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Objective: The aim of this study was to determine whether downstream [peroxisome proliferator-activated-receptor alpha (PPARα) and the G-protein coupled receptor, GPR119] and upstream (a fatty acid translocase, CD36) signaling targets of N-oleoylethanolamide (OEA) were necessary for weight loss, metabolic improvements, and diet preference following vertical sleeve gastrectomy (VSG). Summary Background Data: OEA is an anorectic N-acylethanolamine produced from dietary fats within the intestinal lumen that can modulate lipid metabolism, insulin secretion, and energy expenditure by activating targets such as PPARα and GPR119. Methods: Diet-induced obese mice, including wild-type or whole body knockout (KO) of PPARα, GPR119, and CD36, were stratified to either VSG or sham surgery before body weight, body composition, diet preference, and glucose and lipid metabolic endpoints were assessed. Results: We found increased duodenal production of OEA and expression of both GPR119 and CD36 were upregulated in wild-type mice after VSG. However, weight loss and glucose tolerance were improved in response to VSG in PPARαKO, GPR119KO, and CD36KO mice. In fact, VSG corrected hepatic triglyceride dysregulation in CD36KO mice, and circulating triglyceride and cholesterol levels in PPARαKO mice. Lastly, we found PPARα-mediated signaling contributes to macronutrient preference independent of VSG, while removal of CD36 signaling blunts the VSG-induced shift toward carbohydrate preference. Conclusions: In the search for more effective and less invasive therapies to help reverse the global acceleration of obesity and obesity-related disease OEA is a promising candidate; however, our data indicate that it is not an underlying mechanism of the effectiveness of VSG. [ABSTRACT FROM AUTHOR]

Metabolic surgery is safe and the most effective therapy for obesity and its co-morbidities. New procedures may allow for better tailoring of metabolic surgery to the individual patient. To evaluate the impact, comparative effectiveness, and mechanisms of the partial intestinal diversion (PID), vertical sleeve gastrectomy (VSG), and the combination of PID and VSG on weight and glucose regulation. University research facility, United States. Three cohorts of high-fat diet-induced obese male rats were randomized to distal PID (DPID), proximal PID (PPID), VSG, VSG and DPID (VSG/DPID), or sham operation (Sham). Animals were followed for 11 (cohort 1) or 10 (cohorts 2 and 3) weeks. Outcomes included weight and composition, food intake, glucose metabolism, lipids, bile acids, and energy balance. Statistical comparisons were performed using Tukey's multiple comparison test applied to analysis of variance. DPID and not PPID resulted in significant weight and body fat reductions relative to Sham. Improved glucose tolerance was seen in all surgical groups though this reached statistical significance for only DPID and VSG compared with Sham. Improvements in baseline glucose and insulin, corresponding insulin resistance, and plasma lipids were noted in DPID compared with Sham. Though the magnitude of weight and body composition changes and metabolic benefit tended to be larger for VSG relative to DPID, it only reached statistical significance for lipids. VSG and VSG/DPID resulted in similar outcomes. Markedly reduced food intake occurred after VSG and more modestly after DPID. Stool caloric content was higher in DPID relative to all groups. DPID is an effective metabolic operation resulting in notable weight and fat loss and metabolic improvement relative to sham-operated rodents. Interestingly, combining VSG with DPID added little additional benefit to the effects of VSG. Distal partial intestinal bypass is an effective metabolic operation resulting in weight loss and improvement in glucose tolerance. Analyses performed by Tukey's multiple comparison test applied to values obtained from one-way analysis of variance (ANOVA). Circle denotes the enteroenterostomy. Black arrows indicate the usual path of chyme while white arrows represent to newly created path followed by the fraction of chyme bypassing a loop of small intestine. S; stomach; C, cecum; LoT, ligament of Treitz; ICV, ileocecal valve. DPID, distal partial intestinal diversion; VSG, vertical sleeve gastrectomy; VSG/DPID, vertical sleeve gastrectomy and distal partial intestinal diversion; AUC, Area under curve; *, denotes statistical significance relative to Sham. $ indicates statistical significance relative to DPID. ****, p < 0.0001; ***, p < 0.001; $$, p < 0.01. [ABSTRACT FROM AUTHOR]

