein; alpha-MSH; Body Weight; Combined Modality Therapy; Diet, Reducing; Exercise; Feeding Behavior; Female; Ghrelin; Humans; Hypothalamic Hormones; Leptin; Male; Melanins; Neuropeptide Y; Obesity; Peptide Hormones; Pituitary Hormones; Weight Loss

Alterations in entero-endocrine signaling may play a role in improvements in satiety and glucose tolerance after Roux-en-Y gastric bypass (RYGB). We report our findings of gut hormone secretion in a cohort of diabetic and nondiabetic morbidly obese patients.. Ten morbidly obese subjects who underwent uncomplicated RYGB were studied: 5 were diabetic and 9 were female. Nonfasting plasma levels of glucagon-like peptide-1 (GLP-1), insulin, desacyl ghrelin, active ghrelin, neuropeptide Y (NPY), and gastric inhibitory polypeptide (GIP) were determined preoperatively and 6 months postoperatively.. Mean patient age was 42 +/- 11 years, and the mean preoperative body mass index was 50 +/- 6 kg/m(2). At 6 months mean BMI fell to 33 +/- 5 kg/m(2) (P < 0.0001), and there were no differences between diabetics and nondiabetics with respect to amount of weight loss. In non-diabetics, compared to preoperative levels, there were significant increases in GLP-1 and desacyl-ghrelin in the nondiabetic patients (P = 0.046 and P = 0.016, respectively); no change in plasma insulin, active ghrelin, NPY, or GIP was demonstrated. In contrast, when compared to preoperative levels, there were no significant changes in entero-endocrine hormone levels in the diabetic cohort postoperatively.. At 6 months postoperation, RYGB significantly alters the hormone levels for GLP-1 and desacyl-ghrelin in morbidly obese nondiabetic patients. No significant change was noted in a matched cohort of diabetic patients. Weight loss was similar in diabetics and nondiabetics, suggesting that GLP-1 and ghrelin are not the only mechanisms producing weight loss after RYGB.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Gastrointestinal Tract; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Male; Middle Aged; Neuropeptide Y; Obesity, Morbid; Peptide Hormones; Weight Loss

Correlations between serum leptin (LEP) and BMI and the percentage of fat mass (FM), as well as differences between male and female serum levels and their behaviour during weight loss have already been extensively described in adult obesity, whereas few cases have been examined in child and adolescent obesity. There are also few studies of the alterations in NPY in peripheral blood in obese subjects during weight loss.. This study aimed to evaluate the correlations between LEP and BMI, FM% and NPY in 72 obese subjects, with BMI > 35 (29 males and 43 females) aged between 9.6 and 19.8 years old, during weight loss together with any differences between the sexes.. LEP was positively correlated in both sexes with BMI and FM%, whereas no correlation emerged with NPY; LEP levels decreased gradually during weight loss, whereas no changes were observed in NPY except during the first phases of weight loss in males when the decrease was significant. LEP concentrations were significantly higher in females, who also showed a higher FM% with equal BMI. No difference was observed between NPY levels in both sexes.. The authors conclude that: 1) the behaviour of LEP in child-adolescent obesity is broadly comparable to that described in adult obesity; 2) the highest LEP concentrations with equal BMI in females appear to reflect the different body composition of the two sexes given that females have a higher FM%; 3) the control exerted by LEP on hypothalamic NPY cannot be seen in peripheral blood and no differences emerged between the two sexes.

Topics: Adolescent; Adult; Child; Female; Humans; Leptin; Male; Neuropeptide Y; Obesity; Proteins; Sex Factors; Weight Loss

Energy restriction is a first therapy in the treatment of obesity, but the underlying biological mechanisms have not been completely clarified. We analyzed the effects of restriction of high-fat diet (HFD) on weight loss, circulating gut hormone levels and expression of hypothalamic neuropeptides. Ten-week-old male Wistar rats (

Topics: Adiposity; Agouti-Related Protein; Animals; Caloric Restriction; Diet, Fat-Restricted; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Eating; Ghrelin; Hypothalamus; Leptin; Male; Metabolic Diseases; Neuropeptide Y; Neuropeptides; Obesity; Pro-Opiomelanocortin; Rats; Rats, Wistar; Weight Loss

As the elderly population grows, chronic metabolic dysfunction including obesity and diabetes are becoming increasingly common comorbidities. Hypothalamic inflammation through CNS resident microglia serves as a common pathway between developing obesity and developing systemic aging pathologies. Despite understanding aging as a life-long process involving interactions between individuals and their environment, limited studies address the dynamics of environment interactions with aging or aging therapeutics. We previously demonstrated environmental enrichment (EE) is an effective model for studying improved metabolic health and overall healthspan in mice, which acts through a brain-fat axis. Here we investigated the CSF1R inhibitor PLX5622 (PLX), which depletes microglia, and its effects on metabolic decline in aging in interaction with EE. PLX in combination with EE substantially improved metabolic outcomes in middle-aged female mice over PLX or EE alone. Chronic PLX treatment depleted 75% of microglia from the hypothalamus and reduced markers of inflammation without affecting brain-derived neurotrophic factor levels induced by EE. Adipose tissue remodeling and adipose tissue macrophage modulation were observed in response to CSF1R inhibition, which may contribute to the combined benefits seen in EE with PLX. Our study suggests benefits exist from combined drug and lifestyle interventions in aged animals.

Topics: Adipose Tissue; Aging; Animals; Body Composition; Body Weight; Brain-Derived Neurotrophic Factor; Corticotropin-Releasing Hormone; Female; Glial Fibrillary Acidic Protein; Glucose Tolerance Test; Gonadotropin-Releasing Hormone; Housing, Animal; Hypothalamus; Inflammation; Macrophages; Mice; Microglia; Neuropeptide Y; Organic Chemicals; Pro-Opiomelanocortin; Protein Kinase Inhibitors; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Social Environment; Transcriptome; Weight Loss

Ketogenic diets (KDs) are high-fat, low-carbohydrate diets that have been used therapeutically for decades, most notably for the treatment of epilepsy and diabetes. Recent data, however, suggest that KD may impart protective effects on mood disorders. The current experiments test the hypothesis that KDs can protect from stress-induced symptoms of mood disorders. To test this, we assessed behavioral and neuroendocrine effects of KD in male and female Long Evans rats. Animals experienced three weeks of chronic mild stress (CMS) while consuming KD or control chow (CH). Body weight and food intake data were recorded daily and behaviors were assayed after three weeks. Plasma beta-hydroxybutyrate (βHB), corticosterone (CORT) and interleukin-1 beta (IL-1β) were measured after behavioral testing, along with hypothalamic corticotropin-releasing hormone (CRH) and neuropeptide Y (NPY) mRNA expression. CMS induced weight loss in the CH groups, however the KD-fed rats were resistant to CMS-induced weight loss. Female rats fed KD were protected from CMS-induced reductions in plasma CORT and hypothalamic NPY expression. Collectively, these data suggest protective potential of KDs against chronic stress, particularly in females.

Topics: 3-Hydroxybutyric Acid; Animals; Behavior, Animal; Body Weight; Corticosterone; Corticotropin-Releasing Hormone; Diet, Ketogenic; Eating; Female; Hypothalamus; Interleukin-1beta; Male; Neuropeptide Y; Rats; Rats, Long-Evans; Sex Characteristics; Stress, Psychological; Weight Loss

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

Deregulation of orexigenic and anorexigenic pathways occurs among adolescents with obesity. Alpha-melanocyte-stimulating hormone (α-MSH) is a key catabolic mediator of energy homeostasis and an important anorexigenic neuropeptide in the control of energy balance and thermogenesis. However, it was not well explored if α-MSH can modulate long-term weight loss therapy responses in a dependent manner according to its concentration. Our hypothesis is that a high α-MSH concentration at baseline promotes better modulation of anorexigenic/orexigenic pathways in obese adolescents.. One hundred ten post-pubertal obese adolescents (body mass index >95th percentile) were submitted to 1 year of interdisciplinary therapy (clinical, nutritional, psychological, physical exercise, and physiotherapy support). Body composition and plasma levels of α-MSH, neuropeptide Y (NPY), melanin-concentrating hormone, and agouti-related peptide (AgRP) were measured before and after therapy. The volunteers were grouped on the basis of Tertiles of α-MSH concentration: Low (<0.75 ng/mL), Medium (≤0.76 to ≥1.57 ng/mL), and High (>1.57 ng/mL). Significance was set as p < 0.05.. The treatment promoted a significant improvement in body adiposity and fat free mass for all groups. It is important to note that only in the high α-MSH group, a significant increase of the α-MSH/NPY ratio and decrease NPY/AgRP ratio post treatment were observed.. The high α-MSH concentration promotes better modulation of anorexigenic/orexigenic pathways in obese adolescents following long-term weight loss therapy and this is important in clinical practice.

Topics: Adolescent; alpha-MSH; Energy Metabolism; Exercise; Exercise Therapy; Female; Humans; Hypothalamic Hormones; Male; Melanins; Neuropeptide Y; Pediatric Obesity; Pituitary Hormones; Weight Loss

Food structure contributes to the induction of satiation and the maintenance of satiety following intake of a meal. There is evidence from human studies that protein-crosslinking of a milk-protein based meal may enhance satiety, but the mechanism underpinning this effect is unknown. We investigated whether a rat model would respond in a similar manner and might provide mechanistic insight into enhanced satiety by structural modification of a food source. Rats were schedule fed a modified AIN-93M based diet in a liquid form or protein-crosslinked to produce a soft-solid form. This was compared to a modified AIN-93M solid diet. Average daily caloric intake was in the order solid > liquid > crosslinked. Body composition was unaltered in the solid group, but there was a loss of fat in the liquid group and a loss of lean and fat tissue in the crosslinked group. Compared to rats fed a solid diet, acute responses in circulating GLP-1, leptin and insulin were eliminated or attenuated in rats fed a liquid or crosslinked diet. Quantification of homeostatic neuropeptide expression in the hypothalamus showed elevated levels of Npy and Agrp in rats fed the liquid diet. Measurement of food intake after a scheduled meal indicated that reduced energy intake of liquid and crosslinked diets is not due to enhancement of satiety. When continuously available ad-libitum, rats fed a liquid diet showed reduced weight gain despite greater 24 h caloric intake. During the dark phase, caloric intake was reduced, but compensated for during the light phase. We conclude that structural modification from a liquid to a solidified state is beneficial for satiation, with less of a detrimental effect on metabolic parameters and homeostatic neuropeptides.

Topics: Agouti-Related Protein; Animals; Diet, Reducing; Energy Intake; Food Handling; Gene Expression Regulation; Glucagon-Like Peptide 1; Hypothalamus; Insulin; Insulin Secretion; Leptin; Male; Milk Proteins; Neurons; Neuropeptide Y; Overweight; Rats, Sprague-Dawley; Satiety Response; Transglutaminases; Weight Gain; Weight Loss

Leptin is an adipokine released mainly by adipose tissue, with many functions including regulation of energy balance. However, little is known about the effect of LEPR polymorphism on orexigenic and anorexigenic neuropeptides. Thus, the aim of the present study is to verify the influence of LEPR polymorphism (rs2767485) on serum orexigenic (NPY, MCH and AgRP) and anorexigenic (Leptin and α-MSH) neuropeptides levels among obese adolescents submitted to 1year of multicomponent weight loss therapy.. Seventy-six adolescents with obesity were enrolled in 1year of weight loss therapy including clinical, nutritional, psychological and exercise-related. Blood samples were collected to analyze neuropeptides (NPY, MCH, AgRP and leptin) and LEPR genotyping. Visceral fat was measured by ultrasound and body composition was measured by plethysmography. The parameters were measured at baseline and after one year. Adolescents were grouped according to genotype (TT or CT+CC group). Effect of the weight loss therapy was analyzed through ANOVA and Wilcox, according to normality. Statistic value was set at <0.05.. C-allele carriers have the orexigenic neuropeptides (NPY, AgRP and MCH) levels statistically higher when compared with TT group, at baseline. Furthermore, TT group seems to respond better to the therapy by a greater delta on BMI. Indeed, the data suggest a concomitant increased of AgRP levels in CT+CC genotypes, after weight loss therapy.. Both groups responded to the weight loss intervention, however wildtypes (TT) appear to respond to the intervention most optimally with C carries, where post intervention reduction in BMI was significantly greater in wildtypes. The leptin receptor polymorphism seems to affect neuroendocrine regulation of energy balance among adolescents with obesity.

