Impaired Glucose Tolerance and Reduced Plasma Insulin Precede Decreased AKT Phosphorylation and GLUT3 Translocation in the Hippocampus of Old 3xTg-AD Mice.

Several studies have demonstrated that mouse models of Alzheimer's disease (AD) can exhibit impaired peripheral glucose tolerance. Further, in the APP/PS1 mouse model, this is observed prior to the appearance of AD-related neuropathology (e.g., amyloid-ß plaques; Aß) or cognitive impairment. In the current study, we examined whether impaired glucose tolerance also preceded AD-like changes in the triple transgenic model of AD (3xTg-AD). Glucose tolerance testing (GTT), insulin ELISAs, and insulin tolerance testing (ITT) were performed at ages prior to (1-3 months and 6-8 months old) and post-pathology (16-18 months old). Additionally, we examined for altered insulin signaling in the hippocampus. Western blots were used to evaluate the two-primary insulin signaling pathways: PI3K/AKT and MAPK/ERK. Since the PI3K/AKT pathway affects several downstream targets associated with metabolism (e.g., GSK3, glucose transporters), western blots were used to examine possible alterations in the expression, translocation, or activation of these targets. We found that 3xTg-AD mice display impaired glucose tolerance as early as 1 month of age, concomitant with a decrease in plasma insulin levels well prior to the detection of plaques (∼14 months old), aggregates of hyperphosphorylated tau (∼18 months old), and cognitive decline (≥18 months old). These alterations in peripheral metabolism were seen at all time points examined. In comparison, PI3K/AKT, but not MAPK/ERK, signaling was altered in the hippocampus only in 18-20-month-old 3xTg-AD mice, a time point at which there was a reduction in GLUT3 translocation to the plasma membrane. Taken together, our results provide further evidence that disruptions in energy metabolism may represent a foundational step in the development of AD.

Adaptation of Intestinal and Bile Acid Physiology Accompany the Metabolic Benefits Following Ileal Interposition in the Rat.

PURPOSE: Ileal interposition recapitulates many of the metabolic improvements similar to Roux-en-Y gastric bypass. We aimed to determine whether the metabolic improvements seen following ileal interposition were conferred solely by the interposed segment by examining changes in neighboring intestinal segments as well as the composition of the bile acid pool. MATERIALS AND METHODS: Adult male rats were treated with either sham or ileal interposition surgeries. Glucose tolerance tests, body composition analysis, polymer chain reaction, enzyme-linked immunosorbent assay, and mass spectrometry were done after the surgeries. RESULTS: This study showed that ileal interposition improved glucose tolerance and enhanced both fasting and glucose-stimulated GLP-1 secretion in diabetic rats. Total bile acid pool was similar between groups but the composition favored glycine-conjugation in rats with ileal interposition. Insulin secretion was highly correlated with the 12-alpha-hydroxylase index of activity. The interposed ileum exhibited an increase in mRNA for preproglucagon and peptide YY; however, the bile acid transporter, apical sodium bile acid transporter, was dramatically reduced compared to sham rats. The interposed segment becomes jejunized in its new location as indicated by an increase in Glut2 and Pepck mRNA, genes predominantly synthesized within the jejunum. CONCLUSION: Ileal relocation alone can significantly alter the bile acid pool to favor a more insulin-sensitive metabolism in association with intestinal wide alterations in mRNA for a variety of genes. Ileal interposition may confer metabolic improvement via both the interposed segment and the associated intestinal changes in all segments of the intestine, including the colon.

Metabolic alterations due to caloric restriction and every other day feeding in normal and growth hormone receptor knockout mice.

