An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ

Abstract

Obesity-linked insulin resistance is a major precursor to the development of type 2 diabetes. Previous work has shown that phosphorylation of PPARγ at serine 273 by Cdk5 stimulates diabetogenic gene expression in adipose tissues1. Inhibition of this modification is a key therapeutic mechanism for anti-diabetic PPARγ ligand drugs, such as the thiazolidinediones and PPARγ partial/non-agonists2. To better understand the importance of this obesity-linked PPARγ phosphorylation, we created mice that ablated Cdk5 specifically in adipose tissues. Surprisingly, these mice have both a paradoxical increase in PPARγ phosphorylation at S273 and worsened insulin resistance. Unbiased proteomic studies show that ERK kinases are activated in these KO animals. We show here that ERK directly phosphorylates S273 of PPARγ in a robust manner and that Cdk5 suppresses ERKs through direct action on a novel site in MEK, the ERK kinase. Importantly, pharmacological MEK and ERK inhibition markedly improves insulin resistance in both obese wild type and ob/ob mice, and also completely reverses the deleterious effects of the Cdk5 ablation. These data show that an ERK/Cdk5 axis controls PPARγ function and suggest that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes.

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

“…The statistical significance of the microarray data was evaluated using signal intensity values of probe sets (*, p Ͻ 0.05; **, p Յ 0.01; ***, p Յ 0.001 versus the respective control; ϮS.D., n ϭ 2 gene chips per group, cRNA pooled from four mice/gene chip). tivation of Pparg (36). In agreement with heart failure patients (37), the GRK2 protein levels were significantly up-regulated (i.e.…”

“…In agreement with the ERK-dependent inactivation of Pparg (36,40,43), the enhanced phosphorylation of Pparg on serine 273 and serine 112 of double transgenic Tg-GRKInh/FASN cardiomyocytes was accompanied by a significantly decreased Pparg transcription factor DNA binding activity compared with that of Tg-FASN cardiomyocytes (Fig. 7, M and N).…”

“…Together, these experiments indicate that the UCP1 protein could have a major role in the depressed substrate metabolism of a failing heart because up-regulated UCP1 could account for an enhanced palmitatetriggered uncoupled respiration upon FASN induction. Under those conditions, GRK2 inhibition by GRKInh could confer several modes of cardioprotection as follows: (i) by counteracting mitochondrial uncoupling via ERK activation-mediated down-regulation of UCP1 (36); and (ii) by decreasing the FASNtriggered lipid load, which involves, e.g. down-regulation of hypoxia-induced Pparg targets, Acaca and Fasn, and the resensitization of Prkaa.…”

“…Several lines of evidence support such a relationship. (i) The expression of several heart failure-related Pparg targets such as adiponectin (Adipoq), resistin (Retn), and uncoupling protein 1 (Ucp1) is downregulated by ERK-dependent inactivation of Pparg, partially by involving serine 273 phosphorylation (36,40). (ii) GRK2 inhibition enhances the activation of the ERK cascade (12,41).…”

Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

“…39 Intracellularly, the ERK pathway contributes to CCL19-and CCL21-generated signals governing cell survival and migration, [40][41][42] and it is known that Cdk5 can suppress ERKs through direct action on a novel site in the MAPK/ ERK kinase (MEK). 43 Although ligation of CCR7 by either CCL19 or CCL21 activates the ERK1/2 pathway, CCL19 has been shown to be fourfold more potent in promoting ERK phosphorylation. 44 We found no difference in the surface expression of CCR7 on peripheral blood T cells from Cdk5 T cells.…”