Rictor/mTORC2 Loss in the Myf5 Lineage Reprograms Brown Fat Metabolism and Protects Mice against Obesity and Metabolic Disease

The in vivo functions of mechanistic target of rapamycin complex 2 (mTORC2) and the signaling mechanisms that control brown adipose tissue (BAT) fuel utilization and activity are not well understood. Here, by conditionally deleting Rictor in the Myf5 lineage, we provide in vivo evidence that mTORC2 is dispensable for skeletal muscle development and regeneration but essential for BAT growth. Furthermore, deleting Rictor in Myf5 precursors shifts BAT metabolism to a more oxidative and less lipogenic state and protects mice from obesity and metabolic disease at thermoneutrality. We additionally find that Rictor is required for brown adipocyte differentiation in vitro and that the mechanism specifically requires AKT1 hydrophobic motif phosphorylation but is independent of pan-AKT signaling and is rescued with BMP7. Our findings provide insights into the signaling circuitry that regulates brown adipocytes and could have important implications for developing therapies aimed at increasing energy expenditure as a means to combat human obesity. [Display omitted] •Brown and white adipocyte growth requires mTORC2•mTORC2 promotes lipogenesis and suppresses β-oxidation in brown fat•Brown preadipocytes also require mTORC2 to differentiate in vitro•Inhibiting mTORC2 in BAT enhances diet-induced thermogenesis The signaling pathways that regulate energy storage and expenditure in brown fat are not well understood. By deleting Rictor (an essential mTORC2 subunit) in precursors of skeletal muscle and brown adipocytes, Hung et al. show that mTORC2 is dispensable for muscle growth during development but essential for lipid accumulation in brown fat. Rictor controls brown fat energy balance by promoting lipid metabolism and suppressing β-oxidation. In the absence of Rictor, brown fat mitochondrial activity increases, enhancing thermogenesis and protecting mice against obesity and metabolic disease.