Obesity and obesity-associated diseases are linked to dysregulation of the peroxisome proliferator–activated receptor (PPAR) signaling pathway. Identification of the factors that regulate PPAR expression and activity is crucial for combating obesity. However, the ubiquitin E3 ligases that target PPAR 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 PPAR by promoting its polyubiquitination and proteasomal degradation. Depletion of CUL4B led to upregulation of PPAR-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 PPAR agonists. Collectively, this study establishes a critical role of CRL4B in the regulation of PPAR stability and insulin sensitivity and suggests that CUL4B could be a potential therapeutic target for combating obesity and metabolic syndromes.
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