title: 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. SCFFBXO2acts 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 SCFFBXO2as an E3 ligase for the IR in the liver, which might provide a novel therapeutic target for treating T2DM and related metabolic disorders.
authors.affiliation: Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Huangshi Cental Hospital of Edong Healthcare Group, Hubei Polytechnic University School of Medicine, Huangshi, Hubei, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Han
authors.initials: H
authors.lastname: Lu
authors.affiliation: Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Huangshi Cental Hospital of Edong Healthcare Group, Hubei Polytechnic University School of Medicine, Huangshi, Hubei, China.
authors.forename: Duanzhuo
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Xuelian
authors.initials: X
authors.lastname: Xiong
authors.affiliation: College of Life Sciences, Northeast Agricultural University, Harbin, Heilongjiang, China gaolu@neau.edu.cn zhixiangwu@yahoo.com lu.yan2@zs-hospital.sh.cn.|Department of Pathology, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China gaolu@neau.edu.cn zhixiangwu@yahoo.com lu.yan2@zs-hospital.sh.cn.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Huangshi Cental Hospital of Edong Healthcare Group, Hubei Polytechnic University School of Medicine, Huangshi, Hubei, China gaolu@neau.edu.cn zhixiangwu@yahoo.com lu.yan2@zs-hospital.sh.cn.|Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D002851:Chromatography, High Pressure Liquid; D044783:F-Box Proteins / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D047468:Immunoprecipitation; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
chemical_list: D001786:Blood Glucose; D044783:F-Box Proteins; C500719:Fbx2 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; D011972:Receptor, Insulin; D005947:Glucose