The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuating hepatic lipogenesis

Brown fat activates uncoupled respiration to defend against cold and contributes to systemic metabolic homeostasis. To date, the metabolic action of brown fat has been primarily attributed to its role in fuel oxidation and uncoupling protein 1 (UCP1)-mediated thermogenesis. Whether brown fat engages other tissues through secreted factors remains largely unexplored. Here we show that Neuregulin 4 (Nrg4), a member of the EGF family of extracellular ligands, is highly expressed in adipose tissues, enriched in brown fat, and markedly increased during brown adipocyte differentiation. Adipose tissue Nrg4 expression was reduced in rodent and human obesity. Gain- and loss-of-function studies in mice demonstrated that Nrg4 protects against diet-induced insulin resistance and hepatic steatosis through attenuating hepatic lipogenic signaling. Mechanistically, Nrg4 activates ErbB3/ErbB4 signaling in hepatocytes and negatively regulates de novo lipogenesis mediated by LXR/SREBP1c in a cell-autonomous manner. These results establish Nrg4 as a brown fat-enriched endocrine factor with therapeutic potential for the treatment of obesity-associated disorders, including type 2 diabetes and non-alcoholic fatty liver disease.