Conjugated bile acids as metabolic mediators between gut and fat tissues - Revised Abstract / Summary Although bariatric surgery is the most effective treatment to promote sustained weight loss and metabolic improvement, they are invasive and can cause severe long-term adverse effects. There is a pressing need for safer and more affordable therapies. A greater understanding of the roles of conjugated bile acids in mediating the metabolic benefits of bariatric surgery may provide the background and direction towards developing new approaches to treat obesity and associated fatty liver diseases. Our preliminary data and the experiments proposed in this application propose to understand how conjugated bile acids regulate metabolism after bariatric surgery. After performing VSG in obese mice, we observe that: 1) VSG induced adipocyte lipolysis and enhanced fatty acid β-oxidation; VSG induces adipocyte browning, as well as induced macrophages conversion in the adipose tissues. 2) VSG leads to a strong increase in systemic levels of conjugated bile acids. 3) VSG induces expression of the hepatic enzymes for bile acid conjugation and alters the gut microbiota (GM), including bacteria with bile salt hydrolase (BSH) activity. This may contribute to the increase of conjugated bile acids and decrease of un-conjugated bile acid levels in the serum after VSG. 4) conjugated bile acids increased the expression levels of lipolysis markers in adipocytes in a bile acid receptor, sphingosine-1-phosphate receptor 2 (S1PR2)-dependent manner; and 5) VSG activated S1PR2 downstream signaling in the white adipose tissue (WAT) of mice. Based on these and other preliminary results, we hypothesize that VSG activates a gut–adipose axis which includes a conjugated bile acids mediated S1PR2 signaling pathway to induce fat loss. We propose two specific aims to test our hypothesis: 1) To determine the effects of VSG-altered conjugated bile acids and GM on adipose tissue lipolysis; 2) To identify the molecular mechanism by which conjugated bile acids promote adipocyte lipolysis. The proposed research will expand our understanding of the molecular mechanism by which conjugated bile acids improve metabolism after VSG. This work will also locate new therapeutic targets and/or probiotics for safe, non-surgical, cost-affordable treatment of metabolic diseases.