Post–bariatric surgery hypoglycemia (PBH) is defined as the presence of neuroglycopenic symptoms accompanied by postprandial hypoglycemia in bariatric surgery patients. Recent clinical studies using continuous glucose monitoring (CGM) technology revealed that PBH is more frequently observed in vertical sleeve gastrectomy (VSG) patients than previously recognized. PBH cannot be alleviated by current medication. Therefore, a model system to investigate the mechanism and treatment is required. We used CGM in a rat model of VSG and monitored the occurrence of glycemic variability and hypoglycemia in various meal conditions for 4 weeks after surgery. Another cohort of VSG rats with CGM was used to investigate whether the blockade of glucagon-like peptide-1 receptor (GLP-1R) signaling alleviates these symptoms. A mouse VSG model was used to investigate whether the impaired glucose counterregulatory system causes postprandial hypoglycemia. Like in humans, rats have increased glycemic variability and hypoglycemia after VSG. Postprandial hypoglycemia was specifically detected after liquid versus solid meals. Further, the blockade of GLP-1R signaling raises the glucose nadir but does not affect glycemic variability. Rat bariatric surgery duplicates many features of human post–bariatric surgery hypoglycemia including postprandial hypoglycemia and glycemic variability, while blockade of GLP-1R signaling prevents hypoglycemia but not the variability. • VSG causes glycemic variability during ad lib feeding condition. • Single liquid meal ingestion causes post-VSG hypoglycemia. • Blockade of GLP-1 receptor prevents post-VSG hypoglycemia. [ABSTRACT FROM AUTHOR]

Objective Bariatric surgery is currently our most effective strategy at weight loss, yet the mechanisms for its success remain unknown. Low exercise capacity, in humans and rodents, predicts poor metabolic outcome. The objective of this manuscript was to determine if bariatric surgery could restore metabolic perturbations in rats with low intrinsic exercise capacity. Methods We performed vertical sleeve gastrectomy (VSG) or sham surgery in high fat-fed rats selectively bred for low running capacity. Results We found that VSG reduced body mass through a reduction in fat mass, caused early reductions in food intake, and shifted macronutrient preference away from fat and toward carbohydrates. VSG had no impact on basal glucose but did improve the return to baseline after an oral glucose load. As has been shown previously, VSG increased postprandial insulin, GLP-1, and bile acids. There was no significant impact of VSG on plasma triglycerides, hepatic triglycerides, or cholesterol. Interestingly, the brown adipose tissue to white adipose tissue ratio tended to be greater in VSG compared to sham surgery animals. While VSG positively impacted several aspects of metabolism, it did not enhance maximal oxygen capacity and seemed to lower metabolic efficiency as indicated by lower resting oxygen consumption and fat and carbohydrate oxidation. Conclusion VSG can improve the metabolic status of animals with a low exercise capacity independently of exercise capacity. [ABSTRACT FROM AUTHOR]

