Modified Peptide YY Molecule Attenuates the Activity of NPY/AgRP Neurons and Reduces Food Intake in Male Mice.

To study the effects of an analog of the gut-produced hormone peptide YY (PYY3-36), which has increased selectivity for the Y2 receptor; specifically, to record its effects on food intake and on hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neuron activity. NNC0165-1273, a modified form of the peptide hormone PYY3-36 with potent selectivity at Y2 receptor (>5000-fold over Y1, 1250-fold over Y4, and 650-fold over Y5 receptor), was tested in vivo and in vitro in mouse models. NNC0165-1273 has fivefold lower relative affinity for Y2 compared with PYY3-36, but >250-, 192-, and 400-fold higher selectivity, respectively, for the Y1, Y4, and Y5 receptors. NNC0165-1273 produced a reduction in nighttime feeding at a dose at which PYY3-36 loses efficacy. The normal behavioral satiety sequence observed suggests that NNC0165-1273 is not nauseating and, instead, reduces food intake by producing early satiety. Additionally, NNC0165-1273 blocked ghrelin-induced cFos expression in NPY/AgRP neurons. In vitro electrophysiological recordings showed that, opposite to ghrelin, NNC0165-1273 hyperpolarized NPY/AgRP neurons and reduced action potential frequency. Administration of NNC0165-1273 via subcutaneous osmotic minipump caused a dose-dependent decrease in body weight and fat mass in an obese mouse model. Finally, NNC0165-1273 attenuated the feeding response when NPY/AgRP neurons were activated using ghrelin or more selectively with designer receptors. NNC0165-1273 is nonnauseating and stimulates a satiety response through, at least in part, a direct action on hypothalamic NPY/AgRP neurons. Modification of PYY3-36 to produce compounds with increased affinity to Y2 receptors may be useful as antiobesity therapies in humans.

A novel approach to glycemic control in type 2 diabetes mellitus, partial jejunal diversion: pre-clinical to clinical pathway.

OBJECTIVE: To explore partial jejunal diversion (PJD) via a side-to-side jejuno-jejunostomy for improved glycemic control in type 2 diabetes mellitus (T2DM). PJD is an anatomy-sparing, technically simple surgery in comparison to the predominate metabolic procedures, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). Positive results in a rodent model prompted a human proof-of-concept study. RESEARCH DESIGN AND METHODS: Pre-clinically, 71 rats were studied in a model of metabolic dysfunction induced by a high-fat diet; 33 animals undergoing one of two lengths of PJD were compared with 18 undergoing sham, 10 RYGB and 10 jejuno-ileal bypass. Clinically, 15 adult subjects with treated but inadequately controlled T2DM (hemoglobin A1c (HbA1c) of 8.0%-11.0%), body mass index of 27.0-40.0 kg/m2, and C peptide ≥3 ng/mL were studied. Follow-up was at 2 weeks, and 3, 6, 9, and 12 months post-PJD. RESULTS: Pre-clinically, positive impacts with PJD on glucose homeostasis, cholesterol, and body composition versus sham control were demonstrated. Clinically, PJD was performed successfully without serious complications. Twelve months post-surgery, the mean (SD) reduction from baseline in HbA1c was 2.3% (1.3) (p<0.01). CONCLUSIONS: PJD may provide an anatomy sparing, low-risk, intervention for poorly controlled T2DM without significant alteration of the patient's lifestyle. The proof-of-concept study is limited by a small sample size and advanced disease, with 80% of participants on insulin and a mean time since diagnosis of over 10 years. Further study is warranted. TRIAL REGISTRATION NUMBER: NCT02283632; Pre-results.

The Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice.

