学术报告
题目：The Role of NCoR in Metabolism
报告人：Pingping Li
Department of Medicine,
University of California San Diego, USA
时间：13:00-14:00 PM, May 22, 2014 (Thu.)
地点：Rm. 411, New Life Sciences Building
Insulin resistance, tissue inflammation and adipose tissue dysfunction are features of obesity and Type 2 diabetes. Insulin resistance is a characteristic pathophysiologic defect in the great majority of patients with type 2 diabetes mellitus. Obesity is the most common cause of insulin resistance, and the current obesity epidemic in westernized countries is driving the parallel type 2 diabetes epidemic. Obesity-associated chronic tissue inflammation is a key mechanism for decreased insulin sensitivity and in obesity, excessive numbers of pro-inflammatory, M1-like, macrophages accumulate in adipose tissue and liver, where they locally release a variety of cytokines which act on insulin target cells to impair insulin signaling.
Transcriptional control by nuclear receptors (NRs), including PPARγ, LXR and others, depends on multiprotein coregulatory complexes. In general, co-repressor complexes are recruited to NRs in the absence of ligand, whereas, co-activator complexes are recruited to NRs in the presence of agonists. The Nuclear Receptor Co-repressor (NCoR) interacts with genes related to adipogenesis and inflammation in adipocytes and macrophages respectively. Based on this concept, we generated adipocyte-specific NCoR knock-out (AKO) mice and macrophage/neutrophil NCoR knock-out (MNKO) mice respectively to investigate the function of NCoR in adipocyte biology, inflammation, glucose and insulin homeostasis. We found that despite increased obesity, glucose tolerance was improved in AKO mice, and clamp studies demonstrated enhanced insulin sensitivity in liver, muscle and fat. Adipose tissue macrophage infiltration and inflammation were also decreased. PPARγ response genes were upregulated in adipose tissue from AKO mice and CDK5-mediated PPARγ ser-273 phosphorylation was reduced, creating a constitutively active PPARγ state. This identifies NCoR as an adaptor protein which enhances the ability of CDK5 to associate with, and phosphorylate PPARγ. The dominant function of adipocyte NCoR is to transrepress PPARγ and promote PPARγ ser-273 phosphorylation, such that NCoR deletion leads to adipogenesis, reduced inflammation, and enhanced systemic insulin sensitivity, phenocopying the TZD treated state. Surprisingly, we find that macrophage-specific deletion of NCoR results in an anti-inflammatory phenotype along with robust systemic insulin sensitization in obese mice. We present evidence that de-repression of LXRs contributes to this paradoxical anti-inflammatory phenotype by causing increased expression of genes that direct biosynthesis of palmitoleic acid and 3 fatty acids. Remarkably, the increased 3 fatty acid levels primarily inhibit NF-kB-dependent inflammatory responses by uncoupling NF-kB binding and enhancer/promoter histone acetylation from subsequent steps required for pro-inflammatory gene activation. This provides a mechanism for the in vivo anti-inflammatory insulin sensitive phenotype observed in mice with macrophage-specific deletion of NCoR. Therapeutic methods to harness this mechanism could lead to a new approach to insulin sensitizing therapies.
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