Mutations causing decreased somatotrophic signaling are known to increase insulin sensitivity and extend life span in mammals. Caloric restriction and every other day (EOD) dietary regimens are associated with similar improvements to insulin signaling and longevity in normal mice; however, these interventions fail to increase insulin sensitivity or life span in growth hormone receptor knockout (GHRKO) mice. To investigate the interactions of the GHRKO mutation with caloric restriction and EOD dietary interventions, we measured changes in the metabolic parameters oxygen consumption (VO2) and respiratory quotient produced by either long-term caloric restriction or EOD in male GHRKO and normal mice. GHRKO mice had increased VO2, which was unaltered by diet. In normal mice, EOD diet caused a significant reduction in VO2 compared with ad libitum (AL) mice during fed and fasted conditions. In normal mice, caloric restriction increased both the range of VO2 and the difference in minimum VO2 between fed and fasted states, whereas EOD diet caused a relatively static VO2 pattern under fed and fasted states. No diet significantly altered the range of VO2 of GHRKO mice under fed conditions. This provides further evidence that longevity-conferring diets cause major metabolic changes in normal mice, but not in GHRKO mice.

(+)-z-bisdehydrodoisynolic Acid enhances Basal metabolism and Fatty Acid oxidation in female obese zucker rats.

We have previously reported that the synthetic estrogen, (+)-Z-bisdehydrodoisynolic Acid [(+)-Z-BDDA], attenuated weight gain and cardiovascular risk in obese rodents. To determine if these antiobesity effects were attributed to changes in basal metabolism, we assessed indirect calorimetry and metabolic profile in female obese Zucker (OZR) rats provided (+)-Z-BDDA (0.0002% food admixture) for 11 weeks. Similar to our previous findings, (+)-Z-BDDA reduced weight gain and improved lipid and glucose homeostasis in OZR rats. Furthermore, resting energy expenditure was increased by (+)-Z-BDDA, as evident by heat production and oxygen consumption. We also observed a marked reduction in respiratory quotient (RQ) along with a corresponding induction of hepatic AMPK in rodents provided (+)-Z-BDDA. Collectively, these findings indicate that (+)-Z-BDDA partially attenuated obesity and associated pathologies through increased resting energy expenditure and fatty acid utilization. Further investigation is required to fully elucidate the mechanisms involved as well as to determine the potential therapeutic implications for (+)-Z-BDDA on obesity and its related pathologies.

Ileal interposition attenuates the satiety responses evoked by cholecystokinin-8 and -33.

One of the possible mechanisms by which the weight-reducing surgical procedure ileal interposition (II) works is by increasing circulating levels of lower gut peptides that reduce food intake, such as glucagon like peptide-1 and peptide YY. However, since this surgery involves both lower and upper gut segments, we tested the hypothesis that II alters the satiety responses evoked by the classic upper gut peptide cholecystokinin (CCK). To test this hypothesis, we determined meal size (MS), intermeal interval (IMI) and satiety ratio (SR) evoked by CCK-8 and -33 (0, 1, 3, 5nmol/kg, i.p.) in two groups of rats, II and sham-operated. CCK-8 and -33 reduced MS more in the sham group than in the II group; CCK-33 prolonged IMI in the sham group and increased SR in both groups. Reduction of cumulative food intake by CCK-8 in II rats was blocked by devazepide, a CCK(1) receptor antagonist. In addition, as previously reported, we found that II resulted in a slight reduction in body weight compared to sham-operated rats. Based on these observations, we conclude that ileal interposition attenuates the satiety responses of CCK. Therefore, it is unlikely that this peptide plays a significant role in reduction of body weight by this surgery.

Sensitivity to the anorectic effects of leptin is retained in rats maintained on a ketogenic diet despite increased adiposity.