Objective The prevalence of obesity and related co-morbidities is reaching pandemic proportions. Today, the most effective obesity treatments are glucagon-like peptide 1 (GLP-1) analogs and bariatric surgery. Interestingly, both intervention paradigms have been associated with adaptive growth responses in the gut; however, intestinotrophic mechanisms associated with or secondary to medical or surgical obesity therapies are poorly understood. Therefore, the objective of this study was to assess the local basal endogenous and pharmacological intestinotrophic effects of glucagon-like peptides and bariatric surgery in mice. Methods We used in situ hybridization to provide a detailed and comparative anatomical map of the local distribution of GLP-1 receptor ( Glp1r ), GLP-2 receptor ( Glp2r ), and preproglucagon ( Gcg ) mRNA expression throughout the mouse gastrointestinal tract. Gut development in GLP-1R-, GLP-2R-, or GCG-deficient mice was compared to their corresponding wild-type controls, and intestinotrophic effects of GLP-1 and GLP-2 analogs were assessed in wild-type mice. Lastly, gut volume was determined in a mouse model of vertical sleeve gastrectomy (VSG). Results Comparison of Glp1r , Glp2r , and Gcg mRNA expression indicated a widespread, but distinct, distribution of these three transcripts throughout all compartments of the mouse gastrointestinal tract. While mice null for Glp1r or Gcg showed normal intestinal morphology, Glp2r −/− mice exhibited a slight reduction in small intestinal mucosa volume. Pharmacological treatment with GLP-1 and GLP-2 analogs significantly increased gut volume. In contrast, VSG surgery had no effect on intestinal morphology. Conclusion The present study indicates that the endogenous preproglucagon system, exemplified by the entire GCG gene and the receptors for GLP-1 and GLP-2, does not play a major role in normal gut development in the mouse. Furthermore, elevation in local intestinal and circulating levels of GLP-1 and GLP-2 achieved after VSG has limited impact on intestinal morphometry. Hence, although exogenous treatment with GLP-1 and GLP-2 analogs enhances gut growth, the contributions of endogenously-secreted GLP-1 and GLP-2 to gut growth may be more modest and highly context-dependent. [ABSTRACT FROM AUTHOR]

Objective The GH/IGF-1 axis has important roles in growth and metabolism. GH and GH receptor (GHR) are active in the central nervous system (CNS) and are crucial in regulating several aspects of metabolism. In the hypothalamus, there is a high abundance of GH-responsive cells, but the role of GH signaling in hypothalamic neurons is unknown. Previous work has demonstrated that the Ghr gene is highly expressed in LepRb neurons. Given that leptin is a key regulator of energy balance by acting on leptin receptor (LepRb)-expressing neurons, we tested the hypothesis that LepRb neurons represent an important site for GHR signaling to control body homeostasis. Methods To determine the importance of GHR signaling in LepRb neurons, we utilized Cre/loxP technology to ablate GHR expression in LepRb neurons (Lepr EYFPΔGHR ). The mice were generated by crossing the Lepr cre on the cre-inducible ROSA26-EYFP mice to GHR L/L mice. Parameters of body composition and glucose homeostasis were evaluated. Results Our results demonstrate that the sites with GHR and LepRb co-expression include ARH, DMH, and LHA neurons. Leptin action was not altered in Lepr EYFPΔGHR mice; however, GH-induced pStat5-IR in LepRb neurons was significantly reduced in these mice. Serum IGF-1 and GH levels were unaltered, and we found no evidence that GHR signaling regulates food intake and body weight in LepRb neurons. In contrast, diminished GHR signaling in LepRb neurons impaired hepatic insulin sensitivity and peripheral lipid metabolism. This was paralleled with a failure to suppress expression of the gluconeogenic genes and impaired hepatic insulin signaling in Lepr EYFPΔGHR mice. Conclusion These findings suggest the existence of GHR-leptin neurocircuitry that plays an important role in the GHR-mediated regulation of glucose metabolism irrespective of feeding. [ABSTRACT FROM AUTHOR]

Objective: In addition to adipocytes, adipose tissue contains large numbers of immune cells. A wide range of evidence links the activity of these cells to regulation of adipocyte and systemic metabolic function. Bariatric surgery improves several aspects of metabolic derangements and at least some of these effects occur in a weight-loss independent manner. We sought to investigate the impact of vertical sleeve gastrectomy (VSG) on adipose immune cell frequencies. Methods: We analyzed the frequencies of immune cells within distinct adipose tissue depots in obese mice that had VSG or sham surgery with a portion of the latter group pair-fed such that their body mass was matched to the VSG animals. Results: We demonstrate that VSG induced a shift in the epididymal adipose tissue leukocyte profile including increased frequencies of CD11c− macrophages, increased frequencies of T cells (CD4+, CD8+, and CD4−/CD8− T cells all increased), but a significantly decreased frequency of adipose tissue dendritic cells (ATDC) that, despite the continued high fat feeding of the VSG group, dropped below control diet levels. Conclusions: These results indicate that VSG induces substantial changes in the immune populations residing in the adipose depots independent of weight loss. [ABSTRACT FROM AUTHOR]