Topics: Adiposity; Adolescent; Agouti-Related Protein; Brazil; Energy Metabolism; Female; Humans; Leptin; Male; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Receptors, Leptin; Ultrasonography; Weight Loss

The mitochondrial uncoupling agent 2,4-dinitrophenol (DNP), historically used as a treatment for obesity, is known to cross the blood-brain-barrier, but its effects on central neural circuits controlling body weight are largely unknown. As hypothalamic melanocortin neuropeptide Y/agouti-related protein (NPY/AgRP) and pro-opiomelanocortin (POMC) neurons represent key central regulators of food intake and energy expenditure we investigated the effects of DNP on these neurons, food intake and energy expenditure.. C57BL/6 and melanocortin-4 receptor (MC4R) knock-out mice were administered DNP intracerebroventricularly (ICV) and the metabolic changes were characterized. The specific role of NPY and POMC neurons and the ionic mechanisms mediating the effects of uncoupling were examined with in vitro electrophysiology performed on NPY hrGFP or POMC eGFP mice.. Here we show DNP-induced differential effects on melanocortin neurons including inhibiting orexigenic NPY and activating anorexigenic POMC neurons through independent ionic mechanisms coupled to mitochondrial function, consistent with an anorexigenic central effect. Central administration of DNP induced weight-loss, increased BAT thermogenesis and browning of white adipose tissue, and decreased food intake, effects that were absent in MC4R knock-out mice and blocked by the MC4R antagonist, AgRP.. These data show a novel central anti-obesity mechanism of action of DNP and highlight the potential for selective melanocortin mitochondrial uncoupling to target metabolic disorders.

Topics: 2,4-Dinitrophenol; Adipose Tissue, Brown; Animals; Body Weight; Eating; Energy Metabolism; Male; Melanocortins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Neurons; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Receptors, Melanocortin; Thermogenesis; Uncoupling Protein 1; Weight Loss

The main genetic variant described in NPY gene is rs16147 (G-399A) and it is located within the promoter region upstream of the gene for neropeptide Y (NPY). We evaluate the effects of the rs16147 NPY gene polymorphism on metabolic changes secondary to weight loss after 3 months of a hypocaloric diet in adult obese patients.. A population of 82 obese patients was analysed in an interventional design of one arm. Before and after 3 months on a hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed. The statistical analysis was performed for combined GA and AA as a group (minor allele group) and GG as second group (major allele group) (dominant model).. In A allele carriers, the mean (SD) decrease in weight was -2.8 (2.2) kg [decrease in non A allele carriers -2.6 (1.1) kg, P > 0.05), body mass index was -1.2 (0.6) kg m. We found that the rs164147 genotype affected the reduction of waist circumference, HOMA-IR, insulin, CRP and IL-6 levels in response to weight loss diet in obese subjects.

Topics: Adipokines; Adult; Biomarkers; Blood Glucose; Body Mass Index; C-Reactive Protein; Caloric Restriction; Cardiovascular Diseases; Diet, Fat-Restricted; Diet, Reducing; Female; Follow-Up Studies; Humans; Insulin Resistance; Male; Middle Aged; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Prospective Studies; Risk Factors; Waist Circumference; Weight Loss

Gastric electrical stimulation (GES) has great potential for the treatment of obesity. We investigated the impact of chronic GES on the alteration of adipose tissue and the regulation of neuropeptide Y (NPY), orexin (OX), α-melanocyte-stimulating hormone (α-MSH) and oxytocin (OXT), and their receptors in several tissues.. Most of the experiments included three groups of diet-induced obesity rats: (1) sham-GES (SGES); (2) GL-6mA (GES with 6 mA, 4 ms, 40 Hz, 2 s on, 3 s off at lesser curvature); and (3) SGES-PF (SGES rats receiving pair feeding to match the consumption of GL-6mA rats). Chronic GES was applied for 2 h every day for 4 weeks. During treatment with GES, food intake and body weight were monitored weekly. The alteration of epididymal fat weight, gastric emptying, and expression of peptides and their receptors in several tissues were determined.. GL-6mA was more potent than SGES-PF in decreasing body weight gain, epididymal fat tissue weight, adipocyte size and gastric emptying. Chronic GES significantly altered NPY, OX, α-MSH and OXT and their receptors in the hypothalamus, adipose tissue and stomach.. Chronic GES effectively leads to weight loss by reducing food intake, fat tissue weight and gastric emptying. NPY, α-MSH, orexin and OXT, and their receptors in the hypothalamus, adipose tissue and stomach appear to be involved in the anti-obesity effects of chronic GES.

Topics: Adipocytes; alpha-MSH; Animals; Disease Models, Animal; Eating; Electric Stimulation Therapy; Electrodes, Implanted; Epididymis; Gastric Emptying; Gastric Mucosa; Ghrelin; Hypothalamus; Intra-Abdominal Fat; Leptin; Male; Neuropeptide Y; Obesity; Orexin Receptors; Orexins; Oxytocin; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 3; Receptors, G-Protein-Coupled; Receptors, Melanocortin; Receptors, Neuropeptide; Receptors, Neuropeptide Y; Receptors, Oxytocin; RNA, Messenger; Weight Loss

Thyroid hormone and leptin are essential regulators of energy homeostasis. Both hormones stimulate energy expenditure but have opposite effects on appetite. The mechanisms behind food intake regulation in thyroid dysfunctions are poorly understood. It has been shown that hypothyroid rats exhibited impaired leptin anorexigenic effect and signaling in total hypothalamus, even though they were hypophagic. It was hypothesized that hypothyroidism modulates the expression of neuropeptides: orexigenic neuropeptide Y (NPY) and anorexigenic proopiomelanocortin (POMC), independently of inducing nuclei-specific changes in hypothalamic leptin signaling.. Adult male rats were rendered hypothyroid by administration of 0.03% methimazole in the drinking water for 21 days. Protein content of NPY, POMC, and leptin signaling (the signal transducer and activator of transcription 3 [STAT3] pathway) were evaluated by Western blot, and mRNA levels by real time reverse transcription polymerase chain reaction in arcuate (ARC), ventromedial (VMN), and paraventricular (PVN) hypothalamic nuclei isolated from euthyroid (eu) and hypothyroid (hypo) rats. Leptin anorexigenic effect was tested by recording food intake for two hours after intracerebroventricular (i.c.v.) administration of leptin. Statistical differences were considered significant at p ≤ 0.05.. Hypothyroidism was confirmed by decreased serum triiodothyronine, thyroxine, and increased thyrotropin, in addition to increased levels of pro-TRH mRNA in PVN and Dio2 mRNA in the ARC of hypo rats. Hypothyroidism decreased body weight and food intake associated with decreased protein content of NPY and increased content of POMC in the ARC. Conversely, hypothyroidism induced central resistance to the acute anorexigenic effect of leptin, since while euthyroid rats displayed reduced food intake after leptin i.c.v. injection, hypothyroid rats showed no response. Hypothyroid rats exhibited decreased leptin receptor (ObRb) protein content in ARC and VMN but not in PVN nucleus. ObRb protein changes were concomitant with decreased phosphorylated STAT3 in the ARC, and decreased total STAT3 in VMN and PVN. However, hypothyroidism did not affect mRNA levels of Lepr or Stat3 in the hypothalamic nuclei.. Experimental hypothyroidism induced a negative energy balance accompanied by decreased NPY and increased POMC protein content in the ARC, resulting in predominance of anorexigenic pathways, despite central leptin resistance and impairment of the leptin signaling cascade in a nuclei-specific manner.

Topics: Animals; Appetite Regulation; Arcuate Nucleus of Hypothalamus; Disease Models, Animal; Eating; Energy Metabolism; Feeding Behavior; Hypothyroidism; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Leptin; Male; Methimazole; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Phosphorylation; Pro-Opiomelanocortin; Rats, Wistar; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Thyrotropin-Releasing Hormone; Ventromedial Hypothalamic Nucleus; Weight Loss

Clinical studies indicate alternate-day, intermittent fasting (IMF) protocols result in meaningful weight loss in obese individuals. To further understand the mechanisms sustaining weight loss by IMF, we investigated the metabolic and neural alterations of IMF in obese mice. Male C57/BL6 mice were fed a high-fat diet (HFD; 45% fat) ad libitum for 8 weeks to promote an obese phenotype. Mice were divided into four groups and either maintained on ad libitum HFD, received alternate-day access to HFD (IMF-HFD), and switched to ad libitum low-fat diet (LFD; 10% fat) or received IMF of LFD (IMF-LFD). After 4 weeks, IMF-HFD (∼13%) and IMF-LFD (∼18%) had significantly lower body weights than the HFD. Body fat was also lower (∼40%-52%) in all diet interventions. Lean mass was increased in the IMF-LFD (∼12%-13%) compared with the HFD and IMF-HFD groups. Oral glucose tolerance area under the curve was lower in the IMF-HFD (∼50%), whereas the insulin tolerance area under the curve was reduced in all diet interventions (∼22%-42%). HPLC measurements of hypothalamic tissue homogenates indicated higher (∼55%-60%) norepinephrine (NE) content in the anterior regions of the medial hypothalamus of IMF compared with the ad libitum-fed groups, whereas NE content was higher (∼19%-32%) in posterior regions in the IMF-LFD group only. Relative gene expression of Npy in the arcuate nucleus was increased (∼65%-75%) in IMF groups. Our novel findings indicate that intermittent fasting produces alterations in hypothalamic NE and neuropeptide Y, suggesting the counterregulatory processes of short-term weight loss are associated with an IMF dietary strategy.

Topics: Adipose Tissue; Animals; Anterior Hypothalamic Nucleus; Arcuate Nucleus of Hypothalamus; Body Weight; Chromatography, High Pressure Liquid; Diet, High-Fat; Fasting; Gene Expression; Glucose Tolerance Test; Hypothalamus; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Norepinephrine; Obesity; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Weight Loss

Peripheral blood mononuclear cells (PBMC) constitute an easily obtainable blood cell fraction useful in nutrition and obesity studies. Our aim was to study the potential use of PBMC to reflect metabolic recovery associated with weight loss in rats.. By real-time PCR, the fasting response of key energy homeostatic genes in PBMC samples of control and cafeteria-obese rats and of rats fed a control diet after the intake of a cafeteria diet (post-cafeteria model) was analyzed.. Fasting caused decreased mRNA expression of lipogenic (Fasn and Srebp1a) and adipogenic (Pparγ) genes in PBMC, whereas it increased the expression of the key beta-oxidation gene Cpt1a and the orexigenic gene Npy. Fasting response of the genes studied was impaired in cafeteria-obese animals but was recovered in post-cafeteria rats, which showed a significant body weight decrease and normalization of adipose and metabolic parameters. Npy expression analyzed in PBMC has been revealed to be especially useful as a marker of fasting sensitivity, as its fasting response is not affected by the age of the animals and it is recovered even after shorter time of exposure to a balanced diet.. PBMC reflect homeostatic balance recovery associated with weight loss in obese animals, when reverting from a hyperlipidic to a control balanced diet.

Topics: Adipogenesis; Adiposity; Animals; Biomarkers; Energy Metabolism; Leukocytes, Mononuclear; Lipogenesis; Male; Neuropeptide Y; Obesity; PPAR gamma; Prognosis; Rats; Rats, Wistar; Sterol Regulatory Element Binding Protein 1; Treatment Outcome; Weight Loss; Weight Reduction Programs

Diet-induced weight loss varies considerably between individuals, but the mechanisms driving these individual differences remain largely unknown. Here we investigated whether key neuropeptides involved in the regulation of energy balance or reward systems were differentially expressed in mice that were prone or resistant to caloric restriction (CR) induced weight loss. Mice (n=30 males and n=34 females) were fed 70% of their own baseline ad libitum intake for 25days, after which their brains were collected and expression of various neuropeptides were investigated and compared between the 10 male and 10 female mice that showed the greatest (high weight loss, HWL) or lowest weight loss (LWL) (n=40 in total). HWL mice showed a differential neuropeptide profile to LWL in both sexes, characterised by increased expression of neuropeptide Y (NPY), agouti-related peptide (AgRP), leptin receptor (ObRb), and melanocortin 3 receptor (MC3R) in the arcuate nucleus. No changes in the expression of fat mass and obesity related gene (FTO) or suppressor of cytokine signalling 3 (Socs3) were observed. Levels of dopamine D2 receptor were decreased in the nucleus accumbens in HWL compared to LWL mice. HWL mice showed a stronger increase in food anticipatory activity (FAA) in response to CR than LWL mice. These results indicate that the mice prone to diet-induced weight loss experienced greater hunger, potentially driving their elevated FAA.

Topics: Animals; Anticipation, Psychological; Arcuate Nucleus of Hypothalamus; Caloric Restriction; Diet, Reducing; Energy Metabolism; Female; Food; Gene Expression; Humans; Male; Mice; Mice, Obese; Neuropeptide Y; Obesity; Receptor, Melanocortin, Type 3; Receptors, Dopamine D2; Receptors, Leptin; Treatment Failure; Weight Loss

Weight loss is a prominent early feature of Alzheimer's disease (AD) that often precedes the cognitive decline and clinical diagnosis. While the exact pathogenesis of AD remains unclear, accumulation of amyloid-β (Aβ) derived from the amyloid precursor protein (APP) in the brain is thought to lead to the neuronal dysfunction and death underlying the dementia. In this study, we examined whether transgenic mice overexpressing the Swedish mutation of APP (Tg2576), recapitulating selected features of AD, have hypothalamic leptin signaling dysfunction leading to early body weight deficits. We found that 3-month-old Tg2576 mice, before amyloid plaque formation, exhibit decreased weight with markedly decreased adiposity, low plasma leptin levels, and increased energy expenditure without alterations in feeding behavior. The expression of the orexigenic neuropeptide Y (NPY) in the hypothalamus to the low leptin state was abnormal at basal and fasting conditions. In addition, arcuate NPY neurons exhibited abnormal electrophysiological responses to leptin in Tg2576 hypothalamic slices or wild-type slices treated with Aβ. Finally, the metabolic deficits worsened as Tg2576 mice aged and amyloid burden increased in the brain. These results indicate that excess Aβ can potentially disrupt hypothalamic arcuate NPY neurons leading to weight loss and a pathologically low leptin state early in the disease process that progressively worsens as the amyloid burden increases. Collectively, these findings suggest that weight loss is an intrinsic pathological feature of Aβ accumulation and identify hypothalamic leptin signaling as a previously unrecognized pathogenic site of action for Aβ.