BACKGROUND: Rats maintained on a ketogenic diet (KD; 80% fat, 15% protein, 5% carbohydrate) have increased adiposity and leptin as compared to chow-fed controls (CH; 16% fat, 19% protein, 65% carbohydrate), although body weights and daily caloric intakes do not differ. METHODS: Rats maintained on a KD or CH were assessed for responsivity to intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) leptin. Hypothalamic gene expression was evaluated to determine the effects of KD on proopiomelanocortin (POMC) mRNA expression and components of the leptin-signaling system. RESULTS: Caloric intake by KD rats was decreased at a lower dose of i.p. leptin (100 microg) than was required to reduce intake by CH rats (leptin, caloric intake was reduced in KD rats as compared to intake following i.p. saline; p < 0.05). In a separate experiment to evaluate responsivity to i.c.v. leptin, the minimal dose of leptin required to significantly reduce 24-hour caloric intake did not differ between the groups. In the arcuate nucleus, POMC mRNA was elevated after a lower dose of i.c.v. leptin in KD rats (5 microg) than was required to increase POMC mRNA expression in CH rats (15 microg) or reduce caloric intake in either group. Finally, evaluation of the level of phosphorylated STAT3 (pSTAT3) in the arcuate and SOCS3 mRNA in the hypothalamus revealed significantly more pSTAT3-positive cells and increased SOCS3 mRNA expression at baseline for KD rats, compared to CH, neither of which was further increased following i.p. leptin administration. CONCLUSION: These data demonstrate that despite increased adiposity, leptin and markers of leptin resistance, responsivity to the anorectic effects of exogenous leptin is retainable during maintenance on a KD.

Ileal interposition surgery improves glucose and lipid metabolism and delays diabetes onset in the UCD-T2DM rat.

BACKGROUND & AIMS: Bariatric surgery has been shown to reverse type 2 diabetes; however, mechanisms by which this occurs remain undefined. Ileal interposition (IT) is a surgical model that isolates the effects of increasing delivery of unabsorbed nutrients to the lower gastrointestinal tract. In this study we investigated effects of IT surgery on glucose tolerance and diabetes onset in UCD-T2DM (University of California at Davis type 2 diabetes mellitus) rats, a polygenic obese animal model of type 2 diabetes. METHODS: IT or sham surgery was performed on 4-month-old male UCD-T2DM rats. All animals underwent oral glucose tolerance testing (OGTT). A subset was killed 2 months after surgery for tissue analyses. The remainder was followed until diabetes onset and underwent oral fat tolerance testing (OFTT). RESULTS: IT surgery delayed diabetes onset by 120 +/- 49 days compared with sham surgery (P < .05) without a difference in body weight. During OGTT, IT-operated animals exhibited lower plasma glucose excursions (P < .05), improved early insulin secretion (P < .01), and 3-fold larger plasma glucagon-like peptide-1(7-36) (GLP-1(7-36)) excursions (P < .001), and no difference in glucose-dependent insulinotropic polypeptide responses compared with sham-operated animals. Total plasma peptide YY (PYY) excursions during OFTT were 3-fold larger in IT-operated animals (P < .01). IT-operated animals exhibited lower adiposity (P < .05), smaller adipocyte size (P < .05), 25% less ectopic lipid deposition, lower circulating lipids, and greater pancreatic insulin content compared with sham-operated animals (P < .05). CONCLUSIONS: IT surgery delays the onset of diabetes in UCD-T2DM rats which may be related to increased nutrient-stimulated secretion of GLP-1(7-36) and PYY and improvements of insulin sensitivity, beta-cell function, and lipid metabolism.

Alterations in oxygen consumption, respiratory quotient, and heat production in long-lived GHRKO and Ames dwarf mice, and short-lived bGH transgenic mice.

Growth hormone (GH) signaling influences longevity in mice, with decreased GH signaling associated with longer life span and increased GH signaling with shortened life span. A proposed mechanism through which GH signaling influences life span postulates that decreased GH signaling lowers metabolic rate, thus slowing aging by decreasing production of damaging free radicals. The influence of altered GH signaling on metabolism was tested by monitoring oxygen consumption (VO(2)), respiratory quotient (RQ), and heat production in long-lived GH receptor knockout (GHRKO) and Ames dwarf mice, and short-lived bovine GH-overexpressing transgenic (bGH TG) mice. Intriguingly, both GHRKO and Ames dwarf mice have increased VO(2) and heat per gram body weight, and decreased RQ, whereas bGH TG mice have decreased VO(2) and heat per gram body weight and increased RQ. In conclusion, decreased GH signaling associates with increased metabolism per body weight and may beneficially affect mitochondrial flexibility by increasing the capacity for fat oxidation; generally, GH excess produces opposite metabolic effects.

