Aberrant BCAA utilization in alcohol-induced metabolic dysregulation

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Project Summary Alcohol consumption is the third leading preventable cause of mortality and carries a significant economic burden in the United States. Chronic heavy alcohol drinking increases the risk of metabolic dysregulation, such as type 2 diabetes, fatty liver disease, and cardiovascular disease, and related premature death. However, what has not been well understood is how heavy alcohol consumption is mechanistically associated with the onset and progression of metabolic disorders. Increased blood levels of Branched- Chain Amino Acids (BCAA; valine, leucine, and isoleucine) are associated with obesity, type 2 diabetes, fatty liver disease, and cardiovascular disease in both rodents and humans. Emerging evidence suggests that brown adipose tissue that dissipates excess energy in the form of heat actively utilizes BCAA and improves insulin sensitivity and glucose tolerance through systemic BCAA clearance. Our preliminary data indicated that chronic excessive alcohol caused abnormally highly accumulated BCAA levels in mouse and human primary brown adipocytes. Targeted gene expression analysis suggested impairment of BCAA utilization machinery encompassing mitochondrial BCAA transport, oxidation, and thermogenesis in primary brown adipocytes upon chronic excessive alcohol challenge. In our early animal study, elevated circulating BCAA levels were detected in alcohol-fed animals at the physiological level. Accordingly, we hypothesize that chronic excessive alcohol drinking impairs brown adipose-mediated BCAA utilization, which in turn causes alcoholic metabolic dysregulation via increased systemic BCAA accumulation. Using in vitro and in vivo systems with chronic excessive alcohol challenges, we will thoroughly characterize abnormal brown cellular phenotypes associated with BCAA utilization (Aim 1) and their mechanisms (Aim 2) in a cell- autonomous manner and validate the in vitro findings at the physiological level (Aim 3). Our study will provide the first evidence that chronic heavy alcohol drinking damages thermogenic fat function as a metabolic sink for BCAA and disturbs energy balance, which serves as a pathological mechanism for alcohol-induced systemic metabolic dysregulation. Therefore, the outcome of this study will contribute to filling the existing knowledge gap in understanding alcohol-induced tissue damage and dependent metabolic diseases and developing a therapeutic strategy to reverse a broad range of alcohol-induced metabolic disorders.