Topics: Adiposity; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Arcuate Nucleus of Hypothalamus; Brain; Brain Chemistry; Disease Models, Animal; Disease Progression; Fasting; Feeding Behavior; Female; Genes, Reporter; Humans; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neurons; Neuropeptide Y; Patch-Clamp Techniques; Plaque, Amyloid; Weight Loss

The regulation of energy balance is influenced by physical exercise. Although some studies show a stimulation of hormones related to food intake, others show that exercise provides satiety.. The aim of this study was to compare the effects of aerobic training (AT) and aerobic plus resistance training (AT+RT) on anorexigenic and orexigenic factors in obese adolescents undergoing interdisciplinary weight loss therapy.. A total of 26 obese adolescents, aged 15-19 years with BMI≥P95 were submitted to 12 months of interdisciplinary intervention (clinical support, nutrition, psychology and physical exercise) and divided into two groups, aerobic training (AT) (n=13) or aerobic plus resistance training (AT+RT) (n=13), which were matched according to gender and body mass. Blood samples were collected to analyze orexigenic factors (AgRP, NPY, MCH) and the anorexigenic factor alpha-MSH.. The AT and AT+RT groups significantly reduced body mass, body mass index and body fat mass (kg) during the therapy. The AT group showed no significant changes in body lean mass (kg), whereas the AT+RT group showed an increase in body lean mass (kg) during the interdisciplinary intervention. There was an increase in AgRP levels (ng/ml) only in the AT+RT group after 6 months of interdisciplinary intervention compared with baseline condition. Conversely, α-MSH levels (ng/ml) increased only in the AT group after 12 months of interdisciplinary intervention compared with baseline condition.. Aerobic training (AT) as part of an interdisciplinary therapy is more effective than aerobic plus resistance training (AT+RT) to improve secretion of anorexigenic/orexigenic factors in obese adolescents.

Topics: Adolescent; Agouti-Related Protein; alpha-MSH; Body Composition; Body Mass Index; Eating; Energy Metabolism; Exercise; Female; Humans; Hypothalamic Hormones; Male; Melanins; Neuropeptide Y; Obesity; Pituitary Hormones; Resistance Training; Satiation; Weight Loss; Young Adult

Immune challenge of mice with Bacille Calmette-Guérin (BCG) has been reported to cause transient weight loss and a behavioural sickness response. Although BCG-induced depression involves the kynurenine pathway, weight loss occurs independently of this factor. Because neuropeptide Y (NPY) and peptide YY (PYY) are involved in the regulation of food intake, we hypothesized that they play a role in the BCG-induced weight loss.. Male wild-type, PYY knockout (PYY-/-), NPY knockout (NPY-/-) and NPY-/-;PYY-/- double knockout mice were injected with vehicle or BCG (approximately 10(8) colony-forming units per mouse), and their weight, locomotion, exploration and ingestion were recorded for 2 weeks post-treatment.. Deletion of PYY and NPY aggravated the BCG-induced loss of body weight, which was most pronounced in NPY-/-;PYY-/- mice (maximum loss: 15%). The weight loss in NPY-/-;PYY-/- mice did not normalize during the 2 week observation period. BCG suppressed the circadian pattern of locomotion, exploration and food intake. However, these changes took a different time course than the prolonged weight loss caused by BCG in NPY-/-;PYY-/- mice. The effect of BCG to increase circulating IL-6 (measured 16 days post-treatment) remained unaltered by knockout of PYY, NPY or NPY plus PYY.. These data show that NPY and PYY are both required to protect from the action of BCG-evoked immune challenge to cause prolonged weight loss and disturb energy balance. The findings attest to an important role of NPY and PYY in orchestrating homeostatic reactions to infection and immune stimulation.

Topics: Animals; BCG Vaccine; Behavior, Animal; Circadian Rhythm; Corticosterone; Eating; Energy Metabolism; Exploratory Behavior; Female; Interleukin-6; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Neuropeptide Y; Peptide YY; Time Factors; Weight Loss

Twelve weeks of high-fat diet feeding causes ghrelin resistance in arcuate neuropeptide Y (NPY)/agouti-related protein (AgRP) neurons. In the current study, we investigated whether diet-induced weight loss could restore NPY/AgRP neuronal responsiveness to ghrelin and whether ghrelin mediates rebound weight gain after calorie-restricted (CR) weight loss. Diet-induced obese (DIO) mice were allocated to one of two dietary interventions until they reached the weight of age-matched lean controls. DIO mice received chow diet ad libitum or chow diet with 40% CR. Chow-fed and high-fat-fed mice served as controls. Both dietary interventions normalized body weight, glucose tolerance, and plasma insulin. We show that diet-induced weight loss with CR increases total plasma ghrelin, restores ghrelin sensitivity, and increases hypothalamic NPY and AgRP mRNA expression. We propose that long-term DIO creates a higher body weight set-point and that weight loss induced by CR, as seen in the high-fat CR group, provokes the brain to protect the new higher set-point. This adaptation to weight loss likely contributes to rebound weight gain by increasing peripheral ghrelin concentrations and restoring the function of ghrelin-responsive neuronal populations in the hypothalamic arcuate nucleus. Indeed, we also show that DIO ghrelin-knockout mice exhibit reduced body weight regain after CR weight loss compared with ghrelin wild-type mice, suggesting ghrelin mediates rebound weight gain after CR weight loss.

Topics: Agouti-Related Protein; Animals; Arcuate Nucleus of Hypothalamus; Caloric Restriction; Diet, High-Fat; Diet, Reducing; Drug Resistance; Ghrelin; Male; Mice; Neuropeptide Y; Obesity; RNA, Messenger; Weight Gain; Weight Loss

Resistance to brain-mediated effects of leptin is a characteristic feature of obesity, resulting from alterations in leptin receptor signaling in hypothalamic neurons and/or transport across the blood-brain-barrier. We have shown previously, that the latter can be circumvented by intranasal (i.n.) application of leptin in lean rats. This prompted us to test i.n. leptin in animals with diet-induced obesity (DIO) as a basis for future human administration. DIO was induced in male Wistar rats by feeding a cafeteria diet for 25 or 32 wk, respectively. Consecutively, these DIO animals (seven to eight per treatment) and standard diet rats (lean) (14-15 per treatment, matched for age and diet duration) were treated with 0.1, 0.2 mg/kg leptin, or control solution i.n. daily for 4 wk before onset of dark period. Energy intake and body weight were measured daily; blood glucose, serum insulin, and leptin were measured before and after treatment. Expression of hypothalamic neuropeptides was assessed by quantitative real-time PCR. We demonstrate, for the first time, that i.n. leptin reduces appetite and induces weight loss in DIO to the same extent as in lean rats. Our findings are supported accordingly by an altered expression pattern of anorexigenic and orexigenic neuropeptides in the hypothalamus, e.g. proopiomelanocortin, cocaine and amphetamine-related transcript, neuropeptide Y, agouti-related protein. It now appears clear that i.n. leptin is effectively acting in obese animals in the same fashion as in their lean counterparts. These findings now clearly warrant studies in humans and may open new perspectives in the treatment of obesity.

Topics: Adipose Tissue; Administration, Intranasal; Agouti-Related Protein; Animals; Appetite; Blood Glucose; Blood-Brain Barrier; Corticotropin-Releasing Hormone; Diet; Energy Intake; Gene Expression; Humans; Hypothalamus; Leptin; Male; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Rats; Rats, Wistar; Receptors, Leptin; RNA, Messenger; Signal Transduction; Weight Loss

Hyperthyroidism is characterized in rats by increased energy expenditure and marked hyperphagia. Alterations of thermogenesis linked to hyperthyroidism are associated with dysregulation of hypothalamic AMPK and fatty acid metabolism; however, the central mechanisms mediating hyperthyroidism-induced hyperphagia remain largely unclear. Here, we demonstrate that hyperthyroid rats exhibit marked up-regulation of the hypothalamic mammalian target of rapamycin (mTOR) signalling pathway associated with increased mRNA levels of agouti-related protein (AgRP) and neuropeptide Y (NPY), and decreased mRNA levels of pro-opiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC), an area where mTOR co-localizes with thyroid hormone receptor-α (TRα). Central administration of thyroid hormone (T3) or genetic activation of thyroid hormone signalling in the ARC recapitulated hyperthyroidism effects on feeding and the mTOR pathway. In turn, central inhibition of mTOR signalling with rapamycin in hyperthyroid rats reversed hyperphagia and normalized the expression of ARC-derived neuropeptides, resulting in substantial body weight loss. The data indicate that in the hyperthyroid state, increased feeding is associated with thyroid hormone-induced up-regulation of mTOR signalling. Furthermore, our findings that different neuronal modulations influence food intake and energy expenditure in hyperthyroidism pave the way for a more rational design of specific and selective therapeutic compounds aimed at reversing the metabolic consequences of this disease.

Topics: Agouti-Related Protein; AMP-Activated Protein Kinases; Animals; Disease Models, Animal; Eating; Feeding Behavior; Hyperphagia; Hyperthyroidism; Hypothalamus; Male; Neural Pathways; Neuropeptide Y; Phosphorylation; Pro-Opiomelanocortin; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Signal Transduction; Sirolimus; Thyroid Hormone Receptors alpha; Time Factors; TOR Serine-Threonine Kinases; Triiodothyronine; Weight Loss

The complexity pathogenesis in the nonalcoholic fatty liver disease (NAFLD) involves an interplay between adipokines and neuroendocrine regulation of energy balance, including the role of neuropeptide Y (NPY)/agouti-related protein (AgRP) system. The first aim of this study was to assess the effect of long-term interdisciplinary intervention on NAFLD in obese adolescents, and the second objective was to establish the relationship between NPY/AgRP ratio and adiponectinemia. Fifty-five postpuberty obese adolescents were submitted to interdisciplinary intervention. The group was divided between subjects with and without NAFLD (n = 19 and 36, respectively). Blood samples were collected to measure glycemia, hepatic transaminases, lipid profile, insulin resistance, and sensitivity. Adiponectin, NPY, and AgRP concentrations were measured by enzyme-linked immunosorbent assay. Food intake was measured using 3-day diet records. It was observed at baseline that important clinical parameters including body weight, body mass index, visceral fat, homeostasis model assessment of insulin resistance, quantitative insulin sensitivity check index, triglycerides, very low-density lipoprotein cholesterol, and hepatic transaminases were more altered in NAFLD patients. After the intervention, these parameters, total energy, and macronutrient intake were reduced significantly in both groups. The most important finding was the positive correlation between AgRP and visceral fat in all patients and the negative correlation between NPY/AgRP and adiponectinemia only in NAFLD obese adolescents. The NAFLD patients presented more altered clinical parameters than the non-NAFLD subjects, including the negative correlation between adiponectinemia and NPY/AgRP. These results suggested that NAFLD obese adolescents presented an inflammatory profile that can influence the neuroendocrine regulation of energy balance, suggesting an additional impairment in the weight loss therapy.

Topics: Adiponectin; Adolescent; Agouti-Related Protein; Alanine Transaminase; Aspartate Aminotransferases; Cholesterol; Fatty Liver; Female; gamma-Glutamyltransferase; Humans; Insulin; Intra-Abdominal Fat; Male; Neuropeptide Y; Obesity; Statistics, Nonparametric; Triglycerides; Ultrasonography; Weight Loss; Young Adult

Surgical intervention produces sustainable weight loss and metabolic improvement in obese individuals. Vertical sleeve gastrectomy (VSG) produces dramatic, sustained weight loss; we investigated whether these changes result from improved sensitivity to leptin.. VSG was performed in Long-Evans rats with diet-induced obesity. Naïve or sham-operated rats, fed either ad libitum or pair-fed with the VSG group, were used as controls. Following surgery, body weights and food intake were monitored. We investigated energy expenditure, meal patterns, leptin sensitivity, and expression of pro-opiomelanocortin/agouti-related peptide/neuropeptide Y in the hypothalamus of the rats.. We observed sustained losses in weight and body fat in male and female rats after VSG. Weight loss persisted after the disappearance of a transient, postsurgical food intake reduction. Resting energy expenditure was similar between control and VSG rats. VSG rats maintained their reduced body weights. However, they responded to a chronic food restriction challenge by overeating, which resulted in prerestriction, rather than pre-VSG, body weights. Consistent with lower adiposity, VSG decreased plasma leptin levels. Although VSG slightly improved leptin's anorectic action, the response was comparable to that observed in controls matched for adiposity by caloric restriction. Changes in hypothalamic neuropeptide expression were consistent with the lower body weight and lower leptin levels but cannot account for the sustained weight loss.. VSG causes sustained reduction in body weight, which results from loss of fat mass. The maintenance of weight loss observed did not result from changes in sensitivity to leptin.

