title: 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 (peroxisome proliferator-activated receptor γ) at serine 273 by cyclin-dependent kinase 5 (Cdk5) stimulates diabetogenic gene expression in adipose tissues. Inhibition of this modification is a key therapeutic mechanism for anti-diabetic drugs that bind PPARγ, such as the thiazolidinediones and PPARγ partial agonists or non-agonists. For a better understanding of the importance of this obesity-linked PPARγ phosphorylation, we created mice that ablated Cdk5 specifically in adipose tissues. These mice have both a paradoxical increase in PPARγ phosphorylation at serine 273 and worsened insulin resistance. Unbiased proteomic studies show that extracellular signal-regulated kinase (ERK) kinases are activated in these knockout animals. Here we show that ERK directly phosphorylates serine 273 of PPARγ in a robust manner and that Cdk5 suppresses ERKs through direct action on a novel site in MAP kinase/ERK kinase (MEK). Importantly, pharmacological inhibition of MEK and ERK 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.
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Banks
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: McAllister
authors.affiliation: Yale Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: João Paulo G
authors.initials: JP
authors.lastname: Camporez
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Peter-James H
authors.initials: PJ
authors.lastname: Zushin
authors.affiliation: Yale Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Laznik-Bogoslavski
authors.affiliation: Yale Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: 1] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
mesh_terms: D017667:Adipocytes / Q000201:enzymology / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000172:deficiency / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism*; D059305:Diet, High-Fat; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D047495:PPAR gamma / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: D047495:PPAR gamma; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D048370:MAP Kinase Kinase 2; C482129:Map2k2 protein, mouse