Regulation of cold-induced thermogenesis by the stress granule protein FAM195A

Homeothermic vertebrates are capable of surviving in cold environments by maintaining constant body temperature through thermogenesis, in which brown adipose tissue (BAT) produces heat by increasing mitochondrial oxidation along with the uncoupling of the electron transport chain and activation of uncoupling protein 1 (UCP1). Although the transcription factors that control the expression of UCP1 and genes involved in nutrient oxidation, mitochondrial function, have been extensively studied, only a few other proteins essential for BAT function have been identified. Here we describe the discovery of FAM195A, a disordered domain RNA-binding protein associated with stress granules that is required for cold-dependent thermogenesis in mice. FAM195A expression is enriched in BAT and striated muscles, and mice lacking FAM195A display whitening of BAT and an inability to survive at cold temperatures. In BAT of mice lacking FAM195A, key enzymes involved in branched chain amino acid (BCAA) metabolism, in particular leucine, and fatty acid (FA) oxidation are downregulated, impairing the physiological response to cold stress. Moreover, in vitro knock down of FAM195A impairs expression of leucine oxidation enzymes, revealing a direct role of FAM195A in the regulation of BCAA metabolism during thermogenesis Overall design: Discovery of FAM195A, a RNA-binding protein required for cold-dependent thermogenesis in mice and characterization of FAM195A KO animals