Topics: Agouti-Related Protein; Animals; Eating; Energy Metabolism; Female; Gastrectomy; Leptin; Malabsorption Syndromes; Male; Neuropeptide Y; Obesity; Rats; Rats, Long-Evans; Weight Loss

The aim of this study was to evaluate the role of orexigenic and anorexigenic factors in an interdisciplinary weight loss therapy for obese adolescents with symptoms of eating disorders.. Thirty-seven post-pubertal, obese adolescents (14 to 19 years old) with symptoms of eating disorders were submitted to long-term interdisciplinary therapy (1 year). Bulimic and binge eating symptoms were measured using the Bulimic Investigatory Test, Edinburgh, and the Binge Eating Scale respectively. Neuropeptide Y, melanin-concentrating hormone, total ghrelin, alpha-melanocyte stimulating hormone and leptin were measured using radioimmunoassay.. After long-term interdisciplinary therapy, the adolescents showed significantly improved body composition, visceral and subcutaneous fat and reduced symptoms of bulimia and binge eating. Intriguingly, orexigenic peptides were up-regulated after short-term therapy and down-regulated at the end of therapy, whereas the anorexigenic pathway was improved with therapy. Furthermore, after long-term therapy, a negative correlation was observed between leptin concentration and melanin-concentrating hormone.. We suggest that long-term therapy promotes an intrinsic association between weight loss, improvement of eating disorder symptoms and a decrease in orexigenic factors. Together, these results represent a more effective course by which patients can normalise behaviours related to eating disorders as well the actions of hormones involved in energy balance, and thus advance obesity control.. Long-term interdisciplinary therapy was effective to improve anorexigenic and orexigenic factors that influence energy balance and avoid the development of eating disorders in obese adolescents. However, the associations between eating disorders and neuroendocrine factors need to be confirmed in future studies.

Topics: Adolescent; Binge-Eating Disorder; Body Mass Index; Bulimia Nervosa; Energy Intake; Female; Ghrelin; Humans; Hypothalamic Hormones; Male; Melanins; Neuropeptide Y; Obesity; Patient Care Team; Physical Therapy Modalities; Pituitary Hormones; Weight Loss

To mimic clinical treatment with methylphenidate (MPH; Ritalin) for attention deficit/hyperactivity disorder (ADHD), rat pups were injected with MPH (5 mg/kg, i.p.) or placebo twice daily during their nocturnal active phase from postnatal day (PND) 7-35. Thirty-nine days after the last MPH administration (PND 76), four litters of rats experienced stressful conditions during the 2003 New York City blackout. MPH-treated rats that endured the blackout lost more weight and regained it at a slower pace than controls (p<0.05; N=7-11 per group). Furthermore, MPH-treated rats had elevated systolic arterial blood pressure (from 115.6+/-1.2 to 126+/-1.8 mmHg; p<0.05), assessed on PND 130 by tail cuff plethysmography. Immunocytochemical studies of transmitter systems in the brain demonstrated rearrangements of catecholamine and neuropeptide Y fibers in select brain regions at PND 135, which did not differ between blackout and control groups. However, MPH-treated rats that endured the blackout had more ectopic granule cells in the hilus of the dorsal hippocampal dentate gyrus compared to controls at PND 135 (p<0.05; N=6 per group). These findings indicate that early postnatal exposure to high therapeutic doses of MPH can have long lasting effects on the plasticity of select brain regions and can induce changes in the reactivity to stress that persist into adulthood.

Topics: Analysis of Variance; Animals; Animals, Newborn; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Blood Pressure; Brain; Catecholamines; Cell Count; Central Nervous System Stimulants; Dentate Gyrus; Disease Models, Animal; Female; Hippocampus; Immunohistochemistry; Injections, Intraperitoneal; Male; Methylphenidate; Neurons; Neuropeptide Y; Pregnancy; Rats; Rats, Sprague-Dawley; Stress, Physiological; Weight Loss

Intraventricular administration of glial cell line-derived neurotrophic factor (GDNF) in primate and humans to study Parkinson's disease (PD) has revealed the potential for GDNF to induce weight loss. Our previous data indicate that bilateral continuous hypothalamic GDNF overexpression via recombinant adeno-associated virus (rAAV) results in significant failure to gain weight in young rats and weight loss in aged rats. Based on these previous results, we hypothesized that because the nigrostriatal tract passes through the lateral hypothalamus, motor hyperactivity mediated by nigrostriatal dopamine (DA) may have been responsible for the previously observed effect on body weight. In this study, we compared bilateral injections of rAAV2/5-GDNF in hypothalamus versus substantia nigra (SN) in aged Brown-Norway X Fisher 344 rats. Nigrostriatal GDNF overexpression resulted in significantly greater weight loss than rats treated in hypothalamus. The nigral or hypothalamic GDNF-induced weight loss was unrelated to motor activity levels of the rats, though some of the weight loss could be attributed to a transient reduction in food intake. Forebrain DA levels did not account for the observed effects on body weight, although GDNF-induced increases in nucleus accumbens DA may have partially contributed to this effect in the hypothalamic GDNF-treated group. However, only nigrostriatal GDNF overexpression induced activation of phosphorylated extracellular signal-regulated kinase (p-ERK) in a small population of corticotrophin-releasing factor [corticotrophin-releasing hormone (CRH)] neurons located specifically in the medial parvocellullar division (MPD) of the paraventricular nucleus of the hypothalamus. Activation of these hypothalamic CRH neurons likely accounted for the observed metabolic effects leading to weight loss in obese rats.

Topics: Adiposity; Aging; Animals; Blotting, Western; Body Weight; Catecholamines; Chromatography, High Pressure Liquid; Dependovirus; Dopamine; Eating; Enzyme-Linked Immunosorbent Assay; Glial Cell Line-Derived Neurotrophic Factor; Hypothalamus; Immunohistochemistry; Male; Neuropeptide Y; Obesity; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Substantia Nigra; Weight Loss

The Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) Project uses comprehensive metabolic profiling to probe biochemical mechanisms of weight loss in humans. Measurements at baseline, 2 and 4 weeks, 6 and 12 months included diet, body composition, metabolic rate, hormones, and 80 intermediary metabolites measured by mass spectrometry. In 27 obese adults in a behavioral weight loss intervention, median weight decreased 13.9 lb over the first 6 months, then reverted towards baseline by 12 months. Insulin resistance (HOMA) was partially ameliorated in the first 6 months and showed sustained improvement at 12 months despite weight regain. Ghrelin increased with weight loss and reverted to baseline, whereas leptin and PYY fell at 6 months and remained persistently low. NPY levels did not change. Factors possibly contributing to sustained improvement in insulin sensitivity despite weight regain include adiponectin (increased by 12 months), IGF-1 (increased during weight loss and continued to increase during weight regain), and visceral fat (fell at 6 months but did not change thereafter). We observed a persistent reduction in free fatty acids, branched chain amino acids, and related metabolites that may contribute to improved insulin action. These findings provide evidence for sustained benefits of weight loss in obese humans and insights into mechanisms.

Topics: Adiponectin; Adult; Behavior Therapy; Biomarkers; Body Weight; Diet; Energy Metabolism; Female; Ghrelin; Humans; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Middle Aged; Neuropeptide Y; Obesity; Peptide YY; Weight Gain; Weight Loss

To investigate the effects of medium chain triglycerides (MCT) on adiposity and the modulation of neuropeptide Y (NPY) and leptin in Wistar rats.. 20 Wistar male rats were fed with diets containing 30% MCT or long chain triglycerides (LCT) for 8 weeks. Serum and hypothalamus leptin were detected by ELISA. RT-PCR was used to quantitatively compare the mRNA levels of recetpor of leptin (Ob-Rb) and NPY. The levels of serum and hypothalamic NPY were assessed by radioimmune assay.. Body weight gains and body fat accumulations of rats fed with the MCT diets were more less than those of rats fed with the LCT diets (P < 0.01). Hypothalamus and serum NPY concentrations in rats fed with the MCT diets were more lower than those in rats fed with LCT diets (P < 0.01). Rats fed with MCT diets had significantly higher ratios of hypothalamus/serum leptin in comparition with rats fed with LCT diets. The Ob-Rb mRNA levels in the hypothalamus in the rats fed with the MCT diets were more higher than in those of rats fed with the LCT diets (P < 0.01). There were no significant differences in NPY expressions between the rats fed with the LCT diets and rats fed with MCT diets.. The MCT diet could decrease rats body weight gain by increasing Ob-Rb expression in hypothalamus and decreasing NPY level.

Topics: Animals; Dietary Fats; Hypothalamus; Leptin; Male; Neuropeptide Y; Random Allocation; Rats; Rats, Wistar; Receptors, Leptin; RNA, Messenger; Triglycerides; Weight Loss

Under the hypothesis of obesity as a polygenetic disease numerous genes have been associated with an obese phenotype and metabolic co-morbidities. The cannabinoid receptor 1 (CB 1) is part of an underinvestigated system that participates in appetite control. Previous publications suggest that the endocannabinoid systems interact with the better understood leptin-melanocortin axis. Neuropeptide Y (NPY) is a player in the latter. Finally resistin has been shown to influence NPY expression in the brain. In a cohort of 1721 caucasion men and women with a BMI of 25kg/m(2) or more we therefore investigated three candidate polymorphisms at baseline and following 3 months low fat caloric restriction diet by polymerase chain reaction and restriction digestion: the 1359 G/A variant of the cannabinoid receptor 1 (CB1), the L7P variation in neuropeptide Y (NPY) and the -420C>G polymorphism in resistin. Comparing groups according to genotype for each gene separately revealed significant results at baseline only for the CB1 gene. However, upon dieting significant data was found for all 3 genes. Carriers of at least one A allele in CB1 lost more weight and reduced LDL cholesterol more than wildtype patients. LL homocygotes in NPY had a greater reduction in glucose, triglycerides, and LDL cholesterol whereas in resistin carriers of the G allele had a greater reduction in weight and triglycerides. Creating two groups defined by NPY and resistin genotype, respectively, with similar BMI values resulted in significant differences concerning weight loss and metabolic improvement. In conclusion, genetic polymorphisms associated with obesity may become relevant only under the condition of a low calory diet. The presence of a certain genotype may then be beneficial for obesity treatment.

Topics: Adult; Body Mass Index; Cholesterol, LDL; Cohort Studies; Diet, Fat-Restricted; Female; Genetic Variation; Genotype; Humans; Male; Middle Aged; Neuropeptide Y; Obesity; Polymorphism, Genetic; Receptor, Cannabinoid, CB1; Resistin; Weight Loss

This study aims to clarify the effects of exercise on levels of appetite regulatory hormones in plasma and hypothalamus of obese rats. Diet-induced obese rats undergo short- (40 min) and long-term (40 min, 5 days/week for 8 weeks) exercises. The rats ran at a speed of 20 m/min on a 5 degrees slope treadmill. Rats undergoing short-term exercise were divided into C, E0, E1, E3, E12, and E24. Rats undergoing long-term exercise (LE) were compared to long-term control (LC). Concentrations of ghrelin, obestatin, and neuropeptide Y (NPY) were measured using radio immuno-assay. Expression of ghrelin receptor (GHSR-1a), putative obestatin receptor (GPR-39), and NPY in the hypothalamus was measured by quantitative RT-PCR. After short-term exercise, the plasma concentrations of ghrelin and obestatin were not changed, but NPY decreased. Ghrelin and obestatin in the hypothalamus decreased, and recovered 12 until 24 h. NPY increased and recovered after 24 h. Expression of GHSR-1a and NPY was not changed and GPR-39 was not observed. In LE, these changes are different in plasma and hypothalamus. It would be concluded appetite and body weight of obese rats are decreased by exercise through reduced level of ghrelin in the hypothalamus. Obestatin seems to have no effect in exercise-induced change in appetite.

Topics: Animals; Appetite; Body Weight; Brain Chemistry; Eating; Exercise Test; Exercise Therapy; Ghrelin; Hypothalamus; Lipids; Male; Neuropeptide Y; Obesity; Peptide Hormones; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Receptors, Ghrelin; Time Factors; Tissue Extracts; Weight Loss

Detailed knowledge of the pathways by which ghrelin and leptin signal to AMPK in hypothalamic neurons and lead to regulation of appetite and glucose homeostasis is central to the development of effective means to combat obesity. Here we identify CaMKK2 as a component of one of these pathways, show that it regulates hypothalamic production of the orexigenic hormone NPY, provide evidence that it functions as an AMPKalpha kinase in the hypothalamus, and demonstrate that it forms a unique signaling complex with AMPKalpha and beta. Acute pharmacologic inhibition of CaMKK2 in wild-type mice, but not CaMKK2 null mice, inhibits appetite and promotes weight loss consistent with decreased NPY and AgRP mRNAs. Moreover, the loss of CaMKK2 protects mice from high-fat diet-induced obesity, insulin resistance, and glucose intolerance. These data underscore the potential of targeting CaMKK2 as a therapeutic intervention.

