Bariatric surgery is an effective treatment that promotes sustained weight loss and remission of type 2 diabetes (T2D) and fatty liver diseases. Although bariatric surgery produces the most dramatic metabolic improvements of any obesity and T2D treatments available, it is invasive and has severe long-term side effects. Moreover, the surgery is not routinely available to low-income populations, which are disproportionately affected by obesity and T2D. Therefore, safer and more affordable therapies are urgently needed. Developing a greater understanding of the molecular mechanisms that underlie the metabolic benefits of bariatric surgery may provide a roadmap to develop innovative approaches to treat obesity, T2D, and other metabolic complications. Our preliminary data and the experiments proposed in this application rely on vertical sleeve gastrectomy (VSG) in mice as a model to interrogate the molecular consequences of bariatric surgery. VSG produces prominent physiological effects and generally results in fewer complications than other bariatric surgeries. It has thus become one of the most popular bariatric operations performed in clinical practice. After performing VSG in obese mice, we observe dramatic changes in serum bile acid (BA) composition, as well as downregulation of the enzyme CYP8B1. Specifically, we observe reduced ratios of 12?-hydroxylated (12?-OH) BAs relative to non-12?-OH BAs. 12?-OH BAs require CYP8B1 for synthesis in the liver and have been associated with insulin resistance and non-alcoholic fatty liver disease. Intestinal lipid absorption, which contributes to weight gain, is also substantially lower in mice after VSG. Based on these exciting preliminary results, we hypothesize that VSG alters specific BAs in enterohepatic circulation by downregulating CYP8B1, thus restricting intestinal lipid absorption and changing the gut microbiome, which contributes to the metabolic effects of the surgery. We propose three specific aims to test our hypothesis: (1) To characterize the redistribution of BAs along the enterohepatic circuit after VSG; (2) To determine the extent to which CYP8B1 downregulation mediates the metabolic effects of VSG; and (3) To investigate the mechanisms by which CYP8B1 downregulation contributes to the metabolic effects of VSG. We will compare the effects of VSG on wild type, Cyp8b1 knockout (KO), CYP8B1 overexpressing, as well as Cyp2c70 KO mice that confer more human-like BA pool composition. These studies will provide novel insights into the molecular mechanisms underlying the beneficial effects of bariatric surgery. We anticipate that our findings will lead to the development of safer, non-invasive, and more cost-effective therapies for obesity, T2D, and other metabolic diseases.
Bariatric surgery efficiently and sustainably ameliorates the symptoms of obesity and its complications, including type 2 diabetes and non-alcoholic fatty liver disease, but the precise mechanisms by which the positive effects of bariatric surgery are conferred remain unclear. We propose to leverage our unique surgical mouse models and state-of-the-art technology to examine the role of bile acids in mediating the beneficial effects of bariatric surgery. The results of our studies will provide novel mechanistic insights that may lead to a new generation of cost-effective, non-invasive therapies for obesity and its complications.
