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Publication
An ERK/Cdk5 axis controls the diabetogenic actions of PPAR?.
Authors Banks AS, McAllister FE, Camporez JP, Zushin PJ, Jurczak MJ, Laznik-Bogoslavski
D, Shulman GI, Gygi SP, Spiegelman BM
Submitted By Bruce Spiegelman on 7/24/2015
Status Published
Journal Nature
Year 2015
Date Published 1/15/2015
Volume : Pages 517 : 391 - 395
PubMed Reference 25409143
Abstract Obesity-linked insulin resistance is a major precursor to the development of
type 2 diabetes. Previous work has shown that phosphorylation of PPAR?
(peroxisome proliferator-activated receptor ?) 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 PPAR?, such as the thiazolidinediones and PPAR? partial agonists
or non-agonists. For a better understanding of the importance of this
obesity-linked PPAR? phosphorylation, we created mice that ablated Cdk5
specifically in adipose tissues. These mice have both a paradoxical increase in
PPAR? 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 PPAR? 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 PPAR? function and suggest that MEK/ERK inhibitors may hold
promise for the treatment of type 2 diabetes.




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