Topics: Acetyl-CoA Carboxylase; Agouti-Related Protein; AMP-Activated Protein Kinase Kinases; Animals; Appetite Regulation; Benzimidazoles; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Cells, Cultured; Diet, Atherogenic; Energy Metabolism; Female; Glucose Intolerance; Glucose Tolerance Test; Hypothalamus; Immunoblotting; Immunoenzyme Techniques; Immunoprecipitation; In Situ Hybridization; Insulin; Insulin Resistance; Integrases; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Naphthalimides; Neuropeptide Y; Protein Kinases; RNA, Messenger; Transfection; Weight Loss

Despite high leptin levels, most obese humans and rodents lack responsiveness to its appetite-suppressing effects. We demonstrate that leptin modulates NPY/AgRP and alpha-MSH secretion from the ARH of lean mice. High-fat diet-induced obese (DIO) mice have normal ObRb levels and increased SOCS-3 levels, but leptin fails to modulate peptide secretion and any element of the leptin signaling cascade. Despite this leptin resistance, the melanocortin system downstream of the ARH in DIO mice is over-responsive to melanocortin agonists, probably due to upregulation of MC4R. Lastly, we show that by decreasing the fat content of the mouse's diet, leptin responsiveness of NPY/AgRP and POMC neurons recovered simultaneously, with mice regaining normal leptin sensitivity and glycemic control. These results highlight the physiological importance of leptin sensing in the melanocortin circuits and show that their loss of leptin sensing likely contributes to the pathology of leptin resistance.

Topics: Agouti-Related Protein; alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Body Composition; Diet; Dietary Fats; Dose-Response Relationship, Drug; Gene Expression Regulation; Hypothalamus; In Vitro Techniques; Intercellular Signaling Peptides and Proteins; Leptin; Male; Melanocortins; Mice; Mice, Inbred C57BL; Neurons; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; RNA, Messenger; Signal Transduction; Weight Loss

Endogenous opioids, particularly dynorphins, have been implicated in regulation of energy balance, but it is not known how they mediate this in vivo. We investigated energy homeostasis in dynorphin knockout mice (Dyn(-/-) mice) and probed the interactions between dynorphins and the neuropeptide Y (NPY) system. Dyn(-/-) mice were no different from wild types with regards to body weight and basal and fasting-induced food intake, but fecal output was increased, suggesting decreased nutrient absorption, and they had significantly less white fat and lost more weight during a 24-h fast. The neuroendocrine and thermal responses to fasting were at least as pronounced in Dyn(-/-) as in wild types, and there was no stimulatory effect of dynorphin knockout on 24-h energy expenditure (kilocalories of heat produced) or physical activity. However, Dyn(-/-) mice showed increased circulating concentrations of 3,4-dihydroxyphenlacetic acid and 3,4-dihydroxyphenylglycol, suggesting increased activity of the sympathetic nervous system. The respiratory exchange ratio of male but not female Dyn(-/-) mice was reduced, demonstrating increased fat oxidation. Interestingly, expression of the orexigenic acting NPY in the hypothalamic arcuate nucleus was reduced in Dyn(-/-) mice. However, fasting-induced increases in pre-prodynorphin expression in the arcuate nucleus, the paraventricular nucleus, and the ventromedial hypothalamus but not the lateral hypothalamus were abolished by deletion of Y(1) but not Y(2) receptors. Therefore, ablation of dynorphins results in increases in fatty acid oxidation in male mice, reductions in adiposity, and increased weight loss during fasting, possibly via increases in sympathetic activity, decreases in intestinal nutrient absorption, and interactions with the NPYergic system.

Topics: Adipose Tissue; Animals; Body Weight; Dynorphins; Eating; Energy Metabolism; Fasting; Female; Glucose; Homeostasis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptide Y; Neurosecretory Systems; Physical Exertion; RNA, Messenger; Weight Loss

Peripheral administration of baclofen significantly reduced food intake and body weight increase in both diabetic (db/db) and diet-induced obese mice for 5 weeks, whereas it had no significant effects on energy balance in their lean control mice. Despite the decreased body weight, neuropeptide Y expression in the arcuate nucleus was significantly decreased, whereas pro-opiomelanocortin expression was significantly increased by baclofen treatment. These data demonstrate that the inhibitory effects of baclofen on body weight in the obese mice were mediated via the arcuate nucleus at least partially, and suggest that GABA(B) agonists could be a new therapeutic reagent for obesity.

Topics: Adipokines; Adipose Tissue, White; Administration, Oral; Animals; Anti-Obesity Agents; Arcuate Nucleus of Hypothalamus; Baclofen; Blood Glucose; Diet; Eating; GABA Agonists; GABA-B Receptor Agonists; Male; Mice; Mice, Obese; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; RNA, Messenger; Weight Loss

Chronic rapid eye movement (paradoxical) sleep deprivation (REM-SD) of rats leads to two conspicuous pathologies: hyperphagia coincident with body weight loss, prompted by elevated metabolism. Our goals were to test the hypotheses that 1) as a stressor, REM-SD would increase CRH gene expression in the hypothalamus and that 2) to account for hyperphagia, hypothalamic gene expression of the orexigen neuropeptide Y (NPY) would increase, but expression of the anorexigen proopiomelanocortin (POMC) would decrease. Enforcement of REM-SD of adult male rats for 20 d with the platform (flowerpot) method led to progressive hyperphagia, increasing to approximately 300% of baseline; body weight steadily declined by approximately 25%. Consistent with changes in food intake patterns, NPY expression rapidly increased in the hypothalamic arcuate nucleus by d 5 of REM-SD, peaking at d 20; by contrast, POMC expression decreased progressively during REM-SD. CRH expression was increased by d 5, both in mRNA and ability to detect neuronal perikaryal staining in paraventricular nucleus with immunocytochemistry, and it remained elevated thereafter with modest declines. Taken together, these data indicate that changes in hypothalamic neuropeptides regulating food intake are altered in a manner consistent with the hyperphagia seen with REM-SD. Changes in CRH, although indicative of REM-SD as a stressor, suggest that the anorexigenic actions of CRH are ineffective (or disabled). Furthermore, changes in NPY and POMC agree with current models of food intake behavior, but they are opposite to their acute effects on peripheral energy metabolism and thermogenesis.

Topics: Animals; Corticotropin-Releasing Hormone; Hypothalamus; Male; Neuropeptide Y; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Sleep Deprivation; Sleep, REM; Weight Loss

This study was carried out to determine the effects of the biliopancreatic diversion (BPD), a bariatric surgery applied to the treatment of morbidly obese humans, on energy balance in rats.. BPD was performed on a group of male Wistar rats. Body weight and food intake were measured daily throughout the study. Feces were also collected to assess energy losses and the determination of digestible energy. Energy expenditure and body composition were also determined for the 50-day length of the protocol. On the day of killing, the brain, the entire intestinal tract and white and brown adipose tissues were collected and weighed. Expression of neuropeptide Y (NPY) and agouti-related protein (AgRP) in the ARC nucleus were assessed by in situ hybridization.. Marked changes in the regulation of energy balance were observed in the BPD-operated rats. A decrease in digestible energy and food intake coupled with an increase in the fecal energy density and protein fecal energy led to an important weight loss in the BPD-operated rats. This weight loss was observed in the loss of fat mass (specifically the white epididymal, inguinal, retroperitoneal and brown adipose tissues). The rats modified their food intake pattern to be able to potentially eat more during the entire day. An increase in the surfaces of all intestinal structures (muscular and mucosal layers) was observed in the BPD-operated rats. The NPY and AgRP expression in the brain were both shown to be greater in the BPD-operated rats than in the control animals. At the beginning of the study, the surgery led to an energy expenditure decrease, which, however, did not persist throughout the study despite the fact that BPD-operated rats exhibited persistent lower fat free masses.. BPD led to a noticeable reduction in weight and fat gains in rats, which was in large part owing to a decrease in digestible energy intake led to by the gastrectomy, the intestinal malabsorption inherent to the surgery and to potentially a thermogenesis stimulation that occurred in the second end of the study. The reduction in energy gain occurs despite adaptations to thwart the intestinal malabsorption and the hunger signals from the central nervous system.

Topics: Adipose Tissue; Agouti-Related Protein; Animals; Biliopancreatic Diversion; Body Composition; Body Weight; Brain; Calorimetry, Indirect; Eating; Energy Metabolism; Gene Expression; Ileum; Intercellular Signaling Peptides and Proteins; Intestinal Mucosa; Male; Neuropeptide Y; Peptide Hormones; Rats; Rats, Wistar; RNA, Messenger; Weight Loss

Topics: Adolescent; Anorexia Nervosa; Feeding Behavior; Female; Humans; Neuropeptide Y; Peptide YY; Weight Loss

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

The mammalian Target of Rapamycin (mTOR) protein is a serine-threonine kinase that regulates cell-cycle progression and growth by sensing changes in energy status. We demonstrated that mTOR signaling plays a role in the brain mechanisms that respond to nutrient availability, regulating energy balance. In the rat, mTOR signaling is controlled by energy status in specific regions of the hypothalamus and colocalizes with neuropeptide Y and proopiomelanocortin neurons in the arcuate nucleus. Central administration of leucine increases hypothalamic mTOR signaling and decreases food intake and body weight. The hormone leptin increases hypothalamic mTOR activity, and the inhibition of mTOR signaling blunts leptin's anorectic effect. Thus, mTOR is a cellular fuel sensor whose hypothalamic activity is directly tied to the regulation of energy intake.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Eating; Energy Intake; Energy Metabolism; Fasting; Hypothalamus; Injections, Intraventricular; Leptin; Leucine; Neurons; Neuropeptide Y; Phosphorylation; Protein Kinases; Rats; Rats, Long-Evans; Ribosomal Protein S6; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; STAT3 Transcription Factor; TOR Serine-Threonine Kinases; Valine; Weight Loss

To characterize patients with weight loss-related amenorrhea and controls with respect to the pulsatility of neuropeptide Y (NPY) and luteinizing hormone (LH).. Nine young women (aged 20.23+/-2.11 years) diagnosed with weight loss-related amenorrhea (body mass index (BMI) 17.52+/-2.43 kg/m2) and five age-matched (age 21.88+/-3.12 years) normally menstruating (every 28-33 days) controls with normal BMI (23.62+/-3.11 kg/m2) (mean value+/-standard deviation).. Basal hormonal evaluation included serum follicle-stimulating hormone (FSH), LH, estradiol (E2) and NPY. A pulsatility study investigated NPY and LH episodic release. Patients from control the group were studied during the mid-follicular phase (days 6-8) of the menstrual cycle.. Patients with weight loss-related amenorrhea had lower FSH, LH and E2 levels than controls (p < 0.01). Basal serum NPY levels were lower in amenorrheic patients than in menstruating women (p < 0.01). The numbers of NPY and LH peaks were higher in patients with weigh loss-related amenorrhea than in controls (p < 0.01 and p < 0.05, respectively).. Increased NPY pulsatility may have pathophysiological significance in weight loss-related hypothalamic amenorrhea.

Topics: Adult; Amenorrhea; Body Mass Index; Estradiol; Female; Follicle Stimulating Hormone; Follicular Phase; Humans; Hypothalamus; Luteinizing Hormone; Neuropeptide Y; Periodicity; Weight Loss

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

White adipose tissue (WAT) is innervated by the sympathetic nervous system. A role for WAT sympathetic noradrenergic nerves in lipid mobilization has been suggested. To gain insight into the involvement of nerve activity in the delipidation process, WAT nerves were investigated in rat retroperitoneal and epididymal depots after prolonged fasting. A significant increase in tyrosine hydroxylase (TH) content was found in epididymal and, especially, retroperitoneal WAT by Western blotting. Accordingly, an increased immunoreactivity for TH was detected by immunohistochemistry in epididymal and, especially, retroperitoneal vascular and parenchymal noradrenergic nerves. Neuropeptide Y (NPY)-containing nerves were found around arteries and in the parenchyma. Double-staining experiments and confocal microscopy showed that most perivascular and some parenchymal noradrenergic nerves also contained NPY. Detection of protein gene product (PGP) 9.5, a general marker of peripheral nerves, by Western blotting and PGP 9.5-TH by double-staining experiments showed significantly increased noradrenergic nerve density in fasted retroperitoneal, but not epididymal depots, suggesting that formation of new nerves takes place in retroperitoneal WAT in fasting conditions. On the whole, these data confirm the important role of sympathetic noradrenergic nerves in WAT lipid mobilization during fasting but also raise questions about the physiological role of regional-dependent nerve adjustments and their functional significance in relation to white adipocyte secretory products.

