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PNAS 107 (52): 22617-22622

Copyright © 2010 by the National Academy of Sciences.


IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity

Roberto R. Ricardo-Gonzaleza,b,1, Alex Red Eaglea,c,1, Justin I. Odegaarda,b, Hani Jouihana, Christine R. Morela, Jose E. Herediaa, Lata Mukundana, Davina Wud, Richard M. Locksleyd, and Ajay Chawlaa,b,e,2

aDivision of Endocrinology, Metabolism and Gerontology, Department of Medicine, bGraduate Program in Immunology, and cDepartment of Genetics, Stanford University School of Medicine, Stanford, CA 94305; and dThe Howard Hughes Medical Institute, Department of Medicine and Department of Microbiology and Immunology, and eCardiovascular Research Institute, University of California, San Francisco, CA 94158

Edited* by Ronald M. Evans, Salk Institute for Biological Studies, La Jolla, CA, and approved November 16, 2010 (received for review June 25, 2010)

Abstract: Immune cells take residence in metabolic tissues, providing a framework for direct regulation of nutrient metabolism. Despite conservation of this anatomic relationship through evolution, the signals and mechanisms by which the immune system regulates nutrient homeostasis and insulin action remain poorly understood. Here, we demonstrate that the IL-4/STAT6 immune axis, a key pathway in helminth immunity and allergies, controls peripheral nutrient metabolism and insulin sensitivity. Disruption of signal transducer and activator of transcription 6 (STAT6) decreases insulin action and enhances a peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) driven program of oxidative metabolism. Conversely, activation of STAT6 by IL-4 improves insulin action by inhibiting the PPAR{alpha}-regulated program of nutrient catabolism and attenuating adipose tissue inflammation. These findings have thus identified an unexpected molecular link between the immune system and macronutrient metabolism, suggesting perhaps the coevolution of these pathways occurred to ensure access to glucose during times of helminth infection.

Key Words: insulin resistance • obesity • cytokines • liver • Th2 immunity

Author contributions: R.R.R.-G., A.R.E., J.I.O., H.J., R.M.L., and A.C. designed research; R.R.R.-G., A.R.E., J.I.O., H.J., C.R.M., J.E.H., L.M., and D.W. performed research; R.M.L. contributed new reagents/analytic tools; R.R.R.-G., A.R.E., J.I.O., H.J., C.R.M., J.E.H., and A.C. analyzed data; and A.C. wrote the paper.

1R.R.R.-G. and A.R.E. contributed equally to this work.

The authors declare no conflict of interest.

*This Direct Submission article had a prearranged editor.

This article contains supporting information online at

2To whom correspondence should be addressed. E-mail: Ajay.Chawla{at}

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