There is a pressing need for new therapeutic strategies for addressing the epidemic of obesity and its co-morbidities. Bariatric surgery, such as Roux-en-Y Gastric Bypass (RYGB) and vertical sleeve gastrectomy surgery (VSG), is currently the most effective treatment for obesity and often results in remission or decreased risk of co-morbidities, such as type 2 diabetes, hypertension and cancer. However, the mechanisms by which this occurs are undefined. Improvements in glucose regulation and blood pressure often occur before significant body weight loss, suggesting that these improvements happen independently of body weight loss. Identification of the mechanisms underlying these surgically-induced benefits may allow for the development of novel therapies for managing obesity and its co-morbidities. Thus, the overall theme of our research program is developing, standardizing and studying animal models of bariatric surgery with the goal of identifying the mechanisms by which bariatric surgery causes these metabolic improvements. Several post-operative changes have been suggested to contribute to the benefits of bariatric surgery, including increases in circulating glucagon like peptide-1 (GLP-1) and bile acid concentrations.
GLP-1 is a hormone secreted by gastrointestinal enteroendocrine cells in response to nutrient ingestion. GLP-1 contributes to postprandial glucose clearance by acting as an incretin hormone to potentiate glucose-stimulated insulin secretion. GLP-1 signaling promotes several other metabolic benefits, including decreased energy intake, improved insulin sensitivity and improved lipid metabolism. Therefore, GLP-1 has become an important therapeutic target in the clinical management of obesity and type 2 diabetes. Nutrient-stimulated GLP-1 secretion is remarkably enhanced after several types of bariatric surgery, including RYGB and VSG. Given the anti-diabetic actions of GLP-1 signaling, elevations in circulating GLP-1 concentrations may contribute to post-operative improvements in glucose regulation.
Circulating bile acid concentrations are elevated after several types of bariatric surgery, including RYGB and VSG. Bile acids are amphipathic steroid molecules with detergent properties that aid in the digestion of dietary cholesterol and lipid. Bile acids also contribute to glucose homeostasis by signaling through several receptors, including TGR5. TGR5 is a transmembrane G protein coupled receptor that acts to maintain glucose homeostasis and decreases inflammatory cytokine secretion. The contributions of post-operative changes in GLP-1 and bile acids are being assessed through genetic and pharmaceutical approaches in mouse models of VSG, RYGB and ileal interposition.