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Letters to Nature

Nature 420, 333-336 (21 November 2002) | doi:10.1038/nature01137; Received 26 April 2002; Accepted 3 September 2002

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A central role for JNK in obesity and insulin resistance

Jiro Hirosumi1,2, Gürol Tuncman1,2, Lufen Chang3, Cem Z. Görgün1, K. Teoman Uysal1, Kazuhisa Maeda1, Michael Karin3 & Gökhan S. Hotamisligil1

  1. Division of Biological Sciences and Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA
  2. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, California 92093, USA
  3. These authors contributed equally to this work

Correspondence to: Gökhan S. Hotamisligil1 Correspondence and requests for materials should be addressed to G.S.H. (e-mail: Email: ghotamis@hsph.harvard.edu).

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Obesity is closely associated with insulin resistance and establishes the leading risk factor for type 2 diabetes mellitus, yet the molecular mechanisms of this association are poorly understood1. The c-Jun amino-terminal kinases (JNKs) can interfere with insulin action in cultured cells2 and are activated by inflammatory cytokines and free fatty acids, molecules that have been implicated in the development of type 2 diabetes3, 4. Here we show that JNK activity is abnormally elevated in obesity. Furthermore, an absence of JNK1 results in decreased adiposity, significantly improved insulin sensitivity and enhanced insulin receptor signalling capacity in two different models of mouse obesity. Thus, JNK is a crucial mediator of obesity and insulin resistance and a potential target for therapeutics.