Topics: Adipose Tissue; Animals; Biomarkers; Epididymis; Fasting; Frozen Sections; Immunohistochemistry; Male; Microscopy, Confocal; Neuropeptide Y; Norepinephrine; Organ Specificity; Rats; Rats, Sprague-Dawley; Retroperitoneal Space; Sympathetic Nervous System; Time Factors; Tyrosine 3-Monooxygenase; Ubiquitin Thiolesterase; Weight Loss

C75, a recently derived compound that potently suppresses feeding and induces weight loss, has been proposed to act mainly by inhibiting fatty acid synthase (FAS) in central neurons that control feeding. For example, normal, fasting- associated, hypothalamic increases in neuropeptide Y (NPY)/Agouti-related protein (AGRP) expression and decreases in proopiomelanocortin (POMC)/cocaine and amphetamine regulated transcript (CART) expression were reported to be blocked by C75. Using loose-patch extracellular recording in acute slices, we tested the effect of C75 on anorexigenic POMC neurons and orexigenic NPY neurons of the hypothalamic arcuate nucleus, which were identified by promoter-driven GFP expression, as well as on feeding-unrelated cerebellar Purkinje neurons. We expected C75 to activate POMC neurons, inhibit NPY neurons, and have no effect on Purkinje neurons. Instead, C75 activated all cell types, suggesting that it lacks target specificity. This activation was probably not caused by FAS inhibition, because the classical FAS inhibitor, cerulenin, did not have this effect when tested on POMC and NPY neurons. Nonspecific neuronal activation and resulting neurological effects might contribute to the decreased feeding reported to follow centrally administered C75. Injection, i.p., of C75 induced severe loosening or liquefaction of stools, weight loss, and decreased food intake in both wild-type and melanocortin-4 receptor knockout mice. In contrast, cerulenin failed to loosen stools, even at a molar dose over 9-fold greater than C75, and had a much smaller effect on body weight. FAS inhibitory activity, by itself, seems to be insufficient to reproduce all of the effects of i.p.-injected C75.

Topics: 4-Butyrolactone; Action Potentials; Animals; Arcuate Nucleus of Hypothalamus; Eating; Fatty Acid Synthases; Feces; Female; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Neuropeptide Y; Patch-Clamp Techniques; Pro-Opiomelanocortin; Purkinje Cells; Weight Loss

Effects of Roux-en-Y gastric bypass (RYGB) on hypothalamic food intake regulation have not been investigated. The hypothalamic arcuate nucleus (ARC) and the magnocellular (m) and parvocellular (p) parts of the paraventricular nucleus (PVN) regulate hunger and satiety, and are under control of the orexigenic neuropeptide Y (NPY), and the anorexigenic alpha-melanocyte stimulating hormone (alpha-MSH) and serotonin (5-HT). We hypothesized that after RYGB, weight loss is associated with hypothalamic down regulation of NPY and up regulation of 5-HT and alpha-MSH.. Obesity was induced in 12 Sprague Dawley rats using a high-energy diet for 7 weeks, and then the rats were divided into three groups (n = 4/group): RYGB, sham-operated pair-fed (PF), and sham-operated ad libitum (obese control). Ten days after operation, immunohistochemical quantification of NPY, alpha-MSH, and 5-HT(1B)-receptors in ARC and PVN was performed. Data were analyzed using ANOVA and Tukey's test.. Body weight decreased in RYGB (417 +/- 21 g; mean +/- SE) and in PF (436 +/- 14 g) rats 10 days after operation compared with obese control rats (484 +/- 15 g; p < 0.05 for each comparison). NPY in ARC, pPVN, and mPVN decreased by 43%, 43%, and 61%, respectively in RYGB and by 55%, 42%, and 71% in PF, respectively, compared with obese controls (p < 0.05 for each pairwise comparison). RYGB versus PF did not show differences. alpha-MSH in ARC, pPVN and mPVN increased by 35%, 175%, and 67%, respectively in RYGB and by 29%, 162%, and 116% in PF, respectively, compared with obese controls (each p < 0.05). In mPVN, alpha-MSH significantly decreased by 23% in RYGB versus PF (p < 0.05). 5-HT-(1B)-receptor in pPVN increased by 58% in RYGB and by 26% in PF, compared with obese controls (p < 0.05). Compared with obese controls, 5HT-(1B)-receptor in mPVN increased by 39% in RYGB (p < 0.05) and by 9% in PF (p > 0.05). An increase of 5-HT-(1B)-receptor in pPVN and mPVN occurred in RYGB versus PF (p < 0.05).. Obese rats that undergo weight loss after RYGB demonstrate changes in hypothalamic down regulation of NPY and up regulation of alpha-MSH and serotonin.

Topics: Anastomosis, Roux-en-Y; Animals; Arcuate Nucleus of Hypothalamus; Down-Regulation; Gastric Bypass; Male; Melanocyte-Stimulating Hormones; Neuropeptide Y; Obesity; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Serotonin; Up-Regulation; Weight Loss

Orlistat is an inhibitor of lipase which splits triglycerides into free fatty acides and glycerol. This drug, by inhibiting hydrolysis of triglycerides, is the cause of significant loss of fat in the faeces. 13 obese and 15 nonobese subjects were examined. Obese subjects received orlistat (Xenical, F. Hoffmann La Roche Ltd, Switzerland) 3 x 120 mg/d. Treatment with orlistat for 16 weeks was followed by a significant fall of BMI and MAP, insulinemia, insulin/glucose ratio, leptinemia, serum total cholesterol, triglycerides, HDL-cholesterol and 25-OH-D concentration respectively. Orlistat did not influence significantly serum LDL-cholesterol concentration but unexpectedly increased plasma levels of folic acid, vitamin B12 and NPY.. (1) Monitoring of plasma 25-OH-D levels in obese patients on orlistat therapy seems to be mandatory. (2) In spite of significant changes (in opposite direction) in leptinemia and serum NPY level observed in obese subjects treated with orlistat, presence of a functional relationship between these hormones could not be confirmed.

Topics: Adult; Anti-Obesity Agents; Blood Glucose; Carbohydrates; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Enzyme Inhibitors; Female; Hormones; Humans; Hypercholesterolemia; Hyperlipidemias; Insulin; Lactones; Leptin; Lipase; Lipids; Male; Neuropeptide Y; Obesity; Orlistat; Poland; Time Factors; Treatment Outcome; Triglycerides; Vitamins; Weight Loss

We investigated the effect of repetitive postnatal (2-7 days) intracerebroventricular administration of neuropeptide Y (NPY) on food intake and body weight gain in the 3- to 120-day-old Sprague-Dawley rats. NPY caused a 32% transient increase in body weight gain with elevated circulating insulin concentrations within 24 h. This early intervention led to the persistence of hyperinsulinemia and relative hyperleptinemia with euglycemia in the 120-day-old female alone. This perturbation was associated with 50% suppression in adult female hypothalamic NPY concentrations and a 50-85% decline in NPY immunoreactivity in the paraventricular and arcuate nuclei. This change was paralleled by a approximately 20% decline in food intake and body weight gain at 60 and 120 days. However, when exogenous NPY was stereotaxically reinjected into the paraventricular nucleus of the approximately 120-day-old adult females who were pretreated with NPY postnatally, an increase in food intake and body weight gain was noted, attesting to no disruption in the NPY end-organ responsivity. We conclude that postnatal intracerebroventricular NPY has long-lasting effects that predetermine the resultant adult phenotype in a sex-specific manner.

Topics: Aging; Animals; Animals, Newborn; Blood Glucose; Feeding Behavior; Female; Hypothalamus; Immunohistochemistry; Injections, Intraventricular; Insulin; Leptin; Luteinizing Hormone; Male; Neuropeptide Y; Organ Size; Pregnancy; Rats; Rats, Sprague-Dawley; Sex Characteristics; Time Factors; Weight Loss

Topics: Agouti-Related Protein; alpha-MSH; Animals; Anti-Obesity Agents; Appetite; Arcuate Nucleus of Hypothalamus; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Cyclobutanes; Energy Intake; Ghrelin; Humans; Hunger; Intercellular Signaling Peptides and Proteins; Lactones; Leptin; Mice; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Obesity; Orlistat; Peptide Fragments; Peptide Hormones; Peptide YY; Phentermine; Proteins; Receptors, Corticotropin; Receptors, Melanocortin; Weight Loss

Many hypothalamic neuropeptides are involved in the regulation of energy homeostasis and feeding behavior. We have investigated whether and to what extent neuropeptide Y (NPY), agouti-related protein (AGRP), melanin-concentrating hormone (MCH), and prepro-orexin (prepro-OX) as well as pro-opiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) mRNA levels are affected in rat hypothalamus. An experimental model of long-term fasting rat characterized by three metabolic phases from changes in lipid and protein utilization was used. Except for prepro-OX and compared to fed group, starvation induced an increase in the orexigenic gene expressions that was much more marked in phase 3 (by 2.5-, 8.1-, and 13.5-fold for MCH, AGRP, and NPY, respectively) than in phase 2 (by about 1.5-2.2-fold as an average) of fasting. AGRP and NPY mRNA levels were inversely related to body fat content. Anorexigenic gene expression was only slightly affected at both fasting stages. We conclude that the regulation of NPY and AGRP gene expression is primarily involved during late fasting and could mediate the concomitant enhanced drive for refeeding.

Topics: Adipose Tissue; Agouti-Related Protein; Animals; Fasting; Gene Expression Regulation; Hypothalamic Hormones; Hypothalamus; Intercellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins; Kinetics; Male; Melanins; Nerve Tissue Proteins; Neuropeptide Y; Neuropeptides; Nitrogen; Orexins; Pituitary Hormones; Pro-Opiomelanocortin; Protein Biosynthesis; Protein Precursors; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Weight Loss

Topiramate is currently used in the treatment of epilepsy, but this anticonvulsant drug has also been reported to exert mood-stabilizing effects and induce weight loss in patients. Neuropeptide Y (NPY) is abundantly and widely distributed in the mammalian central nervous system and centrally administered NPY markedly reduces pharmacologically induced seizures and induces antidepressant-like activity as well as feeding behavior. Two other peptides, galanin and corticotropin-releasing hormone (CRH), have also been proposed to play a modulatory role in mood, appetite, and seizure regulation. Consequently, we investigated the effects of single and repeated topiramate (10 days, once daily: 40 mg/kg i.p.) or vehicle treatment in 'depressed' flinders sensitive line (FSL) and control Flinders resistant line (FRL) rats on brain regional peptide concentrations of NPY, galanin, and CRH. The handling associated with repeated injections reduced hippocampal levels of NPY- and galanin-like immunoreactivities (LI) while NPY- and CRH-LI levels were increased in the hypothalamus, regardless of strain or treatment. In the hippocampus, concentrations of NPY-LI, galanin-LI, and CRH-LI were lower in FSL than FRL animals. Repeated topiramate treatment selectively normalized NPY-LI in this region in the FSL animals. In the hypothalamus, galanin-LI was reduced in FSL compared to FRL animals. Topiramate elevated the hypothalamic concentrations of NPY-LI, CRH-LI, and galanin-LI in both strains. Furthermore, topiramate elevated serum leptin but not corticosterone levels. The present findings show that topiramate has distinct effects on abnormal hippocampal levels of NPY, with possible implications for its anticonvulsant and mood-stabilizing effects. Furthermore, stimulating hypothalamic NPY-LI, CRH-LI and galanin-LI as well as serum leptin levels may be associated with the weight loss-inducing effects of topiramate.

Topics: Affect; Animals; Anticonvulsants; Corpus Striatum; Corticosterone; Corticotropin-Releasing Hormone; Depression; Disease Models, Animal; Drug Administration Schedule; Frontal Lobe; Fructose; Galanin; Hippocampus; Hypothalamus; Leptin; Male; Neuropeptide Y; Occipital Lobe; Radioimmunoassay; Rats; Rats, Inbred Strains; Species Specificity; Topiramate; Weight Loss

The present study was conducted in order to analyze the relationship existing between leptin, insulin and neuropeptide Y (NPY) levels in massive weight loss and weight recovery. Twenty-three patients with severe obesity, 23 patients with anorexia nervosa and 28 healthy control subjects were studied. Patients with severe obesity underwent a vertical banded gastroplasty followed by an 800 kcal/day diet during 16 weeks, with evaluation taking place before (Body mass index, BMI, 52,1 8 Kg/m2) and after the drastic weight loss (BMI 39,2 6,2 Kg/m2). Patients with anorexia nervosa were treated with nutritional therapy exclusively during 16 weeks, and they were evaluated in the low weight situation (BMI 15,3 1,7 Kg/m2) and after weight recovery (BMI 18,9 2,8 Kg/m2). Normal subjects had a normal BMI from 20 to 27 (average 21,8 2 Kg/m2). BMI, percentage of body fat, and serum levels of leptin, insulin, and NPY, were determined in each patient and normal subjects. In severe obese patients serum leptin and insulin decreased significantly after drastic weight reduction (leptin: from 48,8 19,2 to 24,3 9,8 ng/ml; insulin: from 26,2 10,8 to 18 6 U/ml). In patients with anorexia nervosa serum leptin mean levels were significantly higher after weight recovery (3,7 1,9 vs 9,2 5,1 ng/ml). In subjects with morbid obesity NPY levels decreased after weight loss below those of control group (43,5 16,1 vs 57,3 12,8 pmol/l). On the other hand, patients with anorexia nervosa had NPY levels superior to those of control group. In subjects with anorexia, NPY levels decreased after weight recovery (69,1 16,7 a 59,1 20,3 pmol/l). In the whole population, Leptin and NPY plasma levels were correlated with body fat percentage. Leptin was positively correlated with BMI and body fat percentage in obese and anorectic subjects after weight loss or recovery, respectively. NPY was inversely correlated with body fat percentage in controls and obese subjects before treatment. These data reveal that the concentration of serum leptin and NPY correlates significantly with the total adiposity in subjects with a wide weight range and caloric intake. Leptin plasma levels are proportional to fat stores in patients with severe obesity and anorexia nervosa after drastic weight loss or recovery, respectively. NPY serum levels are negatively correlated with de total body fat in normal weight subjects and obese patients in their initial weight.

