Aberrant Expression of FBXO2 Disrupts Glucose Homeostasis Through Ubiquitin-Mediated Degradation of Insulin Receptor in Obese Mice

Insulin resistance is a critical factor in the development of metabolic disorders, including type 2 diabetes (T2DM). However, its molecular mechanisms remain incompletely understood. In this study, we found that F-box only protein 2 (FBXO2), a substrate recognition component of the Skp1-Cul1-F-box protein (SCF) E3 ubiquitin ligase complex, was upregulated in livers of obese mice. Furthermore, using a protein purification approach combined with high-performance liquid chromatography/tandem mass spectrometry, we carried out a system-wide screening of FBXO2 substrates, in which the insulin receptor (IR) was identified as a substrate for FBXO2. SCF acts as an E3 ligase targeting the IR for ubiquitin-dependent degradation to regulate insulin signaling integrity. As a result, adenovirus-mediated overexpression of FBXO2 in healthy mice led to hyperglycemia, glucose intolerance, and insulin resistance, whereas ablation of FBXO2 alleviated diabetic phenotypes in obese mice. Therefore, our results identify SCF as an E3 ligase for the IR in the liver, which might provide a novel therapeutic target for treating T2DM and related metabolic disorders.