Glucagon-like peptide 1 (GLP-1) is necessary for normal gluco-regulation, and it has been widely presumed that this function reflects the actions of GLP-1 released from enteroendocrine L cells. To test the relative importance of intestinal versus pancreatic sources of GLP-1 for physiological regulation of glucose, we administered a GLP-1R antagonist, exendin-[9-39] (Ex9), to mice with tissue-specific reactivation of the preproglucagon gene (Gcg). Ex9 impaired glucose tolerance in wild-type mice but had no impact on Gcg-null or GLP-1R KO mice, suggesting that Ex9 is a true and specific GLP-1R antagonist. Unexpectedly, Ex-9 had no effect on blood glucose in mice with restoration of intestinal Gcg. In contrast, pancreatic reactivation of Gcg fully restored the effect of Ex9 to impair both oral and i.p. glucose tolerance. These findings suggest an alternative model whereby islet GLP-1 also plays an important role in regulating glucose homeostasis.

Hypothalamic Vitamin D Improves Glucose Homeostasis and Reduces Weight.

Despite clear associations between vitamin D deficiency and obesity and/or type 2 diabetes, a causal relationship is not established. Vitamin D receptors (VDRs) are found within multiple tissues, including the brain. Given the importance of the brain in controlling both glucose levels and body weight, we hypothesized that activation of central VDR links vitamin D to the regulation of glucose and energy homeostasis. Indeed, we found that small doses of active vitamin D, 1α,25-dihydroxyvitamin D3 (1,25D3) (calcitriol), into the third ventricle of the brain improved glucose tolerance and markedly increased hepatic insulin sensitivity, an effect that is dependent upon VDR within the paraventricular nucleus of the hypothalamus. In addition, chronic central administration of 1,25D3 dramatically decreased body weight by lowering food intake in obese rodents. Our data indicate that 1,25D3-mediated changes in food intake occur through action within the arcuate nucleus. We found that VDR colocalized with and activated key appetite-regulating neurons in the arcuate, namely proopiomelanocortin neurons. Together, these findings define a novel pathway for vitamin D regulation of metabolism with unique and divergent roles for central nervous system VDR signaling. Specifically, our data suggest that vitamin D regulates glucose homeostasis via the paraventricular nuclei and energy homeostasis via the arcuate nuclei.

The role of gut adaptation in the potent effects of multiple bariatric surgeries on obesity and diabetes.

Bariatric surgical procedures such as vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) are the most potent treatments available to produce sustained reductions in body weight and improvements in glucose regulation. While traditionally these effects are attributed to mechanical aspects of these procedures, such as restriction and malabsorption, a growing body of evidence from mouse models of these procedures points to physiological changes that mediate the potent effects of these surgeries. In particular, there are similar changes in gut hormone secretion, bile acid levels, and composition after both of these procedures. Moreover, loss of function of the nuclear bile acid receptor (FXR) greatly diminishes the effects of VSG. Both VSG and RYGB are linked to profound changes in the gut microbiome that also mediate at least some of these surgical effects. We hypothesize that surgical rearrangement of the gastrointestinal tract results in enteroplasticity caused by the high rate of nutrient presentation and altered pH in the small intestine that contribute to these physiological effects. Identifying the molecular underpinnings of these procedures provides new opportunities to understand the relationship of the gastrointestinal tract to obesity and diabetes as well as new therapeutic strategies to harness the effectiveness of surgery with less-invasive approaches.

Effect of guanylate cyclase-C activity on energy and glucose homeostasis.

Uroguanylin is a gastrointestinal hormone primarily involved in fluid and electrolyte handling. It has recently been reported that prouroguanylin, secreted postprandially, is converted to uroguanylin in the brain and activates the receptor guanylate cyclase-C (GC-C) to reduce food intake and prevent obesity. We tested central nervous system administration of two GC-C agonists and found no significant reduction of food intake. We also carefully phenotyped mice lacking the GC-C receptor and found them to have normal body weight, adiposity, and glucose tolerance. Interestingly, uroguanylin knockout mice had a small but significant increase in body weight and adiposity that was accompanied by glucose intolerance. Our data indicate that the modest effects of uroguanylin on energy and glucose homeostasis are not mediated by central GC-C receptors.

Regulation of gastric emptying rate and its role in nutrient-induced GLP-1 secretion in rats after vertical sleeve gastrectomy.

Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are effective weight loss surgeries that also improve glucose metabolism. Rapid, early rises of circulating insulin and glucagon-like peptide-1 (GLP-1) concentrations following food ingestion are characteristic of these procedures. The purpose of the current study was to test the hypothesis that postprandial hormone release is due to increased nutrient emptying from the stomach. Radioscintigraphy and chemical and radiolabeled tracers were used to examine gastric emptying in rat models of VSG and RYGB surgery. Intraduodenal nutrient infusions were used to assess intestinal GLP-1 secretion and nutrient sensitivity in VSG rats compared with shams. Five minutes after a nutrient gavage, the stomachs of RYGB and VSG rats were completely emptied, whereas only 6.1% of the nutrient mixture had emptied from sham animals. Gastric pressure was increased in VSG animals, and rats with this procedure did not inhibit gastric emptying normally in response to increasing caloric loads of dextrose or corn oil, and they did not respond to neural or endocrine effectors of gastric motility. Finally, direct infusion of liquid nutrients into the duodenum caused significantly greater GLP-1 release in VSG compared with shams, indicating that increases in GLP-1 secretion after VSG are the result of both greater gastric emptying rates and altered responses at the level of the intestine. These findings demonstrate greatly accelerated gastric emptying in rat models of RYGB and VSG. In VSG this is likely due to increased gastric pressure and reduced responses to inhibitory feedback from the intestine.

Cannabinoid 1 receptors are critical for the innate immune response to TLR4 stimulation.

Sickness behaviors are host defense adaptations that arise from integrated autonomic outputs in response to activation of the innate immune system. These behaviors include fever, anorexia, and hyperalgesia intended to promote survival of the host when encountering pathogens. Cannabinoid (CB) receptor activation can induce hypothermia and attenuate LPS-evoked fever. The aim of the present study was to examine the role of CB1 receptors in the LPS-evoked febrile response. CB1 receptor-deficient (CB1(-/-)) mice did not display LPS-evoked fever; likewise, pharmacological blockade of CB1 receptors in wild-type mice blocked LPS-evoked fever. This unresponsiveness is not limited to thermogenesis, as the animals were not hyperalgesic after LPS administration. A Toll-like receptor (TLR)3 agonist and viral mimetic polyinosinic:polycytidylic acid evoked a robust fever in CB1(-/-) mice, suggesting TLR3-mediated responses are functional. LPS-evoked c-Fos activation in areas of the brain associated with the febrile response was evident in wild-type mice but not in CB1(-/-) mice. Liver and spleen TLR4 mRNA were significantly lower in CB1(-/-) mice compared with wild-type mice, and peritoneal macrophages from CB1(-/-) mice did not release proinflammatory cytokines in response to LPS. These data indicate that CB1 receptors play a critical role in LPS-induced febrile responses through inhibiting TLR4-mediated cytokine production.

Integration of satiety signals by the central nervous system.

Individual meals are products of a complex interaction of signals related to both short-term and long-term availability of energy stores. In addition to maintaining the metabolic demands of the individual in the short term, levels of energy intake must also maintain and defend body weight over longer periods. To accomplish this, satiety pathways are regulated by a sophisticated network of endocrine and neuroendocrine pathways. Higher brain centers modulate meal size through descending inputs to caudal brainstem regions responsible for the motor pattern generators associated with ingestion. Gastric and intestinal signals interact with central nervous system pathways to terminate food intake. These inputs can be modified as a function of internal metabolic signals, external environmental influences, and learning to regulate meal size.

Roux-en-Y gastric bypass surgery but not vertical sleeve gastrectomy decreases bone mass in male rats.

