Peptide YY ] is a hormone that is released after meal ingestion that is currently being investigated for the treatment of obesity; however, there are conflicting reports of the effects of PYY (3-36) on energy balance in rodent models. To shed light on this controversy, we studied the effect of PYY (3-36) on food intake and body weight in a nonhuman primate. Intravenous PYY (3-36) infusions before a morning meal transiently suppressed the rate of food intake but did not suppress the evening meal or 24-h intake. Twice-daily or continuous intravenous PYY infusions to supraphysiological levels (levels that exceeded normal physiological levels) again suppressed the rate of feeding for the morning but not the evening meal. Twice-daily intravenous PYY (3-36) infusions for 2 weeks significantly decreased body weight in all test animals (average weight loss 1.9%) without changing insulin response to glucose infusion. These results show that endogenous PYY (3-36) may alter morning but not evening meal intake, and supraphysiological doses are required for effective suppression of food intake. Diabetes 54: 3198 -3204, 2005 T he rising prevalence of obesity in the U.S. and other countries (1,2) is linked to increases in the incidence of obesity-related diseases (diabetes, cardiovascular disease, hypertension, and cancer), elevated health care costs, and reduced quality of life (3,4). The success of pharmacological intervention to reverse trends in obesity demographics depends on a better understanding of the physiology of appetite and body weight regulation. Because of their involvement in the regulation of energy homeostasis, hypothalamic and brainstem systems are major targets for pharmacological treatment of obesity (5,6).The arcuate nucleus of the hypothalamus (ARH) contains two cell types that act antagonistically to regulate energy intake and expenditure: activation of cells that express proopiomelanocortin produces anorectic effects, whereas activation of cells that produce neuropeptide Y (NPY) elicits feeding and energy conservation (7). Ingestion of nutrients causes L-cells in the gastrointestinal tract to release PYY , which is an endogenous ligand for several NPY receptors (Y1, Y2, and Y5) (8). However, a cleavage product of PYY , PYY , is relatively selective for the NPY Y2 receptor (9). The NPY Y2 receptor is expressed in the ARH and other sites and is the dominant inhibitory autoreceptor on NPY neurons (10,11). Evidence of a nonsaturable transport mechanism for PYY across the blood-brain barrier (12), coupled with recent data by Riediger et al. (13) that physiological doses of PYY (1-36) induced c-Fos in the ARH but not the area postrema (in the hindbrain), support the hypothesis that circulating PYY is thought to suppress appetite through inhibition of ARH NPY neurons, but this does not exclude other possible sites of action.Peripheral PYY administration reduces food intake in humans and rodents (14 -16). Although the effects of PYY on gastric emptying are reproducible (17-19), the effectiveness of ...

eron. Individual differences in physical activity are closely associated with changes in body weight in adult female rhesus monkeys (Macaca mulatta). Am J Physiol Regul Integr Comp Physiol 291: R633-R642, 2006. First published April 13, 2006; doi:10.1152/ajpregu.00069.2006.-The increased prevalence of overweight adults has serious health consequences. Epidemiological studies suggest an association between low activity and being overweight; however, few studies have objectively measured activity during a period of weight gain, so it is unknown whether low activity is a cause or consequence of being overweight. To determine whether individual differences in adult weight gain are linked to an individual's activity level, we measured activity, via accelerometry, over a prolonged period (9 mo) in 18 adult female rhesus monkeys. Weight, food intake, metabolic rate, and activity were first monitored over a 3-mo period. During this period, there was mild but significant weight gain (5.5 Ϯ 0.88%; t ϭϪ6.3, df ϭ 17, P Ͻ 0.0001), whereas caloric intake and activity remained stable. Metabolic rate increased, as expected, with weight gain. Activity level correlated with weight gain (r ϭ Ϫ0.52, P ϭ 0.04), and the most active monkeys gained less weight than the least active monkeys (t ϭ Ϫ2.74, df ϭ 8, P ϭ 0.03). Moreover, there was an eightfold difference in activity between the most and least active monkeys, and initial activity of each monkey was highly correlated with their activity after 9 mo (r ϭ 0.85, P Ͻ 0.0001). In contrast, food intake did not correlate with weight gain, and there was no difference in weight gain between monkeys with the highest vs. lowest caloric intake, total metabolic rate, or basal metabolic rate. We conclude that physical activity is a particularly important factor contributing to weight change in adulthood and that there are large, but stable, differences in physical activity among individuals.exercise; obesity; weight gain; energy balance EPIDEMIOLOGICAL STUDIES INDICATE that body weight and body fat increase through early and middle adulthood such that by late middle age there is an increased percentage of overweight and obese individuals compared with the early adult period (33,57,63,108,115). Weight gain over the adult years has escalated over the past two decades such that 65% of adults in the United States have a body mass index (BMI) above the healthy range (Ͼ25.0 kg/m 2 ) (32). Weight gain and obesity in adulthood have been associated with overall increases in morbidity and mortality (82) and in the risk of diabetes mellitus (23, 33, 53, 115a), gall bladder disease (115a), coronary heart disease (41, 49, 53, 69, 86, 111, 115a), hypertension (53, 115a), stroke (115a), dyslipidemia (115a), osteoarthritis (115a), gout (115a), pulmonary diseases (115a), colon cancer (35), and breast cancer (118).A large body of epidemiologic data shows an association between low levels of physical activity and a higher rate of adult weight gain, and a greater increase in percent body fat, throughout adult...