Ileal interposition improves glucose tolerance in low dose streptozotocin-treated diabetic and euglycemic rats.

BACKGROUND: The surgical treatment for obesity promotes massive weight loss and early improvement in co-morbid conditions such as type-2 diabetes. Because surgically mediated glycemic improvements are immediate, the mechanisms involved appear to be weight loss independent. Ileal interposition has been used to gain understanding of the relative role that the lower intestine plays in mediating metabolic improvement. Here, we report that ileal interposition is sufficient for improving glucose tolerance in a low-dose streptozotocin-treated diabetic rat model as well as in normal rats with no effect on body weight. METHODS: Male Long-Evans rats were treated with streptozotocin (35 mg/kg) or left untreated and then received sham or ileal interposition. Body weight was measured as well as glucose and insulin tolerance. Plasma insulin and gut hormones were measured during the glucose tolerance test. RESULTS: Streptozotocin treatment resulted in hyperglycemia within 48 h after treatment. Diabetic rats with ileal interposition showed improvement in glucose tolerance as early as 4 weeks after surgery compared to sham (p < 0.05). By 11 weeks after surgery glucose and insulin tolerance was markedly improved in interposed-diabetic compared to sham-diabetic rats (p < 0.05). Normal non-diabetic rats showed improved glucose tolerance after ileal interposition compared to sham (p < 0.05). Insulin secretion was increased in interposed rats following glucose administration (p < 0.05). The ileal-derived hormones glucagon like peptide-1 (GLP-1), peptide YY (PYY), and glucagon were all significantly elevated in the ileal interposed rats (p < 0.01). Gastric inhibitory polypeptide (GIP) was unchanged. In neither study did body weight between the surgical groups differ at any time point. CONCLUSIONS: Ileal interposition effectively improves glucose tolerance in streptozotocin-diabetic and euglycemic rats. Enhanced insulin secretion can explain the lowered glucose concentrations in euglycemic rats following ileal interposition. Ileal interposition is associated with dramatically elevated ileal hormones, GLP-1, PYY, and glucagon (p < 0.01) with no change in the duodenal hormone GIP.

Effect of gonadectomy on AgRP-induced weight gain in rats.

Agouti-related peptide (AgRP), the endogenous antagonist to the melanocortin 3 and 4 receptors, elicits robust hyperphagia and weight gain in rodents when administered directly into the central nervous system. The relative influence of AgRP to cause weight gain in rodents partially depends on the activity level of the melanocortin agonist-producing proopiomelanocortin neurons. Both proopiomelanocortin and AgRP neurons within the arcuate nucleus receive energy storage information from circulating peripheral signals such as leptin and insulin. Another modulator of AgRP activity includes the cell surface molecule syndecan-3. Because leptin and insulin affect food intake in a sexually dimorphic way in rodents and syndecan-3-deficient mice regulate adiposity levels through distinct physiological mechanisms, we hypothesized that AgRP-induced weight gain would also be sexually dimorphic in rats. In the present study, the behavioral and physiological effects of centrally-administered AgRP in male and female were investigated. In male rats, AgRP (1 nmol) induced 5 days (P < 0.0001) of significantly elevated feeding compared with vehicle-treated controls, while females displayed 3 days of hyperphagia (P < 0.05). However, 1 wk after the injection, both male and female rats gained the same percent body weight (6%). Interestingly, female rats exhibited a greater reduction in energy expenditure (Vo2) following AgRP compared with male rats (P < 0.05). Removal of the gonads did not alter cumulative food intake in male or female rats but did attenuate the dramatic reduction in Vo2 exhibited by females. Both intact and gonadectomized rats demonstrated significantly increased respiratory quotient supporting the anabolic action of AgRP (P < 0.01). These findings are novel in that they reveal sex-specific underlying physiology used to achieve weight gain following central AgRP in rats.

