ABSTRACT. Objective. The prevalence of obesity has increased dramatically in recent years. However, the role of dietary composition in body weight regulation remains unclear. The purpose of this work was to investigate the acute effects of dietary glycemic index (GI) on energy metabolism and voluntary food intake in obese subjects.Methods. Twelve obese teenage boys were evaluated on three separate occasions using a crossover study protocol. During each evaluation, subjects consumed identical test meals at breakfast and lunch that had a low, medium, or high GI. The high-and medium-GI meals were designed to have similar macronutrient composition, fiber content, and palatability, and all meals for each subject had equal energy content. After breakfast, plasma and serum concentrations of metabolic fuels and hormones were measured. Ad libitum food intake was determined in the 5-hour period after lunch.Results. Voluntary energy intake after the high-GI meal (5.8 megajoule [mJ]) was 53% greater than after the medium-GI meal (3.8 mJ), and 81% greater than after the low-GI meal (3.2 mJ). In addition, compared with the low-GI meal, the high-GI meal resulted in higher serum insulin levels, lower plasma glucagon levels, lower postabsorptive plasma glucose and serum fatty acids levels, and elevation in plasma epinephrine. The area under the glycemic response curve for each test meal accounted for 53% of the variance in food intake within subjects.Conclusions. The rapid absorption of glucose after consumption of high-GI meals induces a sequence of hormonal and metabolic changes that promote excessive food intake in obese subjects. Additional studies are needed to examine the relationship between dietary GI and long-term body weight regulation. American Heart Association, 7 and American Diabetes Association 8 currently advocate consumption of a low-fat diet in the prevention and treatment of obesity. Recently, however, the relationship between dietary fat and obesity has been questioned on several grounds 9 -11 including that both cross-sectional and longitudinal analyses have failed to show a consistent association between dietary fat and body fat, 10,12,13 and that weight loss on low-fat diets is usually modest and transient. 9,14 In addition, and perhaps of particular significance, mean fat intake in the United States reportedly has decreased over the past 3 decades, from 42% to ϳ34% of dietary energy, 11,12,15,16 whereas the rate of obesity has continued to rise.Another dietary factor that may influence body weight is the glycemic index (GI). GI a is a property of carbohydrate-containing food that describes the rise of blood glucose occurring after a meal. 17 Foods that are rapidly digested and absorbed or transformed metabolically into glucose have a high GI. 18 -22 The GI of a meal is determined primarily by the amount of carbohydrate consumed and by other dietary factors affecting food digestibility, gastrointestinal motility, or insulin secretion (including carbohydrate type, food structure, fiber, protein, and fat). ...

Melanocortin receptor accessory proteins (MRAPs) modulate signaling of melanocortin receptors in vitro. To investigate the physiological role of brain-expressed Melanocortin 2 Receptor Accessory Protein 2 (MRAP2), we characterized mice with whole body and brain-specific targeted deletion of Mrap2, both of which develop severe obesity at a young age. Mrap2 interacts directly with Melanocortin 4 Receptor (Mc4r), a protein previously implicated in mammalian obesity, and it enhances Mc4r-mediated generation of the second messenger cyclic AMP, suggesting that alterations in Mc4r signaling may be one mechanism underlying the association between Mrap2 disruption and obesity. In a study of humans with severe, early-onset obesity, we found four rare, potentially pathogenic genetic variants in MRAP2, suggesting that the gene may also contribute to body weight regulation in humans.

The body responds to stress by activation of the hypothalamic-pituitary-adrenal (HPA) axis and release of glucocorticoids. Glucocorticoid production in the adult regulates carbohydrate and amino-acid metabolism, maintains blood pressure, and restrains the inflammatory response. In the fetus, exogenous glucocorticoids accelerate maturation of lung and gastrointestinal enzyme systems and promote hepatic glycogen deposition. Corticotropin-releasing hormone (CRH), a 41-amino-acid neuropeptide produced in the paraventricular nucleus of the hypothalamus and many regions of the cerebral cortex, has been implicated in both the HPA axis and behavioural responses to stress. To define the importance of CRH in the response of the HPA axis to stress and fetal development, we have constructed a mammalian model of CRH deficiency by targeted mutation in embryonic stem (ES) cells. We report here that corticotropin-releasing hormone-deficient mice reveal a fetal glucocorticoid requirement for lung maturation. Postnatally, despite marked glucocorticoid deficiency, these mice exhibit normal growth, fertility and longevity, suggesting that the major role of glucocorticoid is during fetal rather than postnatal life.