Topics: Adult; Anorexia Nervosa; Anthropometry; Body Composition; Body Mass Index; Combined Modality Therapy; Diet, Reducing; Female; Gastroplasty; Humans; Insulin; Leptin; Male; Middle Aged; Neuropeptide Y; Obesity, Morbid; Radioimmunoassay; Recurrence; Weight Gain; Weight Loss

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

The anorexia of aging syndrome in humans is characterized by spontaneous body weight loss reflecting diminished food intake. We reported previously that old rats undergoing a similar phenomenon of progressive weight loss (i.e., senescent rats) also display altered feeding behavior, including reduced meal size and duration. Here, we tested the hypothesis that blunted responsiveness to neuropeptide Y (NPY), a feeding stimulant, occurs concurrently with senescence-associated anorexia/hypophagia. Young (8 mo old, n = 9) and old (24-30 mo old, n = 11) male Fischer 344 rats received intracerebroventricular NPY or artificial cerbrospinal fluid injections. In response to a maximum effective NPY dose (10 microg), the net increase in size of the first meal after injection was similar in old weight-stable (presenescent) and young rats (10.85 +/- 1.73 and 12.63 +/- 2.52 g/kg body wt (0.67), respectively). In contrast, senescent rats that had spontaneously lost approximately 10% of body weight had significantly lower net increases at their first post-NPY meal (1.33 +/- 0.33 g/kg body wt (0.67)) than before they began losing weight. Thus altered feeding responses to NPY occur in aging rats concomitantly with spontaneous decrements in food intake and body weight near the end of life.

Topics: Aging; Angiotensin II; Animals; Body Weight; Cerebral Ventricles; Dose-Response Relationship, Drug; Energy Intake; Feeding Behavior; Humans; Injections, Intraventricular; Male; Neuropeptide Y; Rats; Rats, Inbred F344; Time Factors; Weight Gain; Weight Loss

To assess the dominance between hypoinsulinemia and hypoleptinemia as factors in the development of hyperphagia in streptozotocin (STZ)-induced diabetes mellitus (STZ-DM) rodents with respect to hormone-neuropeptide interactions, changes in gene expression of agouti gene-related protein (AGRP) in the arcuate nucleus of the hypothalamus were investigated using STZ-DM rats, fasting Zucker fa/fa rats and STZ-DM agouti (STZ-DM A(y)/a) mice. AGRP mRNA and neuropeptide Y mRNA were both significantly up-regulated in STZ-DM rats, which are associated with body weight loss, hyperglycemia, hypoinsulinemia and hypoleptinemia. We proceeded to analyze whether insulin or leptin played the greater role in the regulation of AGRP using Zucker fa/fa rats. The AGRP mRNA did not differ significantly between fasted fa/fa rats, which have both leptin-insensitivity and hypoinsulinemia, and fed Zuckers, which have leptin-insensitivity and hyperinsulinemia. We further found that up-regulation of AGRP expression was normalized by infusion of leptin into the third cerebroventricle (i3vt), but not by i3vt infusion of insulin, although up-regulation of AGRP was partially corrected by systemic insulin infusion. The latter finding supports hypoleptinemia as a key-modulator of STZ-DM-induced hyperphagia because systemic insulin infusion, at least partially, restored hypoleptinemia through its acceleration of fat deposition, as demonstrated by the partial recovery of lost body weight. After STZ-DM induction, A(y)/a mice whose melanocortin-4 receptor (MC4-R) was blocked by ectopic expression of agouti protein additionally accelerated hyperphagia and up-regulated AGRP mRNA, implying that the mechanism is triggered by a leptin deficit rather than by the main action of the message through MC4-R. Hypoleptinemia, but not hypoinsulinemia per se, thus develops hyperphagia in STZ-DM rodents. These results are very much in line with evidence that hypothalamic neuropeptides are potently regulated by leptin as downstream targets of its actions.

Topics: Agouti Signaling Protein; Animals; Blood Glucose; Cerebral Ventricles; Diabetes Mellitus, Experimental; Feeding Behavior; Food Deprivation; Gene Expression Regulation; Hyperphagia; Hypothalamus; Infusions, Parenteral; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptide Y; Protein Precursors; Proteins; Rats; Rats, Wistar; Rats, Zucker; RNA, Messenger; Transcription, Genetic; Weight Loss

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

The objective was to determine the effect of central infusion of insulin and (or) glucose on hypothalamic expression of leptin receptor and pituitary secretion of LH in the ewe. Twenty-two ovariectomized ewes (32 wk of age) were fitted with two lateral cerebroventricular (LCV) cannulae and fed 33% of NRC requirements for 8 wk. Ewes (n> or =5/group) were then infused, via LCV cannulae, with artificial cerebrospinal fluid (aCSF) or aCSF containing physiological concentrations of insulin (INS), glucose (GLU), or INS + GLU; the mass of each increasing linearly from Day 0 (mass = 0 units/h) to Day 8 (mass of INS = 80 mIU/hr and GLU = 10 mg/hr). Jugular serum was collected every 12 min for 4 hr on Days 0, 2, and 4. Ewes treated with INS or INS + GLU had greater (P<0.06) mean concentrations of LH than aCSF treated ewes on Day 2 (13.8+/-1.8 and 12.5+/-1.3 > 8.0+/-3.3 ng/ml). Furthermore, on Day 4, concentrations of LH in INS treated ewes exceeded that (P<0.07) of aCSF treated ewes (14.8+/-2.0 > 7.4+/-3.0 ng/ml). Expression of NPY mRNA did not differ between treatments (P = 0.87). Leptin receptor mRNA expression was dramatically reduced (P<0.0002) in INS+GLU versus aCSF treated ewes. These data provide evidence to suggest that insulin may be an important component of hypothalamic mechanisms regulating secretion of LH and expression of leptin receptors in undernourished ruminants.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Carrier Proteins; Female; Food Deprivation; Glucose; Hypothalamus; In Situ Hybridization; Injections, Intraventricular; Insulin; Leptin; Luteinizing Hormone; Neuropeptide Y; Ovariectomy; Pituitary Gland; Pulsatile Flow; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Sheep; Weight Loss

With the escalation of obesity-related disease, there is great interest in defining the mechanisms that control appetite and body weight. We have identified a link between anabolic energy metabolism and appetite control. Both systemic and intracerebroventricular treatment of mice with fatty acid synthase (FAS) inhibitors (cerulenin and a synthetic compound C75) led to inhibition of feeding and dramatic weight loss. C75 inhibited expression of the prophagic signal neuropeptide Y in the hypothalamus and acted in a leptin-independent manner that appears to be mediated by malonyl-coenzyme A. Thus, FAS may represent an important link in feeding regulation and may be a potential therapeutic target.

Topics: Acetyl-CoA Carboxylase; Animals; Appetite; Appetite Depressants; Cerulenin; Dose-Response Relationship, Drug; Eating; Enzyme Inhibitors; Fasting; Fatty Acid Synthases; Female; Hypothalamus; Injections, Intraventricular; Leptin; Liver; Male; Malonyl Coenzyme A; Mice; Mice, Inbred BALB C; Neurons; Neuropeptide Y; RNA, Messenger; Weight Loss

A multidisciplinary team may have discovered an important new weapon in the battle of the bulge. On page 2379 of this issue, the team reports that a molecule that is needed for fat synthesis in the body may play a key role in appetite signaling in the brain. Moreover, the investigators produced a synthetic inhibitor of this molecule that spurred a dramatic drop in appetite and weight in mice.

Topics: Animals; Appetite; Appetite Depressants; Brain; Enzyme Inhibitors; Fasting; Fatty Acid Synthases; Humans; Liver; Malonyl Coenzyme A; Mice; Neuropeptide Y; Obesity; RNA, Messenger; Weight Loss

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

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: Adolescent; Adult; Animals; Appetite Depressants; Behavior Therapy; Body Mass Index; Body Weight; Child; Diet, Reducing; Exercise; Female; Humans; Leptin; Male; Mice; Middle Aged; Neuropeptide Y; Obesity; Rats; Sex Factors; United States; Weight Loss

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

The effect of food deprivation on hypothalamic neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) gene expression in the Djungarian hamster was quantified by in situ hybridization. Hamsters housed in short days (SD) for 18 wk decreased body weight by 40% and exhibited 200% increases in both NPY and CRF mRNA when deprived of food for 24 h. Prior gonadectomy in long days (LD) affected neither basal gene expression nor the induction of gene expression by food deprivation. Gene expression in juvenile LD hamsters similar in body weight to SD animals was relatively insensitive to food deprivation of either 24- or 48-h duration or to subsequent refeeding. In juvenile hamsters, food deprivation for 24 but not 48 h decreased ob (obese) gene expression in inguinal but not epididymal white adipose tissue; ob mRNA levels were restored by refeeding. All food-deprived hamsters had reduced plasma insulin concentrations, but plasma cortisol was only elevated in SD food-deprived animals. NPY gene expression was also increased after daily dexamethasone injections in adult LD hamsters. These results suggest that the neuroendocrine consequences of food deprivation in SD Djungarian hamsters are determined by some factor other than absolute body mass such as the size of adipose tissue reserves.

Topics: Animal Feed; Animals; Corticotropin-Releasing Hormone; Cricetinae; Dexamethasone; Food Deprivation; Gene Expression; Glucocorticoids; Hypothalamus; Male; Neuropeptide Y; Obesity; Phodopus; Photoperiod; RNA, Messenger; Weight Loss

NPY has been reported to co-exist within catecholaminergic neurons of the central and peripheral nervous systems. The functional significance in noradrenergic neurons has been related to the vasomotor effects of NPY which complement and interact with NE which is known to have central and peripheral effects on resting metabolic rate (RMR), food intake and body weight of rats. We have studied the effect of chronic peripheral administration of NPY on the metabolic action of NE in obese adult male rats. A group of 20 adult male obese (fa/fa) Zucker rats were acclimated to environmental temperature of either 28 degrees C or 17 degrees C. Each group was divided into 5 subgroups: (I) untreated controls; (II) Carrier-treated Controls; (III) NPY treated; (IV) NE treated and (V) NPY + NE treated. In subgroups II-V, Alzet (2002) osmotic minipumps were implanted under the skin in the interscapular region. Pumps were filled with carrier alone (subgroups II) plus NPY (subgroups III), or NE (subgroups IV), or both (subgroups V). Delivery rates were calculated to be 0.5 microgram/h NPY; 20 micrograms/h NE, extending over a period of 14 days. Starting from day 2, cumulative food intake and cumulative changes in total body weight were measured every two days. RMR of the animals was measured on days 2, 8, and 14 (indirectly as minimal oxygen consumption). On day 15 animals were sacrificed and specimens of the interscapular BAT were fixed for microscopic examination and measurement of the cross-sectional area of the triglyceride droplets as index for tissue activity. In warm environmental conditions the combined treatment with NE and NPY was the only treatment that caused significant reduction of total body weight by inhibiting food intake and enhancing RMR. The involvement of BAT in this function was observed. In the cold environment the NE and NPY together showed similar but less enhancing effect on body weight; this was mainly due to the significant depression of food intake and slight metabolic response. BAT of this group showed significant response to the combined treatment and slight response to the separate treatments with either NE or NPY.