The most effective treatment for obesity is bariatric surgery. However, there is increasing concern that bariatric surgery can cause nutrient deficiencies that translate into metabolic bone disease. Whether this is true for all surgery types is not yet clear. We therefore investigated the effects of 2 commonly applied bariatric surgeries (Roux-en-Y gastric bypass [RYGB] and vertical sleeve gastrectomy) on energy and bone metabolism in rats 60 days after surgery. Both surgeries resulted in similar reductions of body weight, body fat, and food intake. Glucose tolerance was improved to a similar extent after both surgeries and was accompanied by increased postprandial secretion of glucose-dependent insulinotropic peptide. Using microcomputed tomography, we found that, relative to sham-operated rats, bone volume was significantly reduced after RYGB but not vertical sleeve gastrectomy. RYGB rats also had markedly reduced lipid absorption from the intestine and significantly lower serum 25-hydroxyvitamin D and calcium levels. Importantly, dietary supplementation with calcium and vitamin D could not fully rescue the reduced bone volume after RYGB surgery. Both surgeries resulted in a significant increase in stomach pH, which may have worsened the malabsorption in RYGB rats. Our findings suggest that bone loss in RYGB rats is not exclusively driven by calcium and vitamin D malabsorption but also by additional factors that may not be rescuable by dietary supplementation. These data point toward important similarities and differences between bariatric procedures that should be considered in clinical settings as guidance for which procedure will be best for specific patient populations.

Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon-like Peptide 1 receptor deficiency.

Glucagon-like peptide 1 (GLP-1) is a peptide hormone that is released from the gut in response to nutrient ingestion and that has a range of metabolic effects, including enhancing insulin secretion and decreasing food intake. Postprandial GLP-1 secretion is greatly enhanced in rats and humans after some bariatric procedures, including vertical sleeve gastrectomy (VSG), and has been widely hypothesized to contribute to reduced intake, weight loss, and the improvements in glucose homeostasis after VSG. We tested this hypothesis using two separate models of GLP-1 receptor deficiency. We found that VSG-operated GLP-1 receptor-deficient mice responded similarly to wild-type controls in terms of body weight and body fat loss, improved glucose tolerance, food intake reduction, and altered food selection. These data demonstrate that GLP-1 receptor activity is not necessary for the metabolic improvements induced by VSG surgery.

The effects of vertical sleeve gastrectomy in rodents are ghrelin independent.

Reductions in levels of the hunger-stimulating hormone ghrelin have been proposed to mediate part of the effects of vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass surgeries for obesity. We studied circulating levels of acyl and desacyl ghrelin in rats after these surgeries. We found that blood levels of ghrelin were reduced after VSG, but not after Roux-en-Y gastric bypass, based on enzyme-linked immunosorbent assay and mass-spectrometry analyses. We compared the effects of VSG in ghrelin-deficient mice and wild-type mice on food intake, body weight, dietary fat preference, and glucose tolerance. We found that VSG produced comparable outcomes in each strain. Reduced ghrelin signaling therefore does not appear to be required for these effects of VSG.

Effect of vertical sleeve gastrectomy on food selection and satiation in rats.

Vertical sleeve gastrectomy (VSG) is a restrictive procedure that reduces food intake to produce weight loss. Here we assess volume and nutrient effects on the ingestive behavior of VSG and sham surgery animals. Rats given access to Ensure or pelleted chow were used to determine if liquid foods would adversely affect weight loss after surgery. Volume effects were studied by altering the caloric density of Ensure, and dietary preferences for fat and carbohydrate (sucrose) were assessed using a two-bottle test. c-Fos was used to measure neuronal activation in the nucleus of the solitary tract and area postrema in response to intragastric infusions of water, sucrose, or Intralipid. The degree of colocalization with catecholaminergic neurons was also assessed. VSG rats did not show the expected preference for a liquid diet over chow and lacked dietary preferences for fat seen in shams. Preferences for carbohydrate/sucrose solutions were unaffected by surgery. Meal size was reduced by VSG; however, VSG rats were able to alter their volume of intake to compensate for changes in caloric density, and intragastric infusions of water produced similar levels of neuronal activation among VSG, sham, and pair-fed rats. In comparison, nutrient-induced c-Fos activation was substantially increased by VSG. Colocalization between c-Fos and catecholaminergic-expressing neurons was similar among rats treated with water, sucrose, or Intralipid. VSG alters nutrient sensing in a manner that lowers the threshold for satiety and reduces fat preference to induce and maintain weight loss.

