The efficacy of Roux-en-Y gastric-bypass (RYGB) and other bariatric surgeries in the management of obesity and type 2 diabetes mellitus and novel developments in gastrointestinal (GI) endocrinology have renewed interest in the roles of GI hormones in the control of eating, meal-related glycemia, and obesity. Here we review the nutrient-sensing mechanisms that control the secretion of four of these hormones, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide tyrosine tyrosine [PYY(3-36)], and their contributions to the controls of GI motor function, food intake, and meal-related increases in glycemia in healthy-weight and obese persons, as well as in RYGB patients. Their physiological roles as classical endocrine and as locally acting signals are discussed. Gastric emptying, the detection of specific digestive products by small intestinal enteroendocrine cells, and synergistic interactions among different GI loci all contribute to the secretion of ghrelin, CCK, GLP-1, and PYY(3-36). While CCK has been fully established as an endogenous endocrine control of eating in healthy-weight persons, the roles of all four hormones in eating in obese persons and following RYGB are uncertain. Similarly, only GLP-1 clearly contributes to the endocrine control of meal-related glycemia. It is likely that local signaling is involved in these hormones' actions, but methods to determine the physiological status of local signaling effects are lacking. Further research and fresh approaches are required to better understand ghrelin, CCK, GLP-1, and PYY(3-36) physiology; their roles in obesity and bariatric surgery; and their therapeutic potentials.

Several sex differences in eating, their control by gonadal steroid hormones and their peripheral and central mediating mechanisms are reviewed. Adult female rats and mice as well as women eat less during the peri-ovulatory phase of the ovarian cycle (estrus in rats and mice) than other phases, an effect under the control of cyclic changes in estradiol secretion. Women also appear to eat more sweets during the luteal phase of the cycle than other phases, possibly due to simultaneous increases in estradiol and progesterone. In rats and mice, gonadectomy reveals further sex differences: orchiectomy decreases food intake by decreasing meal frequency and ovariectomy increases food intake by increasing meal size. These changes are reversed by testosterone and estradiol treatment, respectively. A variety of peripheral feedback controls of eating, including ghrelin, cholecystokinin (CCK), glucagon, hepatic fatty acid oxidation, insulin and leptin, has been shown to be estradiolsensitive under at least some conditions and may mediate the estrogenic inhibition of eating. Of these, most progress has been made in the case of CCK. Neurons expressing estrogen receptor-a in the nucleus tractus solitarius of the brainstem appear to increase their sensitivity to CCK-induced vagal afferent input so as to lead to an increase in the satiating potency of CCK, and consequently decreased food intake, during the peri-ovulatory period in rats. Central serotonergic mechanisms also appear to be part of the effect of estradiol on eating. The physiological roles of other peripheral feedback controls of eating and their central mediators remain to be established.

(HPG) axis function fundamentally affects the physiology of eating. We review sex differences in the physiological and pathophysiological controls of amounts eaten in rats, mice, monkeys, and humans. These controls result from interactions among genetic effects, organizational effects of reproductive hormones (i.e., permanent early developmental effects), and activational effects of these hormones (i.e., effects dependent on hormone levels). Male-female sex differences in the physiology of eating involve both organizational and activational effects of androgens and estrogens. An activational effect of estrogens decreases eating 1) during the periovulatory period of the ovarian cycle in rats, mice, monkeys, and women and 2) tonically between puberty and reproductive senescence or ovariectomy in rats and monkeys, sometimes in mice, and possibly in women. Estrogens acting on estrogen receptor-␣ (ER␣) in the caudal medial nucleus of the solitary tract appear to mediate these effects in rats. Androgens, prolactin, and other reproductive hormones also affect eating in rats. Sex differences in eating are mediated by alterations in orosensory capacity and hedonics, gastric mechanoreception, ghrelin, CCK, glucagon-like peptide-1 (GLP-1), glucagon, insulin, amylin, apolipoprotein A-IV, fatty-acid oxidation, and leptin. The control of eating by central neurochemical signaling via serotonin, MSH, neuropeptide Y, Agouti-related peptide (AgRP), melanin-concentrating hormone, and dopamine is modulated by HPG function. Finally, sex differences in the physiology of eating may contribute to human obesity, anorexia nervosa, and binge eating. The variety and physiological importance of what has been learned so far warrant intensifying basic, translational, and clinical research on sex differences in eating.neuroendocrinology; estrogens; testosterone; eating disorders; obesity SEX DIFFERENCES ARE PERVASIVE in physiology and medicine (51,64,73,109,110,466,797,826). The controls of eating and energy homeostasis are no exceptions. It was observed approximately 100 years ago that removal of the ovaries leads to marked accretion of adipose tissue in rats (697), that daily food intake expressed as kilocalories per gram body weight differs between male and female rats (778), and that food intake varies regularly through the ovarian cycle in intact female rats (674, 779). Sex differences in eating have been the subject of physiological research ever since. The clinical relevance of this work is increasingly evident. In the United States, women are approximately threefold more vulnerable than men to psychiatric eating disorders (346,351) and approximately twofold more vulnerable to severe and morbid obesity (BMI Ն 35 and 40 kg/m 2 , respectively, mass/height 2 ) (226). Women also appear to suffer more from these disorders in terms of physical and psychological functioning and quality of life (24,84,273,292,465,531,762). The increased obesity burden suffered by women is reflected in the fact that Ͼ80% of bariatric surgery patients in the U...

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The markedly greater obesity burden in women makes understanding the diverse effects of ovarian hormones on eating, EE and body adiposity urgent research challenges. A variety of research modalities can be used to investigate these effects in women, and most of the mechanisms reviewed are accessible in animal models. Therefore, human and translational research on the roles of ovarian hormones in women's obesity and its causes should be intensified to gain further mechanistic insights that may ultimately be translated into novel anti-obesity therapies and thereby improve women's health.

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17beta-estradiol (E2), acting via estrogen receptor (ER)-alpha, inhibits feeding in animals. One mechanism apparently involves an increase in the satiating potency of cholecystokinin (CCK) released from the small intestine by ingested food. For example, the satiating potency of intraduodenal lipid infusions is increased by E2 in ovariectomized rats; this increased satiation is dependent on CCK, and it is accompanied by increases in the numbers of ERalpha-positive cells that express c-Fos in a subregion of the caudal nucleus tractus solitarius (cNTS) that receives abdominal vagal afferent projections. To test whether direct administration of E2 to this area of the hindbrain is sufficient to inhibit food intake, we first implanted 0.2 microg estradiol benzoate (EB) in cholesterol or cholesterol alone either sc or onto the surface of the hindbrain over the cNTS. Food intake was significantly reduced after hindbrain EB implants but not after sc EB implants. Next we verified that equimolar hindbrain implants of E2 and EB had similar feeding-inhibitory effects and determined that only small amounts of E2 reached brain areas outside the dorsal caudal hindbrain after hindbrain implants of (3)H-labeled E2. Neither plasma estradiol concentration nor plasma inflammatory cytokine concentration was increased by either hindbrain or sc EB implants. Finally, hindbrain EB implants, but not sc implants, increased c-Fos in ERalpha-positive cells in the cNTS after ip injection of 4 microg/kg CCK-8. We conclude that E2, acting via ERalpha in cNTS neurons, including neurons stimulated by ip CCK, is sufficient to inhibit feeding.