Central activation of fibroblast growth factor (FGF) receptors regulates peripheral glucose homeostasis and reduces food intake in preclinical models of obesity and diabetes. The current work was undertaken to advance our understanding of the receptor expression, as sites of ligand action by FGF19, FGF21, and FGF1 in the mammalian brain remains unresolved. Recent advances in automated RNAscope in situ hybridization and droplet digital PCR (ddPCR) technology allowed us to interrogate central FGFR/beta klotho (Klb) system at the cellular level in the mouse, with relevant comparisons to nonhuman primate and human brain. FGFR1‐3 gene expression was broadly distributed throughout the CNS in Mus musculus, with FGFR1 exhibiting the greatest heterogeneity. FGFR4 expression localized only in the medial habenula and subcommissural organ of mice. Likewise, Klb mRNA was restricted to the suprachiasmatic nucleus (SCh) and select midbrain and hindbrain nuclei. ddPCR in the rodent hypothalamus confirmed that, although expression levels are indeed low for Klb, there is nonetheless a bonafide subpopulation of Klb+ cells in the hypothalamus. In NHP and human midbrain and hindbrain, Klb + cells are quite rare, as is expression of FGFR4. Collectively, these data provide the most robust central map of the FGFR/Klb system to date and highlight central regions that may be of critical importance to assess central ligand effects with pharmacological dosing, such as the putative interactions between the endocrine FGFs and FGFR1/Klb, or FGF19 with FGFR4.

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SULLIVAN, ELINOR L., ALEJANDRO J. DANIELS, FRANK H. KOEGLER, AND JUDY L. CAMERON. Evidence in female rhesus monkeys (Macaca mulatta) that nighttime caloric intake is not associated with weight gain. Obes Res. 2005;13:2072-2080. Objective: To evaluate the hypothesis that nighttime consumption of calories leads to an increased propensity to gain weight. Research Methods and Procedures: Sixteen female rhesus monkeys (Macaca mulatta) were ovariectomized and placed on a high-fat diet to promote weight gain, and we examined whether monkeys that ate a high percentage of calories at night were more likely to gain weight than monkeys that ate the majority of calories during the day. Results: Within 6 weeks post-ovariectomy, calorie intake and body weight increased significantly (129 Ϯ 14%, p ϭ 0.04; 103 Ϯ 0.91%, p ϭ 0.02, respectively). Subsequent placement on high-fat diet led to further significant increases in calorie intake and body weight (368 Ϯ 56%, p ϭ 0.001; 113 Ϯ 4.0%, p ϭ 0.03, respectively). However, there was no correlation between the increase in calorie intake and weight gain (p ϭ 0.34). Considerable individual variation existed in the percentage of calories consumed at night (6% to 64% total daily caloric intake). However, the percentage of calorie intake occurring at night was not correlated with body weight (r ϭ 0.04; p ϭ 0.87) or weight gain (r ϭ 0.07; p ϭ 0.79) over the course of the study. Additionally, monkeys that showed the greatest nighttime calorie intake did not gain more weight (p ϭ 0.94) than monkeys that showed the least nighttime calorie intake. Discussion: These results show that eating at night is not associated with an increased propensity to gain weight, suggesting that individuals trying to lose weight should not rely on decreasing evening calorie intake as a primary strategy for promoting weight loss.

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In rodents, stimulation of melanocortin-3 and -4 receptor subtypes (MC3-R and MC4-R) causes a reduction in food intake, whereas antagonism of MC3-R and MC4-R increases food intake. This report describes the effects of the stable alphaMSH analog, NDP-MSH ([Nle(4), D-Phe(7)]alphaMSH), and the endogenous alphaMSH receptor antagonist, agouti-related protein, on feeding behavior in adult male rhesus macaques. Infusion of NDP-MSH into the lateral cerebral ventricle dose dependently suppressed intake of a normally scheduled meal without affecting nonfeeding behaviors. Conversely, infusion of agouti-related protein stimulated food intake during the scheduled afternoon meal. In addition to these physiological experiments, the effect of fasting on hypothalamic POMC gene expression was assessed by in situ hybridization. Missing a single meal or fasting for 48 h caused a similar reduction in POMC gene expression in the arcuate nucleus. These results demonstrate that in the primate, central melanocortin receptors can acutely regulate food intake and suggest that the central melanocortinergic system is a physiological regulator of energy balance in primate species.