An Erk/Cdk5 axis controls the diabetogenic actions of PPARγ

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 an...

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Main Authors:	Banks, Alexander S., McAllister, Fiona E., Camporez, João Paulo G., Zushin, Peter-James H., Jurczak, Michael J., Laznik-Bogoslavski, Dina, Shulman, Gerald I., Gygi, Steven P., Spiegelman, Bruce M.
Format:	Online
Language:	English
Published:	2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297557/

id	pubmed-4297557
recordtype	oai_dc
spelling	pubmed-42975572015-07-15 An Erk/Cdk5 axis controls the diabetogenic actions of PPARγ Banks, Alexander S. McAllister, Fiona E. Camporez, João Paulo G. Zushin, Peter-James H. Jurczak, Michael J. Laznik-Bogoslavski, Dina Shulman, Gerald I. Gygi, Steven P. Spiegelman, Bruce M. Article 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. 2014-11-17 2015-01-15 /pmc/articles/PMC4297557/ /pubmed/25409143 http://dx.doi.org/10.1038/nature13887 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Banks, Alexander S. McAllister, Fiona E. Camporez, João Paulo G. Zushin, Peter-James H. Jurczak, Michael J. Laznik-Bogoslavski, Dina Shulman, Gerald I. Gygi, Steven P. Spiegelman, Bruce M.
spellingShingle	Banks, Alexander S. McAllister, Fiona E. Camporez, João Paulo G. Zushin, Peter-James H. Jurczak, Michael J. Laznik-Bogoslavski, Dina Shulman, Gerald I. Gygi, Steven P. Spiegelman, Bruce M. An Erk/Cdk5 axis controls the diabetogenic actions of PPARγ
author_facet	Banks, Alexander S. McAllister, Fiona E. Camporez, João Paulo G. Zushin, Peter-James H. Jurczak, Michael J. Laznik-Bogoslavski, Dina Shulman, Gerald I. Gygi, Steven P. Spiegelman, Bruce M.
author_sort	Banks, Alexander S.
title	An Erk/Cdk5 axis controls the diabetogenic actions of PPARγ
title_short	An Erk/Cdk5 axis controls the diabetogenic actions of PPARγ
title_full	An Erk/Cdk5 axis controls the diabetogenic actions of PPARγ
title_fullStr	An Erk/Cdk5 axis controls the diabetogenic actions of PPARγ
title_full_unstemmed	An Erk/Cdk5 axis controls the diabetogenic actions of PPARγ
title_sort	erk/cdk5 axis controls the diabetogenic actions of pparγ
description	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.
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297557/
_version_	1613177775107080192

An Erk/Cdk5 axis controls the diabetogenic actions of PPARγ

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