Background Prader-Willi syndrome (PWS) is a genetic disorder characterized by hyperphagia, obesity, cardiopulmonary diseases, and increased mortality. Although successful weight loss improves health in PWS, few treatments cause sustained weight loss in obese patients let alone obese individuals with PWS. Objectives The present study uses the Magel2 knockout (KO) mouse, an animal model of PWS, to conduct a preclinical study on the efficacy of sleeve gastrectomy (SG) in PWS. Setting Academic research laboratory, United States. Method s We performed sham or SG surgeries in 24- to 28-week-old male Magel2 KO and wild-type littermate control mice (WT) who had been maintained on a high-fat diet for 10 weeks. We monitored weight, food intake, and fat and lean mass pre- and postoperatively. Fasting glucose, glucose tolerance, and counter-regulation were measured postoperatively. Results Magel2 KO animals had similar recovery and mortality rates compared with WT. SG resulted in similar weight loss, specifically loss of fat but not lean mass, in both Magel2 KO and WT mice. SG also resulted in significantly lower fasting glucose levels and a reduction in fat intake in both Magel2 KO and WT mice. We also found that Magel2 KO mice failed to increase their food intake in response to the glucoprivic agent 2-deoxy-D-glucose, suggesting impaired glucose counter-regulation, but this occurred regardless of surgical status. All results were considered significant when P < .05. Conclusion We find in this mouse model of PWS, SG is a well-tolerated, effective strategy for weight and fat loss. [ABSTRACT FROM AUTHOR]

Changing composition of the gut microbiome is an important component of the gut adaptation to various environments, which have been implicated in various metabolic diseases including obesity and type 2 diabetes, but the mechanisms by which the microbiota influence host physiology remain contentious. Here we find that both diets high in the fermentable fiber inulin and vertical sleeve gastrectomy increase intestinal expression and circulating levels of the anti-microbial peptide Reg3g. Moreover, a number of beneficial effects of these manipulations on gut function, energy balance, and glucose regulation are absent in Reg3g knockout mice. Peripheral administration of various preparations of Reg3g improves glucose tolerance, and this effect is dependent on the putative receptor Extl3 in the pancreas. These data suggest Reg3g acts both within the lumen and as a gut hormone to link the intestinal microbiome to various aspects of host physiology that may be leveraged for novel treatment strategies. [Display omitted] • Reg3g is required for metabolic benefits of surgical or dietary interventions • Surgical or dietary intervention improves gut function in a Reg3g-dependent manner • Alteration of microbiome composition can provoke Reg3g in the system • Pharmacological application of Reg3g improves glucose tolerance in DIO mice Shin et al. find that both surgical and dietary gut manipulations increase the gut peptide Reg3g and require Reg3g for their beneficial effects on body weight, glucose levels, and gut function. Reg3g may also act as a gut hormone since systemic administration improves glucose regulation via actions on the pancreas. [ABSTRACT FROM AUTHOR]

