Role of Transcription Factor NFAT in Glucose and Insulin Homeostasis

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.

We thank members of our laboratories for their critical reading of the manuscript. We also thank the Diabetes Research Training Center and the Marion Bessin Liver Research Center at AECOM for their support.

H.Y.S. is a trainee sponsored by 5T32 GM07491. This research was supported, in part, by grants from the National Institutes of Health (C.-W.C., G.R.C., L.A.J., L.R., and P.E.S.), Howard Hughes Medical Institute (G.R.C.), American Diabetes Association (C.-W.C. and P.E.S.), and American Heart Association (C.-W.C.).