Topics: Adipose Tissue, Brown; Animals; Basal Metabolism; Eating; Infusion Pumps, Implantable; Male; Neuropeptide Y; Norepinephrine; Obesity; Oxygen Consumption; Rats; Rats, Zucker; Temperature; Weight Loss

Manipulation of diet is known to affect the secretion of the gonadotropins and growth hormone (GH). The former are under the direct regulation of hypothalamic gonadotropin-releasing hormone (GnRH) and the latter is under the dual control of GH-releasing hormone (GHRH) and somatostatin (SRIH). At the level of the hypothalamus, both galanin (GAL) and neuropeptide Y (NPY) are thought to regulate the secretion of the above releasing and inhibiting factors. Both peptides are also potent orexigenic agents. We have studied ovariectomised ewes that were either well-fed (HIGHs) or underfed (LOWs) and used immunocytochemistry and image analysis to measure the levels of GAL and NPY in hypothalamic nuclei in which GnRH, GHRH and SRIH are found and which are also involved in the regulation of appetite and feeding. The sheep were given a normal diet or a restricted diet for 15 months. Four pairs of ewes were then blood-sampled to measure GH, luteinising hormone (LH), and follicle-stimulating hormone (FSH) and then killed for recovery of the brains. After perfusion, cryostat sections were cut through the entire hypothalamus, mounted, and stained fro NPY or GAL. All treatments and analyses were performed in pairs. The number of immunoreactive cells, density of terminals and total immunoreactivity (IR) were quantified by image analysis by sampling 6-16 subareas (depending on region) on sections through the pre-optic area (POA), paraventricular nucleus (PVN), arcuate nucleus (ARC) and median eminence (ME). Mean (+/- SEM) live weight of the LOWs was significantly (p < 0.0001) lower than that of the HIGHs (37.6 +/- 0.6 kg vs. 60.6 +/- 0.5 kg). There was no difference in the plasma levels of LH and FSH but the area under the GH curve (ng/ml/h) was significantly (p < 0.0001) greater in the LOWs (320 +/- 40.9 vs. 67.3 +/- 16.1). There was an increased number of cells staining for NPY but not GAL in the ARC/ME of the LOWs. Nevertheless, the oveall level of immunostaining for both peptides was increased in the LOWs. GAL IR was restricted to the mediobasal hypothalamus. In the LOWs, the density of NPY terminal fields in each area of the ARC was significantly (p < 0.05) increased. Food restriction also increased the density of NPY terminals in the POA and PVN (p < 0.025) but not in the ME. These data indicate that a dietary manipulation which affects GH secretion but not the gonadotropins may be mediated by NPY and GAL neuronal systems in specific brain regions within the hypothala

Topics: Animals; Body Weight; Female; Galanin; Gonadotropins, Pituitary; Growth Hormone; Hypothalamus; Image Processing, Computer-Assisted; Immunohistochemistry; Neuropeptide Y; Ovariectomy; Ovary; Sheep; Time Factors; Weight Loss

Cobalt protoporphyrin (CoPP) reduces food intake and body weight following intracerebroventricular (i.c.v.) administration in rats. We injected 0.2 mumol CoPP per kg body weight i.c.v. and monitored body weight and daily food intake for 7 days. The body weight and 24 h food intake of CoPP-treated animals was significantly lower than that of vehicle-treated animals in all studies (P < 0.01) from day 2 to day 7. The 2 h feeding response (CoPP vs. vehicle-treated) to 10 micrograms neuropeptide Y (NPY) (4.0 vs. 7.1 g; P < 0.05), the 1 h feeding response to 10 micrograms galanin (1.3 vs. 3.2 g; P < 0.05) and 30 micrograms norepinephrine (0.6 vs. 1.9 g; P < 0.05) in CoPP-treated animals were all reduced compared to the vehicle-treated group. In addition there was no change in hypothalamic NPY mRNA in CoPP-treated animals. I.c.v. CoPP decreases sensitivity to exogenous NPY, galanin and norepinephrine. The effect of CoPP is not specific to NPY as previously described.

Topics: Animals; Eating; Male; Neuropeptide Y; Protoporphyrins; Rats; Rats, Wistar; Weight Loss

Anorexia and weight loss produced by estradiol (E2) may involve altered expression of neuropeptide Y (NPY) in the hypothalamus. We tested this hypothesis using ovariectomized (OVX) rats by replacing E2 with SILASTIC brand capsule implants and measuring NPY messenger RNA (mRNA) levels in the arcuate nucleus by in situ hybridization. To equalize the effects of weight loss on NPY mRNA expression, E2 deficient OVX rats were pair-fed (n = 10) for 2 days to an OVX group receiving E2 (n = 12). Compared with the weight gain (P < 0.02) of E2 deficient OVX rats (n = 10), OVX rats replaced with E2 and pair-fed OVX rats both had 12.5% lower food intake and weight (P < 0.05). E2 replacement elevated insulin 52% (P < 0.05) and lowered NPY hybridization 32% (P < 0.05) compared with pair-fed controls. During a 2-day fast, E2 replacement (N = 12) attenuated the elevation of NPY mRNA levels 50% (P < 0.01) compared with E2 deficiency (n = 15). Therefore, when E2 is administered to OVX rats, reduced NPY mRNA expression in the hypothalamus is unlikely to be a primary cause of weight loss, although it may contribute to the maintenance of reduced food intake and body weight.

Topics: Animals; Estradiol; Female; Gene Expression Regulation; Hypothalamus; Male; Neuropeptide Y; Ovariectomy; Rats; Rats, Wistar; RNA, Messenger; Weight Loss

Neuropeptide Y is demonstrated as a potent orexigenic peptide when injected into the rat hypothalamic paraventricular nuclei. The neuropeptide Y innervation of paraventricular nuclei originates from both hypothalamic arcuate nuclei and brainstem neurons, whose specific role in the control of food intake is still under discussion. To assess the role of the arcuate neuropeptide Y in the regulation of food intake, we propose a new method for immunologically impairing the neuronal secretion of neuropeptide Y from a unique brain site. The monoclonal antibody to the neuropeptide Y precursor epitope, the C-flanking peptide, was microinjected with two cellular toxins (the ricin A chain and the monensin) into the hypothalamic arcuate nuclei or paraventricular nuclei. One microinjection into the arcuate nuclei reduced the food intake and body weight gain for 10 days. It prevented the food intake stimulation usually induced by a 12 h food deprivation. This decrease of food intake was not due to the aversive properties of monoclonal antibody or cellular toxins, or the immunoneutralization of the biologically active neuropeptide Y, because (i) the acute effect of the microinjection into the arcuate nuclei promoted a transient increase of the food intake likely induced by a strong release of neuropeptide Y from the arcuate neurons which were immunologically damaged, and (ii) the C-flanking peptide monoclonal antibody binds neither neuropeptide Y nor its receptors. The microinjection was inefficient when C-flanking peptide monoclonal antibody was replaced by non-specific rat immunoglobulins or when the C-flanking peptide monoclonal antibody/toxins mixture was injected into the paraventricular nuclei. The data bring further arguments in two domains.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antibodies, Monoclonal; Arcuate Nucleus of Hypothalamus; Drinking; Eating; Food Deprivation; Immunoglobulins; Immunotoxins; Male; Microinjections; Neurons; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Rats; Ricin; Weight Loss

Tolerance to the anorectic effect of dexfenfluramine (DFEN) is shown in rats treated either chronically with low doses or once with a high dose of the agent. Rats given DFEN regimens that result in complete loss of DFEN anorexia showed no change in the anorexia caused by peripheral injection of cholecystokinin (CCK). The orexigenic effects of metergoline and neuropeptide Y were also unaltered as a function of DFEN pretreatment. Both the magnitude and duration of tolerance to a test dose of DFEN seemed to depend, in part, upon contingent (situational) factors, and were independent of whether brain serotonin (5-HT) measures were either unaffected or decreased by the DFEN pretreatment (low and high doses, respectively).

Topics: Animals; Appetite Depressants; Brain; Brain Chemistry; Cholecystokinin; Drug Tolerance; Eating; Female; Fenfluramine; Food Deprivation; Male; Metergoline; Neuropeptide Y; Paroxetine; Rats; Rats, Sprague-Dawley; Serotonin; Weight Loss

Neuropeptide Y (NPY) is a potent central appetite stimulant whose concentrations rise markedly in hypothalamic appetite-regulating regions in food-deprived rats. To determine whether increased energy expenditure also affects hypothalamic NPY, we studied the effects of intense physical exercise in rats (n = 10) running voluntarily on a large-diameter exercise wheel. Running was initiated by restricting food intake but stabilized at an average of 8 km/day when food intake was matched to that in 11 nonexercised, freely fed controls [23.9 +/- 1.9 (SE) g/day vs. 24.7 +/- 1.3 g/day; P > 0.5]. Running expended approximately 40% of daily energy intake, and weight gain was significantly inhibited. A separate group (n = 10) of nonexercised rats was food restricted (approximately 15 g/day) to match the weights of the exercised rats. The rats were killed after 40 days, when both experimental groups weighed 30% less than controls (P < 0.01). Hypothalamic NPY concentrations showed significant (P < 0.01) increases of 30-70% in specific regions (arcuate and dorsomedial nuclei and medial preoptic and lateral hypothalamic areas) in both the running and food-restricted groups, compared with controls. There were no significant differences between the two experimental groups in NPY concentrations in any hypothalamic region. These findings suggest that negative energy balance, whether caused by reduced energy intake or increased expenditure, increases hypothalamic NPYergic activity. As NPY acts on the hypothalamus to increase body weight, these data support the postulated homeostatic role of NPY in maintaining nutritional state.

Topics: Animals; Food Deprivation; Hypothalamus; Male; Neuropeptide Y; Osmolar Concentration; Physical Exertion; Rats; Rats, Inbred Strains; Tissue Distribution; Weight Loss

The mechanism whereby neurally or peripherally administered cobalt-protoporphyrin (CoPP) leads to transient hypophagia and prolonged weight reduction in normal and genetically obese animals is unknown. Neuropeptide Y (NPY) is a known endogenous stimulator of feeding behavior and is elevated in the hypothalamus of food-deprived rats. Accordingly, we examined the interaction between CoPP and NPY in the central nervous system. Concentrations of NPY mRNA in the hypothalami of rats treated intracerebroventricularly with vehicle or CoPP responded to decreased food intake with comparable increases. However, intracerebroventricular infusions of NPY elicited increased intake of food in vehicle-treated rats but were without effect in CoPP-treated animals. The results suggest that CoPP acts, at least in part, by blocking the feeding response to NPY.

Topics: Animals; Blotting, Northern; Feeding Behavior; Food Deprivation; Gene Expression; Hypothalamus; Male; Microinjections; Neuropeptide Y; Protoporphyrins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Weight Loss

These studies demonstrate that the competitive antagonist of nitric oxide synthesis, L-NG-nitro-arginine methyl ester (NO Arg ME), produces an L-arginine reversible decrease in food intake in mice. NO Arg ME also blocked the feeding effect of the potent orexigenic peptide, neuropeptide Y. NO Arg ME produced weight loss when administered over 5 days. The studies suggest that nitric oxide is a physiological modulator of food intake and that nitric oxide synthetase inhibitors may be useful in the management of obesity.

Topics: Amino Acid Oxidoreductases; Analysis of Variance; Animals; Appetite Depressants; Appetite Regulation; Arginine; Dose-Response Relationship, Drug; Injections, Intraventricular; Male; Mice; Mice, Inbred Strains; Neuropeptide Y; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Weight Loss

Neuropeptide Y (NPY) is a major hypothalamic peptide which is implicated in the regulation of energy balance and in the activation of the hypothalamo-pituitary adrenal axis. This study aimed primarily to determine the effects on regional hypothalamic NPY levels, of catabolism and weight loss induced in rats by the synthetic glucocorticoid, dexamethasone, injected daily at a dose of 0.4 mg/kg for 7 days. NPY concentrations were significantly raised in the paraventricular nucleus (PVN) of male Wistar rats (45%, p = 0.009; n = 10) compared with saline-injected controls (n = 10). Body weight (p less than 0.001) and food intake (p less than 0.001) were significantly reduced, plasma insulin concentrations were increased (p less than 0.001), but there was no change in glucose concentrations. Chronic dexamethasone treatment did not cause the marked NPY increases in the arcuate nucleus (ARC) and other hypothalamic regions which have been observed in other catabolic states causing weight loss. One possible explanation is the high insulin levels induced by dexamethasone, which may have prevented compensatory hyperphagia by suppressing an increase in hypothalamic NPYergic activity. We also examined the acute effects of a single dexamethasone injection on regional hypothalamic levels, to determine whether the drug had a direct action separate from that due to sustained weight loss. In the acute study, groups of rats (n = 7) were examined at 4 h after a single injection of dexamethasone or saline. NPY concentrations were significantly increased in the lateral hypothalamic area (LHA), (60%, p = 0.008) when compared with saline-injected controls, but there was no change in body weight or glucose or insulin concentrations during the 4h interval. Altered transport or release of NPY in the lateral hypothalamic area may be a result of acute feedback regulation by glucocorticoids on the hypothalamus.

Topics: Analysis of Variance; Animals; Blood Glucose; Dexamethasone; Hypothalamus; Insulin; Male; Neuropeptide Y; Rats; Rats, Wistar; Weight Loss

Central and lateral hypothalamic concentrations of 9 regulatory peptides implicated in the control of feeding behaviour were measured in corpulent (cp/cp) JCR:LA-cp rats which develop spontaneous obesity, hyperinsulinaemia and hyperlipidaemia, and in lean (+/?) controls. In female cp/cp rats, central hypothalamic levels of neuropeptide Y (NPY), neurotensin, somatostatin and substance P were significantly lower (p less than 0.02) than in lean female controls. Following food restriction with a 16% reduction in body weight, these differences were apparently reversed and there were also significant rises in the lateral hypothalamic concentrations of neurotensin and of galanin. The other 4 peptides examined (bombesin, calcitonin gene-related peptide, neuromedin B and vasoactive intestinal peptide) did not differ significantly between cp/cp and lean females, either fed freely or food-restricted. Male cp/cp rats showed no significant differences from lean males in central or lateral hypothalamic concentrations of any of the 9 peptides. NPY and galanin are powerful and specific central appetite stimulants, whereas neurotensin, substance P and somatostatin inhibit feeding when injected centrally. Disturbances in these putative appetite-regulating peptides may be involved in the hyperphagia and other hypothalamic abnormalities in this spontaneous obesity syndrome. The apparent absence of differences between the male corpulent and lean groups may relate to sexual dimorphism of the syndrome, which is more marked in the females.

Topics: Animals; Diet, Reducing; Female; Galanin; Hypothalamus; Insulin; Neuropeptide Y; Neuropeptides; Neurotensin; Obesity; Organ Specificity; Peptides; Rats; Rats, Mutant Strains; Reference Values; Somatostatin; Substance P; Weight Loss