Objective Melanocortin-4 receptors (MC4Rs) are highly expressed by dopamine-secreting neurons of the mesolimbic tract, but their functional role has not been fully resolved. Voluntary wheel running (VWR) induces adaptations in the mesolimbic dopamine system and has a myriad of long-term beneficial effects on health. In the present experiments we asked whether MC4R function regulates the effects of VWR, and whether VWR ameliorates MC4R-associated symptoms of the metabolic syndrome. Methods Electrically evoked dopamine release was measured in slice preparations from sedentary wild-type and MC4R-deficient Mc4r K314X (HOM) rats. VWR was assessed in wild-type and HOM rats, and in MC4R-deficient loxTB Mc4r mice, wild-type mice body weight-matched to loxTB Mc4r mice, and wild-type mice with intracerebroventricular administration of the MC4R antagonist SHU9119. Mesolimbic dopamine system function (gene/protein expression) and metabolic parameters were examined in wheel-running and sedentary wild-type and HOM rats. Results Sedentary obese HOM rats had increased electrically evoked dopamine release in several ventral tegmental area (VTA) projection sites compared to wild-type controls. MC4R loss-of-function decreased VWR, and this was partially independent of body weight. HOM wheel-runners had attenuated markers of intracellular D1-type dopamine receptor signaling despite increased dopamine flux in the VTA. VWR increased and decreased ΔFosB levels in the nucleus accumbens (NAc) of wild-type and HOM runners, respectively. VWR improved metabolic parameters in wild-type wheel-runners. Finally, moderate voluntary exercise corrected many aspects of the metabolic syndrome in HOM runners. Conclusions Central dopamine dysregulation during VWR reinforces the link between MC4R function and molecular and behavioral responding to rewards. The data also suggest that exercise can be a successful lifestyle intervention in MC4R -haploinsufficient individuals despite reduced positive reinforcement during exercise training. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: Glucagon-like peptide-1 (GLP-1), an insulinotropic gut peptide released after eating, is essential for normal glucose tolerance (GT). To determine whether this effect is mediated directly by GLP-1 receptors (GLP1R) on islet β cells, we developed mice with β cell-specific knockdown of Glp1r. β cell Glp1r knockdown mice had impaired GT after intraperitoneal (i.p.) glucose and did not secrete insulin in response to i.p. or intravenous GLP-1. However, they had normal GT after oral glucose, a response that was impaired by a GLP1R antagonist. β cell Glp1r knockdown mice had blunted responses to a GLP1R agonist but intact glucose lowering with a dipeptidylpeptidase 4 (DPP-4) inhibitor. Thus, in mice, β cell Glp1rs are required to respond to hyperglycemia and exogenous GLP-1, but other factors compensate for reduced GLP-1 action during meals. These results support a role for extraislet GLP1R in oral glucose tolerance and paracrine regulation of β cells by islet GLP-1. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Vertical Sleeve Gastrectomy (VSG) is one of the most efficacious treatments for obesity and its comorbidities. Although a range of evidence suggests that alterations of the microbiota in the distal gut following VSG are pivotal to these metabolic improvements, the effect of surgery to alter the microbiota of the proximal intestine and its effect on host physiology remain largely unknown. As the main bacteria in the upper small intestine, Lactobacillus subspecies have been appreciated as important regulators of gut function. These bacteria also regulate intestinal Hypoxia- Inducible Factor 2α (HIF2α) signaling that plays an integral role in gut physiology and iron absorption. In the present study, we sought to determine the impact of VSG on Lactobacillus spp. in the small intestine and potential downstream impacts of Lactobacillus spp. on HIF2α, specifically in the duodenum. To determine the effects of VSG on the microbiota and HIF2α signaling in the duodenum, VSG surgeries were performed on diet-induced obese mice. To further probe the relationship between Lactobacillus spp. and HIF2α signaling in the duodenum, we applied a customized high-fat but iron-deficient diet on mice to increase duodenal HIF2α signaling and determined alterations of gut bacteria. To explore the causal role of Lactobacillus spp. in duodenal HIF2α signaling activation, we chronically administered probiotics containing Lactobacillus spp. to high-fat-fed obese mice. Lastly, we studied the effect of lactate, the major metabolite of Lactobacilli , on HIF2α in ex vivo duodenal organoids. There were pronounced increases in the abundance of Lactobacillus spp. in samples isolated from duodenal epithelium in VSG-operated mice as compared to sham-operated mice. This was accompanied by an increase in the expression of genes that are targets of HIF2α in the duodenum of VSG-treated mice. Activating HIF2α signaling with a high-fat but iron-deficient diet resulted in weight loss, improvements in glucose regulation, and increased Lactobacillus spp. richness in the duodenum as compared to mice on an iron-replete diet. Chronic administration of probiotics containing Lactobacillus spp. not only increased HIF2α signaling in the duodenum such as occurs after VSG but also resulted in reduced weight gain and improved glucose tolerance in high-fat-fed mice. Furthermore, lactate was able to activate HIF2α in ex vivo duodenal organoids. These results support a model whereby VSG increases duodenal Lactobacillus richness and potentially stimulates intestinal HIF2α signaling via increased lactate production. [Display omitted] • Vertical sleeve gastrectomy increases Lactobacillus richness in the duodenum. • Vertical sleeve gastrectomy activates HIF2α signaling in the duodenum. • Increased Lactobacillus is linked to diet-induced HIF2α activation in the duodenum. • Probiotics containing Lactobacillus spp. activate HIF2α signaling in the duodenum. • Lactate can directly activate HIF2α signaling in the intestinal cells. [ABSTRACT FROM AUTHOR]

