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

Abstract

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^FBXO2 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^FBXO2 as an E3 ligase for the IR in the liver, which might provide a novel therapeutic target for treating T2DM and related metabolic disorders.