E3 ligase FBXO2-mediated protein stability of insulin receptor regulates adipogenesis and metabolic health in obesity

Adipogenesis, a crucial physiological process, serves to safely sequester lipids, thereby preventing lipotoxicity in peripheral organs and preserving metabolic health during obesity. While insulin signaling plays a pivotal role in adipogenesis, regulating factors, especially the braking mechanism governing this process, warrant further investigation. Our study identified proteasome-dependent degradation of the insulin receptor (IR) during the early stages of adipogenesis as a critical event for the mitotic clonal expansion phase of the adipocyte differentiation program. A series of studies confirmed that the ubiquitinated modification of IR is regulated by E3 ligase FBXO2, and this is based on IR phosphorylation. We further elucidated that the FBD domain of FBXO2 is indispensable for its function in catalyzing p-IR ubiquitination. Gain or loss of function of Fbxo2 inhibited or promoted SVF or 3T3L1 cells proliferation and adipogenesis both in vitro and in vivo, which regulated adipose hyperplasia and plasticity of adipose tissue. Moreover, FBXO2 played an important role in regulating the metabolic health of mice when subjected to caloric excess. Collectively, our findings unveil FBXO2 as a negative regulator of adipogenesis by impairing the insulin signaling pathway.