Sexually different actions of leptin in proopiomelanocortin neurons to regulate glucose homeostasis.

Leptin regulates energy balance and glucose homeostasis, at least in part, via activation of receptors in the arcuate nucleus of the hypothalamus located in proopiomelanocortin (POMC) neurons. Females have greater sensitivity to central leptin than males, suggested by a greater anorectic effect of central leptin administration in females. We hypothesized that the regulation of energy balance and peripheral glucose homeostasis of female rodents would be affected to a greater extent than in males if the action of leptin in POMC neurons were disturbed. Male and female mice lacking leptin receptors only in POMC neurons gained significantly more body weight and accumulated more body fat. However, female mice gained disproportionately more visceral adiposity than males, and this appeared to be largely the result of differences in energy expenditure. When maintained on a high-fat diet (HFD), both male and female mutants had higher levels of insulin following exogenous glucose challenges. Chow- and HFD-fed males but not females had abnormal glucose disappearance curves following insulin administrations. Collectively, these data indicate that the action of leptin in POMC neurons is sexually different to influence the regulation of energy balance, fat distribution, and glucose homeostasis.

The effect of fat removal on glucose tolerance is depot specific in male and female mice.

Energy is stored predominately as lipid in white adipose tissue (WAT) in distinct anatomical locations, with each site exerting different effects on key biological processes, including glucose homeostasis. To determine the relative contributions of subcutaneous and visceral WAT on glucose homeostasis, comparable amounts of adipose tissue from abdominal subcutaneous inguinal WAT (IWAT), intra-abdominal retroperitoneal WAT (RWAT), male gonadal epididymal WAT (EWAT), or female gonadal parametrial WAT (PWAT) were removed. Gonadal fat removal in both male and female chow-fed lean mice resulted in lowered glucose levels across glucose tolerance tests. Female lean C57BL/6J mice as well as male and female lean FVBN mice significantly improved glucose tolerance, indicated by decreased areas under glucose clearance curves. For the C57BL/6J mice maintained on a high-fat butter-based diet, glucose homeostasis was improved only in female mice with PWAT removal. Removal of IWAT or RWAT did not affect glucose tolerance in either dietary condition. We conclude that WAT contribution to glucose homeostasis is depot specific, with male gonadal EWAT contributing to glucose homeostasis in the lean state, whereas female gonadal PWAT contributes to glucose homeostasis in both lean and obese mice. These data illustrate both critical differences among various WAT depots and how they influence glucose homeostasis and highlight important differences between males and females in glucose regulation.

The effects of the melanocortin agonist (MT-II) on subcutaneous and visceral adipose tissue in rodents.

The melanocortin system is a critical pathway in the regulation of energy balance. In this study, we analyzed the peripheral effects of the synthetic melanocortin agonist melanotan-II (MT-II) in rodents fed a low-fat or high-fat diet. MT-II-treated high-fat diet-induced obese (DIO) mice lost weight and body fat, whereas MT-II-treated low-fat-fed mice maintained their original body weight. Specifically, MT-II treatment led to a general reduction in both visceral and subcutaneous adipose tissue in high-fat-fed mice compared with Vehicle (ad libitum) controls. Vehicle-treated pair-fed DIO mice lost an equivalent amount of body weight compared with MT-II-treated mice but retained more adipose tissue. Pair-fed mice showed a reduction in visceral adipose tissue and no effect on subcutaneous adipose tissue compared with MT-II-treated mice. It is surprising that subcutaneous lean mass was significantly reduced in the pairfed mice. The data were replicated in DIO rats and indicated that MT-II treatment led to a generalized reduction in adipose tissue. These results indicate that peripheral MT-II treatment leads to weight loss that affects both the visceral and subcutaneous fat compartments. This finding illustrates the complexity of analyzing weight-reducing compounds. Although the present data suggest that the anorectic effect of MT-II is primarily a consequence of reduced food intake, the body composition data suggest that other mechanisms are involved.

