Glia maturation factor-β deficiency improves insulin resistance by promoting CARM1-mediated lipid turnover

Insulin resistance (IR) is a major factor for obesity-associated type 2 diabetes. The molecular mechanisms of IR and its systemic control remain poorly understood, and pharmacological drugs to ameliorate IR are an unmet need. So finding new therapeutic targets and drugs is important. Here, we report that glia maturation factor-β (GMFB), a growth and differentiation factor for glia and neurons, is a systemic regulator of IR, and we developed its inhibitor. We found that GMFB expression in adipose tissue is related to IR in rats, mice and humans. Systemic or adipocyte-specific Gmfb depletion improved IR and the lipotoxicity of plasma long chain fatty acids. Gmfb KO promotes lipid turnover (adipogenesis and lipid removal (lipolysis and fatty acid β-oxidation)) in adipocytes. Mechanistically, GMFB was degraded via chaperone-mediated autophagy under insulin stimulation in adipocytes. Gmfb KO boosted its interacting protein coactivator-associated arginine methyltransferase 1 (CARM1) nuclear translocation to coactivate peroxisome proliferator-activated receptor gamma (PPARγ), thereby promoting lipid turnover in adipocytes to improve IR. DS19, a potential GMFB inhibitor, showed strong insulin sensitizing effect by attenuating GMFB-CARM1 interaction. In conclusion, our results uncover GMFB, regulating adipocyte lipid turnover, as a novel therapeutic target in obesity-induced IR. The GMFB inhibitor DS19 will merit further clinical investigation. • GMFB expression in adipose tissue is related to insulin resistance (IR), and Gmfb KO protects against HFD-induced systemic IR. • Gmfb KO reduces the elevated plasma level of long chain fatty acids and promotes lipid turnover (adipogenesis and lipid removal (lipolysis and fatty acid β-oxidation)) in adipocytes to improve IR. • Insulin induces GMFB protein degradation via chaperone-mediated autophagy in adipocytes in physiological conditions. • Gmfb KO promotes the nuclear translocation of its interacting protein CARM1 to coactivate PPARγ, thereby promoting lipid turnover in adipocytes to improve IR. • DS19 is identified as a potential small-molecule inhibitor of GMFB and shows strong protective effects on IR through attenuating the interaction of GMFB-CARM1 and thus promoting more nuclear translocation of CARM1.