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Abstract: The link between obesity and insulin resistance largely accounts for the pathogenesis of metabolic syndrome and diabetes mellitus, in which adipokine expression plays a key role. Puerarin, a major active isoflavone extracted from the traditional Chinese medicine Radix Puerariae, has been studied for its comprehensive biological actions. However, its effect on high-fat diet (HFD)-induced insulin resistance and adipokine expression in rat has not been well investigated. In the present study, male Sprague–Dawley rats were fed on a normal control diet (NCD) or HFD for 6weeks, followed by administration of puerarin (100 and 200mg/kg) for up to 8weeks. Compared to NCD, HFD feeding for 6weeks led to increased body weight gain and impaired glucose/insulin tolerance manifested by oral glucose/intraperitoneal insulin tolerance tests in rats. These exacerbations prolonged through HFD feeding, but were effectively reversed by puerarin administration. Enzyme-linked immunosorbent assay demonstrated that, serum levels of leptin and resistin, but not that of adiponectin, were markedly augmented by HFD and retarded by puerarin treatment. Real-time reverse transcription polymerase chain reaction results showed that, in agreement with the circulating levels, mRNA expression of leptin and resistin in epididymal white adipose tissue was modified by HFD and improved by puerarin in the same pattern. Collectively, we revealed that puerarin could improve body weight gain, glucose/insulin intolerance and adipokine expression in HFD-induced insulin resistant rats, indicating its potential value for treatment of metabolic syndrome. [ABSTRACT FROM AUTHOR]

MED20 is a non-essential subunit of the transcriptional coactivator Mediator complex, but its physiological function remains largely unknown. Here, we identify MED20 as a substrate of the anti-obesity CRL4-WDTC1 E3 ubiquitin ligase complex through affinity purification and candidate screening. Overexpression of WDTC1 leads to degradation of MED20, whereas depletion of WDTC1 or CUL4A/B causes accumulation of MED20. Depleting MED20 inhibits adipogenesis, and a non-degradable MED20 mutant restores adipogenesis in WDTC1-overexpressing cells. Furthermore, knockout of Med20 in preadipocytes abolishes development of brown adipose tissues. Removing one allele of Med20 in preadipocytes protects mice from diet-induced obesity and reverses weight gain in Cul4a- or Cul4b -depleted mice. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis reveals that MED20 organizes the early adipogenic complex by bridging C/EBPβ and RNA polymerase II to promote transcription of the central adipogenic factor, PPARγ. Our findings have thus uncovered a critical role of MED20 in promoting adipogenesis, development of adipose tissue and diet-induced obesity. [Display omitted] • MED20 is a substrate of the CRL4-WDTC1 E3 ubiquitin ligase complex • MED20 is required for adipogenesis • MED20 bridges C/EBPβ and RNA polymerase II to promote transcription • Deleting one allele of Med20 protects mice from diet-induced obesity Tang et al. show that the Mediator complex subunit MED20 is the substrate of the CRL4-WDTC1 E3 ubiquitin ligase complex and bridges C/EBPβ and RNA polymerase II to stimulate adipogenesis and diet-induced obesity in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Obesity has become a global pandemic. Identification of key factors in adipogenesis helps to tackle obesity and related metabolic diseases. Here, we show that DDB1 binds the histone reader BRWD3 to promote adipogenesis and diet-induced obesity. Although typically recognized as a component of the CUL4-RING E3 ubiquitin ligase complex, DDB1 stimulates adipogenesis independently of CUL4. A DDB1 mutant that does not bind CUL4A or CUL4B fully restores adipogenesis in DDB1-deficient cells. Ddb1 +/− mice show delayed postnatal development of white adipose tissues and are protected from diet-induced obesity. Mechanistically, by interacting with BRWD3, DDB1 is recruited to acetylated histones in the proximal promoters of ELK1 downstream immediate early response genes and facilitates the release of paused RNA polymerase II, thereby activating the transcriptional cascade in adipogenesis. Our findings have uncovered a CUL4-independent function of DDB1 in promoting the transcriptional cascade of adipogenesis, development of adipose tissues, and onset of obesity. [Display omitted] • DDB1 works independently of CUL4 E3 ubiquitin ligase to promote adipogenesis • Deleting one allele of Ddb1 protects mice from diet-induced obesity • Binding to BRWD3 recruits DDB1 to histones • DDB1 recruits P-TEFb to initiate the transcriptional cascade in adipogenesis Obesity has become a global pandemic. Wang et al. show that DDB1 is a potential therapeutic target. By interacting with the histone reader BRWD3 and positive transcription elongation factor b, DDB1 promotes transcriptional initiation of adipogenesis, development of adipose tissues, and onset of diet-induced obesity. [ABSTRACT FROM AUTHOR]