TRIM32 regulates insulin sensitivity by controlling insulin receptor degradation in the liver

Impaired insulin receptor signaling is strongly linked to obesity-related metabolic conditions like non-alcoholic fatty liver disease (NAFLD) and Type 2 diabetes (T2DM). However, the exact mechanisms behind impaired insulin receptor (INSR) signaling in obesity induced by a high-fat diet remain elusive. In this study, we identify an E3 ubiquitin ligase, tripartite motif-containing protein 32 (TRIM32), as a key regulator of hepatic insulin signaling that targets the insulin receptor (INSR) for ubiquitination and protea-somal degradation in high-fat diet (HFD) mice. HFD induces the nuclear translocation of SREBP-1c (Sterol Regulatory Element-Binding Protein 1c), resulting in increased expression of TRIM32 in hepatocytes. TRIM32 ubiquitylates INSR and facilitates its pro-teasomal degradation, leading to severe insulin resistance and fat accumulation within the liver of high-fat diet induced obese (DIO) mice. Conversely, liver-specific knockdown of TRIM32 enhances INSR expression and hepatic insulin sensitivity. Reduced AMPK signaling and phosphorylation of SREBP-1c at S372 in high-fat DIO mice promotes the nuclear translocation of SREBP-1c, leading to increased TRIM32 expression. In conclusion, our results demonstrate that TRIM32 promotes diet-induced hepatic insulin resistance by targeting the INSR to degradation.