All bariatric surgeries are not created equal: insights from mechanistic comparisons.

Despite considerable scientific progress on the biological systems that regulate energy balance, we have made precious little headway in providing new treatments to curb the obesity epidemic. Diet and exercise are the most popular treatment options for obesity, but rarely are they sufficient to produce long-term weight loss. Bariatric surgery, on the other hand, results in dramatic, sustained weight loss and for this reason has gained increasing popularity as a treatment modality for obesity. At least some surgical approaches also reduce obesity-related comorbidities including type 2 diabetes and hyperlipidemia. This success puts a premium on understanding how these surgeries exert their effects. This review focuses on the growing human and animal model literature addressing the underlying mechanisms. We compare three common procedures: Roux-en-Y Gastric Bypass (RYGB), vertical sleeve gastrectomy (VSG), and adjustable gastric banding (AGB). Although many would group together VSG and AGB as restrictive procedures of the stomach, VSG is more like RYGB than AGB in its effects on a host of endpoints including intake, food choice, glucose regulation, lipids and gut hormone secretion. Our strong belief is that to advance our understanding of these procedures, it is necessary to group bariatric procedures not on the basis of surgical similarity but rather on how they affect key physiological variables. This will allow for greater mechanistic insight into how bariatric surgery works, making it possible to help patients better choose the best possible procedure and to develop new therapeutic strategies that can help a larger portion of the obese population.

The role of neuropeptide Y in energy homeostasis.

When administered into the brain, NPY acts at Y1 and Y5 receptors to increase food intake. The response occurs with a short latency and is quite robust, such that exogenous NPY is generally considered to be the most potent of a growing list of orexigenic compounds that act in the brain. The role of endogenous NPY is not so straightforward, however. Evidence from diverse types of experiments suggests that rather than initiating behavioral eating per se, endogenous NPY elicits autonomic responses that prepare the individual to better cope with consuming a calorically large meal.

Sleeve gastrectomy in rats improves postprandial lipid clearance by reducing intestinal triglyceride secretion.

BACKGROUND & AIMS: Postprandial hyperlipidemia is a risk factor for atherosclerotic heart disease and is associated with the consumption of high-fat diets and obesity. Bariatric surgeries result in superior and more durable weight loss than dieting. These surgeries are also associated with multiple metabolic improvements, including reduced plasma lipid levels. We investigated whether the beneficial effects of vertical sleeve gastrectomy (VSG) on plasma lipid levels are weight independent. METHODS: VSG was performed on Long-Evans rats with diet-induced obesity. Controls were sham-operated animals who were either pair-fed or ad libitum-fed. We measured fasting and postprandial levels of plasma lipid. To determine hepatic and intestinal triglyceride secretion, we injected the lipase inhibitor poloxamer 407 alone or before oral lipid gavage. (13)C-Triolein was used to estimate postprandial uptake of lipid in the intestine. RESULTS: Rats that received VSG and high-fat diets had markedly lower fasting levels of plasma triglyceride, cholesterol, and phospholipid than obese and lean (pair-fed) controls that were fed high-fat diets. Rats that received VSG had a marked, weight-independent reduction in secretion of intestinal triglycerides. VSG did not alter total intestinal triglyceride levels or size of the cholesterol storage pool nor did it affect the expression of genes in the intestine that control triglyceride metabolism and synthesis. VSG did not affect fasting secretion of triglyceride, liver weight, hepatic lipid storage, or transcription of genes that regulate hepatic lipid processing. CONCLUSIONS: VSG reduced postprandial levels of plasma lipid, independently of body weight. This resulted from reduced intestinal secretion of triglycerides following ingestion of a lipid meal and indicates that VSG has important effects on metabolism.

Weight-independent changes in blood glucose homeostasis after gastric bypass or vertical sleeve gastrectomy in rats.

