Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ 3 by Cdk5

Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 41.46). 07/2010; 466(7305):451-6. DOI: 10.1038/nature09291
Source: PubMed


Obesity induced in mice by high-fat feeding activates the protein kinase Cdk5 (cyclin-dependent kinase 5) in adipose tissues. This results in phosphorylation of the nuclear receptor PPARgamma (peroxisome proliferator-activated receptor gamma), a dominant regulator of adipogenesis and fat cell gene expression, at serine 273. This modification of PPARgamma does not alter its adipogenic capacity, but leads to dysregulation of a large number of genes whose expression is altered in obesity, including a reduction in the expression of the insulin-sensitizing adipokine, adiponectin. The phosphorylation of PPARgamma by Cdk5 is blocked by anti-diabetic PPARgamma ligands, such as rosiglitazone and MRL24. This inhibition works both in vivo and in vitro, and is completely independent of classical receptor transcriptional agonism. Similarly, inhibition of PPARgamma phosphorylation in obese patients by rosiglitazone is very tightly associated with the anti-diabetic effects of this drug. All these findings strongly suggest that Cdk5-mediated phosphorylation of PPARgamma may be involved in the pathogenesis of insulin-resistance, and present an opportunity for development of an improved generation of anti-diabetic drugs through PPARgamma.

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Available from: Jorge Lira Ruas
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    • "Therefore, a promising approach for the development of PPARc agonists, with an acceptable safety profile, is the search for agonists that partially modulate PPARc target genes (Argmann et al., 2005; Cock et al., 2004; Liu et al., 2015). Despite weak receptor activation, partial PPARc agonists may have a higher selectivity and fewer side effects (Choi et al., 2010). Structurally, full agonists generally make interactions with residues of H12, whereas partial agonists stabilize other regions of the ligand binding pocket (LBP), without direct contact with the H12 (Bruning et al., 2007). "
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    • "Recent studies have suggested, however, that CDK5 protein levels oscillate during the cell cycle (Zhang et al., 2012; Nagano et al., 2013), providing a novel aspect of CDK5 regulation. CDK5 activity is also recognized to contribute to other pathological conditions, including diabetes (Choi et al., 2010) and inflammation (Pareek et al., 2010; Berberich et al., 2011), and it has been shown to be overexpressed in many cancers (Eggers et al., 2011; Levacque et al., 2012; Liang et al., 2013). Although a number of studies have associated CDK5 with prostate cancer, the various roles suggested for CDK5 appear somewhat contradictory. "
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    • "The role of PTMs in gene-specific regulation in physiology and disease and their high potential for treating obesity and diabetes were demonstrated in recent studies of PPARc and FoxO1. Aberrant phosphorylation of PPARc by cdk5 in obesity was shown to selectively regulate a subset of genes, and anti-diabetic agonists of PPARc had therapeutic benefits with fewer side effects by blocking the obesity-induced phosphorylation (Choi et al, 2010). Analysis of the effects of FoxO1 acetylation mutations in knock-in mice showed that acetylation of FoxO1 is critically involved in organismal survival during development and in maintaining metabolic homeostasis and that acetylation of FoxO1 mediates these functions by selective regulation of gene expression (Banks et al, 2011). "
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