Vertical sleeve gastrectomy induces enteroendocrine cell differentiation of intestinal stem cells through bile acid signaling.

Vertical sleeve gastrectomy (VSG) results in an increase in the number of hormone-secreting enteroendocrine cells (EECs) in the intestinal epithelium; however, the mechanism remains unclear. Notably, the beneficial effects of VSG are lost in a mouse model lacking the nuclear bile acid receptor farnesoid X receptor (FXR). FXR is a nuclear transcription factor that has been shown to regulate intestinal stem cell (ISC) function in cancer models. Therefore, we hypothesized that the VSG-induced increase in EECs is due to changes in intestinal differentiation driven by an increase in bile acid signaling through FXR. To test this, we performed VSG in mice that express EGFP in ISC/progenitor cells and performed RNA-Seq on GFP-positive cells sorted from the intestinal epithelia. We also assessed changes in EEC number (marked by glucagon-like peptide-1, GLP-1) in mouse intestinal organoids following treatment with bile acids, an FXR agonist, and an FXR antagonist. RNA-Seq of ISCs revealed that bile acid receptors are expressed in ISCs and that VSG explicitly alters expression of several genes that regulate EEC differentiation. Mouse intestinal organoids treated with bile acids and 2 different FXR agonists increased GLP-1-positive cell numbers, and administration of an FXR antagonist blocked these effects. Taken together, these data indicate that VSG drives ISC fate toward EEC differentiation through bile acid signaling.

Glycemic effect of pancreatic preproglucagon in mouse sleeve gastrectomy.

Intestinally derived glucagon-like peptide-1 (GLP-1), encoded by the preproglucagon (Gcg) gene, is believed to function as an incretin. However, our previous work questioned this dogma and demonstrated that pancreatic peptides rather than intestinal Gcg peptides, including GLP-1, are a primary regulator of glucose homeostasis in normal mice. The objective of these experiments was to determine whether changes in nutrition or alteration of gut hormone secretion by bariatric surgery would result in a larger role for intestinal GLP-1 in the regulation of insulin secretion and glucose homeostasis. Multiple transgenic models, including mouse models with intestine- or pancreas tissue-specific Gcg expression and a whole-body Gcg-null mouse model, were generated to study the role of organ-specific GLP-1 production on glucose homeostasis under dietary-induced obesity and after weight loss from bariatric surgery (vertical sleeve gastrectomy; VSG). Our findings indicated that the intestine is a major source of circulating GLP-1 after various nutrient and surgical stimuli. However, even with the 4-fold increase in intestinally derived GLP-1 with VSG, it is pancreatic peptides, not intestinal Gcg peptides, that are necessary for surgery-induced improvements in glucose homeostasis.

Vertical sleeve gastrectomy corrects metabolic perturbations in a low-exercise capacity rat model.

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.