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Mol. Cell. Biol. 26 (20): 7372-7387

Copyright © 2006 by the American Society for Microbiology. All rights reserved.

Role of Transcription Factor NFAT in Glucose and Insulin Homeostasis{triangledown}

Teddy T. C. Yang,1 Hee Yun Suk,1 XiaoYong Yang,1 Opeyemi Olabisi,1 Raymond Y. L. Yu,1 Jorge Durand,2 Linda A. Jelicks,2 Ja-Young Kim,3 Philipp E. Scherer,3,4 Yuhua Wang,4 Yun Feng,4 Luciano Rossetti,1,4 Isabella A. Graef,5 Gerald R. Crabtree,5, and Chi-Wing Chow1*

Department of Molecular Pharmacology,1 Department of Physiology and Biophysics,2 Department of Cell Biology,3 Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461,4 Department of Developmental Biology and Department of Pathology, Howard Hughes Medical Institute, Stanford University Medical School, Stanford, California 943055

Received for publication 3 April 2006. Revision received 16 May 2006. Accepted for publication 2 August 2006.

Abstract: Compromised immunoregulation contributes to obesity and complications in metabolic pathogenesis. Here, we demonstrate that the nuclear factor of activated T cell (NFAT) group of transcription factors contributes to glucose and insulin homeostasis. Expression of two members of the NFAT family (NFATc2 and NFATc4) is induced upon adipogenesis and in obese mice. Mice with the Nfatc2–/– Nfatc4–/– compound disruption exhibit defects in fat accumulation and are lean. Nfatc2–/– Nfatc4–/– mice are also protected from diet-induced obesity. Ablation of NFATc2 and NFATc4 increases insulin sensitivity, in part, by sustained activation of the insulin signaling pathway. Nfatc2–/– Nfatc4–/– mice also exhibit an altered adipokine profile, with reduced resistin and leptin levels. Mechanistically, NFAT is recruited to the transcription loci and regulates resistin gene expression upon insulin stimulation. Together, these results establish a role for NFAT in glucose/insulin homeostasis and expand the repertoire of NFAT function to metabolic pathogenesis and adipokine gene transcription.


* Corresponding author. Mailing address: Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-2716. Fax: (718) 430-8922. E-mail: cchow{at}aecom.yu.edu.

{triangledown} Published ahead of print on 14 August 2006.



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