Sexually dimorphic responses to fat loss after caloric restriction or surgical lipectomy.

White adipose tissue is the principal site for lipid accumulation. Males and females maintain distinctive white adipose tissue distribution patterns. Specifically, males tend to accumulate relatively more visceral fat, whereas females accumulate relatively more subcutaneous fat. The phenomenon of maintaining typical sex-specific fat distributions suggests sex-specific mechanisms that regulate energy balance and adiposity. We used two distinct approaches to reduce fat mass, caloric restriction (CR), and surgical fat removal (termed lipectomy) and assessed parameters involved in the regulation of energy balance. We found that male and female mice responded differentially to CR- and to lipectomy-induced fat loss. Females decreased energy expenditure during CR or after lipectomy. In contrast, males responded by eating more food during food return after CR or after lipectomy. Female CR mice conserved subcutaneous fat, whereas male CR mice lost adiposity equally in the subcutaneous and visceral depots. In addition, female mice had a reduced capability to restore visceral fat after fat loss. After CR, plasma leptin levels decreased in male but not in female mice. The failure to increase food intake after returning to ad libitum intake in females could be due to the relatively stable levels of leptin. In summary, we have found sexual dimorphisms in the response to fat loss that point to important underlying differences in the strategies by which male and female mice regulate body weight.

Estradiol-dependent decrease in the orexigenic potency of ghrelin in female rats.

Ghrelin, the only known orexigenic gut hormone, is secreted mainly from the stomach, increases with fasting and before meal initiation in humans and rats, and increases food intake after central or peripheral administration. To investigate sex differences in the action of ghrelin, we assessed the effects of exogenous ghrelin in intact male and female rats, the effects of exogenous ghrelin in ovariectomized (OVX) and estradiol (E2)-treated female rats, as well as the effects of OVX on plasma ghrelin and hypothalamic orexigneic neuropeptide expression in rats and on food intake and weight gain in transgenic mice lacking the ghrelin receptor (Ghsr(-/-) mice). Male and OVX female rats were significantly more sensitive than intact female rats to the orexigenic effects of both centrally (intra-third ventricular, i3vt, 0.01, 0.1, and 1.0 nmol) and systemically (ip, 3, 6, and 9 nmol) administered ghrelin. This difference is likely to be estradiol dependent because E2 attenuated the orexigenic action of ghrelin in OVX female and male rats. Furthermore, OVX increased food intake and body weight in wild-type mice, but not in Ghsr(-/-) mice, suggesting that OVX increases food intake by releasing ghrelin from a tonic inhibitory effect of estradiol. In addition, following OVX, there was an increase in plasma ghrelin that was temporally associated with increased food intake, body weight, and hypothalamic neuropeptide Y and Agouti-related protein mRNA expression. Collectively, these data suggest that estradiol inhibits the orexigenic action of ghrelin in females, that weight gain associated with OVX is ghrelin mediated, and that this endocrine interaction may account for an important sex differences in food intake and the regulation of body weight.

Ileal transposition provides insight into the effectiveness of gastric bypass surgery.

