Investigation of The Role of Farnesoid X Receptor (FXR) In The Metabolic Improvements Following Bypass Surgery

Vanderbilt University Medical Center, Nashville TN

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Abstract

Abstract Obesity and diabetes are worldwide challenges. Bariatric procedures such as Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are the most effective and long-term treatment for obesity and its associated comorbidities such as diabetes. Interestingly, the metabolic improvements such as glucose homeostasis and insulin sensitivity following bariatric surgeries occur prior to any significant weight loss. The mechanisms responsible for these improvements are unknown but recent findings have identified bile acids as the major contributor to these metabolic benefits. It is now clear that bile acids have hormonal activity and are involved in glucose and lipid metabolism and energy expenditure. Our laboratory has been successful in establishing mouse models of RYGB and VSG similar to those performed clinically. In an attempt to understand the potential role of bile acids in the metabolic improvements seen after bariatric procedures, we have developed a new mouse model that enables diversion of bile acids to ileum (GB-IL) without altering the anatomy of the stomach. Our recent observations demonstrate that GB-IL leads to more weight loss and metabolic improvement compared to RYGB. These findings were linked to the farnesoid X receptor (FXR) that is highly expressed in the intestine and liver. FXR is the major regulator of bile acid synthesis by controlling the expression of cholesterol 7?-hydroxylase (CYP7A1), the rate limiting enzyme in bile acid biosynthesis pathway. In this proposal we will investigate the role of intestinal FXR in mediating the metabolic improvements after bariatric surgery. To address this, we will perform RYGB, VSG, and GB-IL in diet induced obese mice and compare the results to sham-operated control group. . As the secondary aim, we will also investigate the impact of absence of intestinal FXR in bile acid pool and composition on the observed metabolic benefits after bariatric surgery. In this regard we will perform the same bariatric procedures as first aim in two additional groups of mice: wild type and intestinal-FXR knockout. This work will lead to better understanding of the role of FXR signaling in glucose homeostasis and insulin sensitivity and bile acids contribution to this complex interaction. The findings of this proposal may help develop novel therapeutics and potentially more effective surgical procedures for obesity and diabetes.