Hepatic DNAJB9 Drives Anabolic Biasing to Reduce Steatosis and Obesity

Nutrients stimulate the anabolic synthesis of proteins and lipids, but selective insulin resistance in obesity biases the anabolic program toward lipogenesis. Here, we report the identification of a DNAJB9-driven program that favors protein synthesis and energy production over lipid accumulation. We show there are two pools of DNAJB9 cochaperone. DNAJB9 in the ER lumen promotes the degradation of the lipogenic transcription factor SREBP1c through ERAD, whereas its counterpart on the ER membrane promotes the assembly of mTORC2 in the cytosol and stimulates the synthesis of proteins and ATP. The expression of Dnajb9 is induced by nutrients and downregulated in the obese mouse liver. Restoration of hepatic DNAJB9 expression effectively improves insulin sensitivity, restores protein synthesis, and suppresses food intake, accompanied by reduced hepatic steatosis and adiposity in multiple mouse models of obesity. Therefore, targeting the anabolic balance may provide a unique opportunity to tackle obesity and diabetes. [Display omitted] •DNAJB9 adopts a dual topology to promote SREBP1c degradation and mTORC2 assembly•DNAJB9's dual-activity biases cellular metabolism against energy deposition•The development of obesity is accompanied by hepatic DNAJB9 downregulation•Hepatic DNAJB9 re-expression improves whole-body energy homeostasis Sun et al. show that DNAJB9 promotes SREBP1c degradation and mTORC2 assembly to stimulate protein synthesis and ATP production at the cost of lipogenesis. The anabolic biasing function of DNAJB9 drives cellular metabolism toward energy expenditure, and it provides a paradigm for tackling hyperphagia, obesity, and fatty liver diseases.