BACKGROUND & AIMS: Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) reduce weight and improve glucose metabolism in obese patients, although it is not clear if metabolic changes are independent of weight loss. We investigated alterations in glucose metabolism in rats following RYGB or VSG. METHODS: Rats underwent RYGB or VSG and were compared to sham-operated rats fed ad lib or pair-fed to animals that received RYGB. Intraperitoneal glucose tolerance and insulin sensitivity tests were performed to assess glycemic function independent of incretin response. A hyperinsulinemic euglycemic clamp was used to compare tissue-specific changes in insulin sensitivity following each procedure. A mixed-meal tolerance test was used to assess the effect of each surgery on postprandial release of glucagon-like peptide 1 (GLP-1)(7-36) and glucose tolerance, and was also performed in rats given GLP-1 receptor antagonist exendin(9-39). RESULTS: Following RYGB or VSG, glucose tolerance and insulin sensitivity improved in proportion to weight loss. Hepatic insulin sensitivity was significantly better in rats that received RYGB or VSG compared with rats fed ad lib or pair-fed, whereas glucose clearance was similar in all groups. During the mixed-meal tolerance test, plasma levels of GLP-1(7-36) and insulin were greatly and comparably increased in rats that received RYGB and VSG compared with those that were pair-fed or fed ad lib. Administration of a GLP-1 receptor antagonist prevented improvements in glucose and insulin responses after a meal among rats that received RYGB or VSG. CONCLUSIONS: In obese rats, VSG is as effective as RYGB for increasing secretion of GLP-1 and insulin and improving hepatic sensitivity to insulin; these effects are independent of weight loss.

Similar effects of roux-en-Y gastric bypass and vertical sleeve gastrectomy on glucose regulation in rats.

Bariatric surgery is the most efficacious procedure for eliciting weight loss in humans, and many patients undergoing the procedure experience significant lessening of their symptoms of type-2 diabetes in addition to losing weight. We have adapted two bariatric surgical procedures commonly employed in humans to a rat model to begin to understand the mechanisms underlying the improvements in energy homeostasis. Young adult male rats received either roux-en-Y gastric bypass (RYGB) or vertical sleeve gastrectomy (VSG) and were assessed for body weight, food intake and parameters of glucose homeostasis over a 28-week period. Control rats received either a sham surgical procedure or else were unoperated. RYGB and VSG had comparable beneficial effects relative to controls. They ate less food and lost more weight, and they both had improved glucose parameters. The most intriguing aspect of the findings is that the two surgical procedures had such similar effects in spite of quite different rearrangements of the gastrointestinal system.

The neutral cannabinoid CB1 receptor antagonist AM4113 regulates body weight through changes in energy intake in the rat.

The aim of this study was to determine if the neutral cannabinoid CB1 receptor antagonist, AM4113, regulates body weight in the rat via changes in food intake. We confirmed that the AM4113-induced reduction in food intake is mediated by CB1 receptors using CB1 receptor knockout mice. In rats, intraperitoneally administered AM4113 (2, 10 mg kg⁻¹) had a transient inhibitory effect on food intake, while body weight gain was suppressed for the duration of the study. AM4113-induced hypophagia was no longer observed once the inhibitory effect of AM4113 on body weight stabilized, at which time rats gained weight at a similar rate to vehicle-treated animals, yet at a lower magnitude. Pair-feeding produced similar effects to treatment with AM4113. Food intake and body weight gain were also inhibited in rats by oral administration of AM4113 (50 mg kg⁻¹). Dual energy x-ray absorptiometry (DEXA) was used to measure lean and fat mass. The AM4113 treated group had 29.3±11.4% lower fat mass than vehicle-treated rats; this trend did not reach statistical significance. There were no differences in circulating levels of the endogenous cannabinoid 2-arachidonoyl glycerol (2-AG), glucose, triglycerides, or cholesterol observed between treatment groups. Similarly, 2-AG hypothalamic levels were not modified by AM4113 treatment. These data suggest that blockade of an endocannabinoid tone acting at CB1 receptors induces an initial, transient reduction in food intake which results in long-term reduction of body weight gain.

Sleeve gastrectomy induces loss of weight and fat mass in obese rats, but does not affect leptin sensitivity.

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.