Abstract: Ethanol (OH) has been reported to blunt counterregulation and increase insulin sensitivity, thereby causing greater hypoglycemia in patients with diabetes mellitus. The aim of this study was to determine if fore- or hindbrain sensing of OH differentially affects autonomic and metabolic counterregulatory responses to hypoglycemia. Forty-one Sprague-Dawley rats received 5% OH or isotonic sodium chloride solution (or normal saline; SAL) infused peripherally or into the lateral (forebrain) or fourth cerebral ventricles (hindbrain) from time 0 to 120 minutes. From time 120 to 240 minutes, rats were exposed to a hyperinsulinemic (5 mU/[kg min]) hypoglycemic (2.9 ± 0.1 mmol/L) clamp. The 4 groups of rats studied were as follows: SAL (n = 8), peripheral alcohol (POH) (n = 10), lateral ventricle alcohol (LVOH) (n = 12), and left ventricle alcohol (4VOH) (n = 11). After OH, basal levels of norepinephrine were lower in the POH and 4VOH groups (P < .05). Epinephrine and norepinephrine responses to hypoglycemia were significantly lower in POH, 4VOH, and LVOH vs SAL. However, the magnitude of blunting was significantly greater in POH and 4VOH vs LVOH. Other counterregulatory hormones and glucose kinetics were not significantly different among all groups during hypoglycemia. In summary, peripheral and central nervous system OH infusion blunted autonomic nervous system counterregulatory (epinephrine, norepinephrine) responses to subsequent hypoglycemia. The greater impact of 4VOH compared with LVOH administration suggests that OH exerts its effects to blunt autonomic nervous system counterregulatory responses during hypoglycemia primarily by actions on the hindbrain. [Copyright &y& Elsevier]

Type I diabetes mellitus patients who tightly control blood glucose levels toward normal have increased frequency of hypoglycemia, a major barrier to physical activity. This article presents the hypothesis that dysfunctional autonomic regulation of metabolism after recent bouts of exercise or hypoglycemia contributes to exercise-induced hypoglycemia in these patients. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 is a nutrient-sensitive hormone secreted from enteroendocrine L cells within the small and large bowel. Although GLP-1 levels rise rapidly in response to food ingestion, the greatest density of L cells is localized to the distal small bowel and colon. Here, we assessed the importance of the distal gut in the acute L cell response to diverse secretagogues. Circulating levels of glucose and plasma GLP-1 were measured in response to the administration of L cell secretagogues in wild-type mice and in mice with (1) genetic reduction of Gcg expression throughout the small bowel and large bowel (Gcg Gut−/-) and (2) selective reduction of Gcg expression in the distal gut (Gcg DistalGut−/-). The acute GLP-1 response to olive oil or arginine administration was markedly diminished in Gcg Gut−/- but preserved in Gcg DistalGut−/- mice. In contrast, the increase in plasma GLP-1 levels following the administration of the GPR119 agonist AR231453, or the melanocortin-4 receptor (MC4R) agonist LY2112688, was markedly diminished in the Gcg DistalGut−/- mice. The GLP-1 response to LPS was also markedly attenuated in the Gcg Gut−/- mice and remained submaximal in the Gcg DistalGut−/- mice. Doses of metformin sufficient to lower glucose and increase GLP-1 levels in the Gcg Gut+/+ mice retained their glucoregulatory activity, yet they failed to increase GLP-1 levels in the Gcg Gut−/- mice. Surprisingly, the actions of metformin to increase plasma GLP-1 levels were substantially attenuated in the Gcg DistalGut−/- mice. These findings further establish the importance of the proximal gut for the acute response to nutrient-related GLP-1 secretagogues. In contrast, we identify essential contributions of the distal gut to (i) the rapid induction of circulating GLP-1 levels in response to pharmacological selective agonism of G-protein-coupled receptors, (ii) the increased GLP-1 levels following the activation of Toll-Like Receptors with LPS, and iii) the acute GLP-1 response to metformin. Collectively, these results reveal that distal gut Gcg + endocrine cells are rapid responders to structurally and functionally diverse GLP-1 secretagogues. Image 1 • Distal gut Gcg expression is dispensable for GLP-1 response to olive oil and arginine. • GLP-1 response to GPR119 and MCR4 agonism requires distal gut Gcg expression. • The maximal GLP-1 response to lipopolysaccharide requires distal gut Gcg expression. • The distal gut is a substantial source of GLP-1 release in response to metformin. [ABSTRACT FROM AUTHOR]

