(OR34-07-24) Chronic Alcohol Consumption Impairs BCAA Catabolism in Brown Fat

Objectives: Alcohol consumption is the third leading preventable cause of mortality in the United States. Chronic heavy alcohol drinking increases the risk of metabolic dysregulation, such as fatty liver and cardiovascular disease, and related premature death. However, it remains unclear how 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 linked with metabolic diseases. Brown adipose tissue (BAT) actively utilizes BCAA for thermogenesis and improves energy homeostasis through systemic BCAA clearance. We aimed to identify a previously unknown pathological mechanism in BAT-mediated systemic BCAA regulation for alcoholic metabolic dysfunctions.

Methods: Following the NIAAA protocol, adult C57BL/6J mice were chronically fed a Lieber-DeCarli liquid diet with ethanol or its control diet. Their metabolic phenotypes were characterized by blood BCAA detection and BCAA or glucose tolerance test. BATs and livers, as major organs for BCAA oxidation, were subjected to gene expression analysis. The cell-autonomous response to ethanol was tested in primary murine and human brown adipocytes by measuring cellular BCAA levels and BCAA oxidation gene expression.

Results: Compared to the control group, ethanol-fed mice showed a higher concentration of circulating BCAA with intolerance to BCAA or glucose challenge, revealing impaired BCAA clearance and metabolic disturbances. Notably, gene expression analysis of BATs and livers indicated that BAT was the primary organ responsible for defective systemic BCAA clearance upon chronic alcohol challenge by demonstrating molecular impairment of BCAA utilization machinery encompassing mitochondrial BCAA transport, oxidation, and thermogenesis. Consistently, chronic excessive alcohol exposure caused abnormally highly accumulated BCAA levels with impaired BCAA catabolism gene regulation in mouse and human primary brown adipocytes.

Conclusions: Chronic alcohol consumption damages BAT function as a metabolic sink for BCAA and disturbs energy homeostasis, which may serve as a pathological mechanism for alcohol-induced systemic metabolic dysregulation.

Funding Sources: National Institute on Alcohol Abuse and Alcoholism (NIAAA)