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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    • "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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    ABSTRACT: Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-dependent transcription factors that control various functions in human organism, including the control of glucose and lipid metabolism. PPARγ is a target of TZD agonists, clinically used to improve insulin sensitivity whereas fibrates, PPARα ligands, lower serum triglyceride levels. We report here the structural studies of GL479, a synthetic dual PPARα/γ agonist, designed by a combination of clofibric acid skeleton and a phenyldiazenyl moiety, as bioisosteric replacement of stilbene group, in complex with both PPARα and PPARγ receptors. GL479 was previously reported as a partial agonist of PPARγ and a full agonist of PPARα with high affinity for both PPARs. Our structural studies reveal different binding modes of GL479 to PPARα and PPARγ, which may explain the distinct activation behaviors observed for each receptor. In both cases the ligand interacts with a Tyr located at helix 12 (H12), resulting in the receptor active conformation. In the complex with PPARα, GL479 occupies the same region of the ligand-binding pocket (LBP) observed for other full agonists, whereas GL479 bound to PPARγ displays a new binding mode. Our results indicate a novel region of PPARs LBP that may be explored for the design of partial agonists as well dual PPARα/γ agonists that combine, simultaneously, the therapeutic effects of the treatment of insulin resistance and dyslipidemia. Copyright © 2015. Published by Elsevier Inc.
    Journal of Structural Biology 07/2015; 191(3). DOI:10.1016/j.jsb.2015.07.006 · 3.23 Impact Factor
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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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    ABSTRACT: Acetylation of transcriptional regulators is normally dynamically regulated by nutrient status but is often persistently elevated in nutrient-excessive obesity conditions. We investigated the functional consequences of such aberrantly elevated acetylation of the nuclear receptor FXR as a model. Proteomic studies identified K217 as the FXR acetylation site in diet-induced obese mice. In vivo studies utilizing acetylation-mimic and acetylation-defective K217 mutants and gene expression profiling revealed that FXR acetylation increased proinflammatory gene expression, macrophage infiltration, and liver cytokine and triglyceride levels, impaired insulin signaling, and increased glucose intolerance. Mechanistically, acetylation of FXR blocked its interaction with the SUMO ligase PIASy and inhibited SUMO2 modification at K277, resulting in activation of inflammatory genes. SUMOylation of agonist-activated FXR increased its interaction with NF-κB but blocked that with RXRα, so that SUMO2-modified FXR was selectively recruited to and trans-repressed inflammatory genes without affecting FXR/RXRα target genes. A dysregulated acetyl/SUMO switch of FXR in obesity may serve as a general mechanism for diminished anti-inflammatory response of other transcriptional regulators and provide potential therapeutic and diagnostic targets for obesity-related metabolic disorders. © 2014 The Authors.
    The EMBO Journal 11/2014; 34(2). DOI:10.15252/embj.201489527 · 10.43 Impact Factor
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    • "Until recently, cyclin-dependent kinase 5 (CDK5)- stimulated phosphorylation at serine 273 of PPARγ (pSer273PPARγ), which lead to dysregulation of a set of gene expression in adipose tissue, especially epididymal white fat tissue (eWAT), was revealed as the critical link between obesity and insulin resistance [15]. Furthermore, TZDs and several sPPARγMs were demonstrated to inhibit p273SerPPARγ equally, indicating that the mechanism underlying PPARγ ligands resulted in insulin sensitizing activity, largely depended on the inhibition of pSer273PPARγ [15], which gives rise to a novel viewpoint to understand the mechanisms underlying sPPARγM mediated insulin sensitizing activity. Moreover, changes of pSer273PPARγ had no effect on PPARγ agonistic activity. "
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    ABSTRACT: Background: Selective PPARγ modulators (sPPARγM) retains insulin sensitizing activity but with minimal side effects compared to traditional TZDs agents, is thought as a promising strategy for development of safer insulin sensitizer. Methods: We used a combination of virtual docking, SPR-based binding, luciferase reporter and adipogenesis assays to analyze the interaction mode, affinity and agonistic activity of L312 to PPARγ in vitro, respectively. And the anti-diabetic effects and underlying molecular mechanisms of L312 was studied in db/db mice. Results: L312 interacted with PPARγ-LBD in a manner similar to known sPPARγM. L312 showed similar PPARγ binding affinity, but displayed partial PPARγ agonistic activity compared to PPARγ full agonist pioglitazone. In addition, L312 displayed partial recruitment of coactivator CBP yet equal disassociation of corepressor NCoR1 compared to pioglitazone. In db/db mice, L312 (30 mg/kg•day) treatment considerably improved insulin resistance with the regard to OGTT, ITT, fasted blood glucose, HOMA-IR and serum lipids, but elicited less weight gain, adipogenesis and hemodilution compared with pioglitazone. Further studies demonstrated that L312 is a potent inhibitor of CDK5-mediated PPARγ phosphorylation and displayed a selective gene expression profile in epididymal WAT. Conclusions: L312 is a novel sPPARγM. General significance: L312 may represent a novel lead for designing ideal sPPARγM for T2DM treatment with advantages over current TZDs.
    Biochimica et Biophysica Acta (BBA) - General Subjects 10/2014; 1850(1). DOI:10.1016/j.bbagen.2014.09.027 · 4.38 Impact Factor
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