To understand hindbrain pathways involved in the control of food intake, we examined roles for calcitonin receptor (CALCR)-containing neurons in the NTS. Ablation of NTS Calcr abrogated the long-term suppression of food intake, but not aversive responses, by CALCR agonists. Similarly, activating CalcrNTS neurons decreased food intake and body weight but (unlike neighboring CckNTS cells) failed to promote aversion, revealing that CalcrNTS neurons mediate a non-aversive suppression of food intake. While both CalcrNTS and CckNTS neurons decreased feeding via projections to the PBN, CckNTS cells activated aversive CGRPPBN cells while CalcrNTS cells activated distinct non-CGRP PBN cells. Hence, CalcrNTS cells suppress feeding via non-aversive, non-CGRP PBN targets. Additionally, silencing CalcrNTS cells blunted food intake suppression by gut peptides and nutrients, increasing food intake and promoting obesity. Hence, CalcrNTS neurons define a hindbrain system that participates in physiological energy balance and suppresses food intake without activating aversive systems. • NTS Calcr mediates food intake suppression but not aversive responses to sCT • Activating NTS Calcr neurons non-aversively suppresses feeding • These neurons act via non-CGRP PBN neurons • These neurons control long-term energy balance, not just short-term feeding While the hindbrain is often postulated to control only short-term parameters of feeding via circuits that mediate aversive responses when activated strongly, Cheng et al. have identified a hindbrain system that participates in the physiological control of energy balance and suppresses food intake without activating aversive systems or symptoms. [ABSTRACT FROM AUTHOR]

The importance of pancreatic versus intestinal-derived GLP-1 for glucose homeostasis is controversial. We detected active GLP-1 in the mouse and human pancreas, albeit at extremely low levels relative to glucagon. Accordingly, to elucidate the metabolic importance of intestinal proglucagon-derived peptides (PGDPs), we generated mice with reduction of Gcg expression within the distal (Gcg DistalGut−/−) or entire (Gcg Gut−/−) gut. Substantial reduction of gut Gcg expression markedly reduced circulating levels of GLP-1, and impaired glucose homeostasis, associated with increased levels of GIP, and accelerated gastric emptying. Gcg DistalGut−/− mice similarly exhibited lower circulating GLP-1 and impaired oral glucose tolerance. Nevertheless, plasma levels of insulin remained normal following glucose administration in the absence of gut-derived GLP-1. Collectively, our findings identify the essential importance of gut-derived PGDPs for maintaining levels of circulating GLP-1, control of gastric emptying, and glucose homeostasis. • The mouse and human pancreas contain low levels of active GLP-1 • The gut enteroendocrine system is responsible for 95% of circulating active GLP-1 • The proximal gut sustains normal plasma GLP-1 levels in response to enteral glucose • Gut Gcg expression controls glucose tolerance and gastric emptying The gut-derived hormone GLP-1 also functions as an islet-derived insulinotropic peptide. Song and Koehler et al. now show that whereas the pancreas contains active GLP-1, deletion of the Gcg gene from the gut lowers circulating GLP-1, impairs glucose tolerance, and accelerates gastric emptying, highlighting essential metabolic roles of the gut GLP-1 system. [ABSTRACT FROM AUTHOR]

Summary 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. 13C-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. [ABSTRACT FROM AUTHOR]

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. [Copyright &y& Elsevier]