Despite dramatically increased research efforts to discover cures for the rising health issue of obesity, bariatric (obesity) surgery remains the most effective treatment. Obese people and especially those classified as morbidly obese often suffer from associated co-morbid conditions such as type-II diabetes. In most cases, bariatric surgery results in rapid and sustained decreases in excess body weight. Recent reports have identified significant improvements in glucose homeostasis after surgery that are coincident and often precedent to any measurable weight loss. These studies suggest an inhibition or enhancement of a "factor" within the intestinal tract that improves glycemia independent of body fat stores. These observations have sparked renewed investigation into the mechanisms underlying successful obesity surgeries such as gastric bypass. It is becoming increasingly clear that restriction and malabsorption are not the only two mechanisms important for inducing long-term weight loss or the improvements in diabetes. Investigating the hypothesis that the distal intestine (ileum) holds additional answers into a third mechanism, I used the model of ileal transposition to help identify endocrine changes in the gut following obesity surgery. This review will explore the model of ileal transposition and speculate on its usefulness as a tool to dissect out additional mechanisms underlying effective obesity surgeries. Also discussed will be the ileal-produced hormone glucagon-like peptide and its role in mediating the improvements in diabetes and weight loss after bariatric surgery.

A role for syndecan-3 in the melanocortin regulation of energy balance.

Since the discovery that central melanocortin peptides play an important role in the control of body weight, an impressive amount of research has focused on understanding this complex neuroendocrine system. However, this research has also uncovered new complexities. One of these complexities is the recently discovered putative melanocortin "co-receptor," syndecan-3. In this review, we present an overview of the biology and potential functions of syndecan-3 and describe a novel hypothesis for its regulation of energy balance.

Chronic food restriction and reduced dietary fat: risk factors for bouts of overeating.

The purpose of this study was to determine the effect of chronic food restriction and reduced dietary fat on feeding behavior and body weight. Young female rats were fed ad lib or food restricted on a low-fat (LF) or a fat-free (FF) diet for 4 weeks. Rats then received 24-h free access to 2 diets, the maintenance diet (LF or FF) plus a novel high-fat (HF) diet (24-h intake test). After the test, all the rats were allowed chronic free access to the HF diet until body weight was stable. During the 24-h test, the restricted groups ate significantly more calories than the ad lib groups, and the FF-restricted rats ate significantly more total food, carbohydrate and protein than the LF-restricted rats; there were no differences between the two ad lib groups. During chronic free access to the HF diet, the formerly restricted rats achieved and defended lower body weights than the formerly non-restricted rats. Throughout the experiment, the ad lib groups had more body fat than the restricted groups independent of the dietary subgroup. Hence, a history of chronic food restriction predisposes to consuming more food in acute feeding situations, particularly when dietary fat is reduced, and lowers the level of body weight maintained and defended. Chronic food restriction accompanied by reduced dietary fat may increase risk for bouts of overeating.

Gastrointestinal hormones and food intake.

Despite dramatic fluctuations in calorie intake, animals maintain a very stable body weight. The reason is that energy intake and expenditure are precisely matched. Long-term regulation of energy balance is dependent on the coordination and interpretation of signals such as those given by insulin and leptin indicating sufficient long-term energy stores as well as short-term, meal-related signals such as those given by cholecystokinin (CCK). Within the last 30 years, our knowledge of short-term signals has increased dramatically. Throughout the cephalo-caudal axis of the gastrointestinal system, discrete enteroendocrine cells respond to both mechanical and chemical stimulation. Meal-associated hormone release is dependent on the concentration and composition of the nutrients ingested. Released signals are transmitted neurally through vagal afferents or humorally as circulating ligands for specific receptor populations in the periphery and central nervous system. These signals are interpreted by the CNS and manifested as a behavioral modification of feeding. This review will present past and recent literature in support of gut hormones and their roles as mediators of satiety. Evidence from pharmacologic and physiologic studies involving both humans and rodents will be presented, along with a short section outlining the knowledge gained through the use of murine knockout models. Last, the contribution of satiety hormones as likely mediators of the effectiveness seen following obesity surgery will be reviewed. Although traditionally thought of as short-term, meal-related signals, enhanced, chronic hormone secretion and signaling resulting from gut reconstruction as seen with gastric bypass surgery most likely contributes to the superior efficacy of surgery as a treatment for obesity.