Joyce E. Sorrell

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.

Perinatal Exposure to Bisphenol-A and the Development of Metabolic Syndrome in CD-1 Mice

Bisphenol-A (BPA) is an endocrine-disrupting chemical used in the production of plastic food and beverage containers, leading to ubiquitous low-dose human exposure. It has been suggested that exposure to even low doses of BPA during development may be associated with increased susceptibility to obesity and diabetes later in life. Despite growing public concern, the existing empirical data are equivocal, prompting The Endocrine Society, the National Institute of Environmental Health Sciences, and others to call for further research. In this study, we tested the hypothesis that perinatal exposure to an ecologically relevant dose of BPA (1 part per billion via the diet) results in increased susceptibility to high-fat diet-induced obesity and glucose intolerance in adult CD-1 mice. The data did not support this hypothesis. In agreement with previous reports, we find that weanling mice exposed to BPA during gestation and lactation are heavier compared with control mice. We also find that BPA mice are longer than controls at 4 wk of age, but these differences are no longer apparent when the mice reach adulthood, even when tested on a high-fat diet. We conclude that this larger size-for-age represents a faster rate of growth early in development rather than an obese, diabetic phenotype in adulthood.

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.

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.

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 roles of leptin receptors on POMC neurons in the regulation of sex-specific energy homeostasis.

Leptin regulates energy homeostasis and reproduction. One key population of leptin receptors (Lepr) are found on proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus, and evidence links the action of gonadal estrogens to these same POMC neurons. To determine whether Lepr on POMC neurons are critical for reproductive capacity or for sex-specific energy and glucose homeostasis, we studied Cre/loxP mice lacking Lepr specifically on POMC neurons (Pomc-Cre, Lepr(flox/flox) mice) and their controls with normal Lepr (Lepr(flox/flox) mice). Pomc-Cre, Lepr(flox/flox) mice maintained normal reproductive capacity and accumulated more body fat than their same sex controls. Ovariectomy (OVX) was performed to investigate the effects of the estrogens and Lepr on POMC neurons on body fat accumulation and glucose tolerance. OVX Pomc-Cre, Lepr(flox/flox) females accumulated more fat than OVX Lepr(flox/flox) females did. Pomc-Cre, Lepr(flox/flox) males were glucose intolerant and insulin insensitive compared with control males. In contrast, control and Pomc-Cre, Lepr(flox/flox) females had similar glucose tolerance before and after OVX. Therefore leptins action on POMC neurons reduces body fat accumulation, but is not critical for regulation of reproduction. The sex difference in leptin signaling on POMC neurons on glucose tolerance appears independent of ovarian hormones.

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.

Vertical sleeve gastrectomy restores glucose homeostasis in apolipoprotein A-IV KO mice.

Bariatric surgery is the most successful strategy for treating obesity, yet the mechanisms for this success are not clearly understood. Clinical literature suggests that plasma levels of apolipoprotein A-IV (apoA-IV) rise with Roux-en-Y gastric bypass (RYGB). apoA-IV is secreted from the intestine postprandially and has demonstrated benefits for both glucose and lipid homeostasis. Because of the parallels in the metabolic improvements seen with surgery and the rise in apoA-IV levels, we hypothesized that apoA-IV was necessary for obtaining the metabolic benefits of bariatric surgery. To test this hypothesis, we performed vertical sleeve gastrectomy (VSG), a surgery with clinical efficacy very similar to that for RYGB, in whole-body apoA-IV knockout (KO) mice. We found that VSG reduced body mass and improved both glucose and lipid homeostasis similarly in wild-type mice compared with apoA-IV KO mice. In fact, VSG normalized the impairment in glucose tolerance and caused a significantly greater improvement in hepatic triglyceride storage in the apoA-IV KO mice. Last, independent of surgery, apoA-IV KO mice had a significantly reduced preference for a high-fat diet. Altogether, these data suggest that apoA-IV is not necessary for the metabolic improvements shown with VSG, but also suggest an interesting role for apoA-IV in regulating macronutrient preference and hepatic triglyceride levels. Future studies are necessary to determine whether this is the case for RYGB as well.

The anorectic effect of CNTF does not require action in leptin-responsive neurons.

Leptin resistance is a feature of obesity that poses a significant therapeutic challenge. Any treatment that is effective to reduce body weight in obese patients must overcome or circumvent leptin resistance, which promotes the maintenance of excess body fat in obese individuals. Ciliary neurotrophic factor (CNTF) is unique in its ability to reduce food intake and body weight in obese, leptin-resistant humans and rodents. Although attempts to use CNTF as an obesity therapy failed due to the development of neutralizing antibodies to the drug, efforts to understand mechanisms for CNTFs anorectic effects provide an opportunity to develop new drugs for leptin-resistant individuals. CNTF and leptin share several structural, anatomic, and signaling properties, but it is not understood whether or how the two cytokines might interact to affect energy balance. Here, we conditionally deleted the CNTF receptor (CNTFR) subunit, CNTFRα, in cells expressing leptin receptors. We found that CNTFR signaling in leptin-responsive neurons is not required for endogenous maintenance of energy balance and is not required for the anorectic response to exogenous administration of a CNTF agonist. These results indicate that despite anatomical overlap for CNTF and leptin action, CNTF appears to act within a distinct neuronal population to elicit its potent anorectic effect.

Impact of intestinal electrical stimulation on nutrient-induced GLP-1 secretion in vivo.

Increases in L‐cell release of GLP‐1 are proposed to serve as a negative feedback signal for postprandial changes in gastric emptying and/or motility. Previous ex vivo data suggests that direct electrical stimulation (E‐stim) of ileal segments stimulates secretion of GLP‐1. This suggests potential feed‐forward increases in GLP‐1 driven by intestinal neuronal and/or motor activity.