title: Lack of CUL4B in Adipocytes Promotes PPARγ-Mediated Adipose Tissue Expansion and Insulin Sensitivity.
abstract: Obesity and obesity-associated diseases are linked to dysregulation of the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway. Identification of the factors that regulate PPARγ expression and activity is crucial for combating obesity. However, the ubiquitin E3 ligases that target PPARγ for proteasomal degradation have been rarely identified, and their functions in vivo have not been characterized. Here we report that CUL4B-RING E3 ligase (CRL4B) negatively regulates PPARγ by promoting its polyubiquitination and proteasomal degradation. Depletion of CUL4B led to upregulation of PPARγ-regulated genes and facilitated adipogenesis. Adipocyte-specific Cul4b knockout (AKO) mice being fed a high-fat diet exhibited increased body fat accumulation that was mediated by increased adipogenesis. However, AKO mice showed improved metabolic phenotypes, including increased insulin sensitivity and glucose tolerance. Correspondingly, there was a decreased inflammatory response in adipose tissues of AKO mice. Genetic inhibition of CUL4B thus appears to phenocopy the beneficial effects of PPARγ agonists. Collectively, this study establishes a critical role of CRL4B in the regulation of PPARγ stability and insulin sensitivity and suggests that CUL4B could be a potential therapeutic target for combating obesity and metabolic syndromes.
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, People's Republic of China.
authors.forename: Peishan
authors.initials: P
authors.lastname: Li
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Song
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, People's Republic of China.
authors.forename: Wenying
authors.initials: W
authors.lastname: Zan
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, People's Republic of China.
authors.forename: Liping
authors.initials: L
authors.lastname: Qin
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, People's Republic of China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Han
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, People's Republic of China.
authors.forename: Baichun
authors.initials: B
authors.lastname: Jiang
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Dou
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, People's Republic of China.
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, People's Republic of China yxg8@sdu.edu.cn.
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics*; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002633:Chemotaxis; D044842:Cullin Proteins / Q000235:genetics*; D059305:Diet, High-Fat; D005260:Female; D005434:Flow Cytometry; D005951:Glucose Tolerance Test; D006801:Humans; D007249:Inflammation; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; C524851:Cul4B protein, mouse; D044842:Cullin Proteins; D007328:Insulin; D047495:PPAR gamma; D044767:Ubiquitin-Protein Ligases