No NFAT, No Fat

Science's STKE  17 Oct 2006:
Vol. 2006, Issue 357, pp. tw356
DOI: 10.1126/stke.3572006tw356

Obesity is a common health problem in the United States and other countries, so intensive efforts are focused on understanding the signaling pathways that control metabolism and the growth and physiology of fat-storing cells (adipocytes). Noting that there are similarities in obesity and inflammatory responses, Yang et al. explored the role of members of the NFAT (nuclear factor of activated T cells) family for a possible role in regulating glucose homeostasis, insulin sensitivity, and obesity. NFAT proteins are best known as critical mediators for expression of cytokines in response to activation of T cells in the immune system. However, Yang et al. found that increased expression of NFATc2 and NFATc4 was associated with differentiation of cultured mouse 3T3-L1 adipocytes or with obesity in a mouse model. Consistent with such effects, NFATc4 is expressed primarily in nonimmune tissues, including muscle and fat. Double knockout mice lacking NFATc2 and NFATc4 (Nfatc2−/− Nfatc4−/− mice) were resistant to obesity caused by ingestion of a high-fat diet and accumulated fewer adipocytes than did normal animals (regardless of their diet). The Nfatc2−/− Nfatc4−/− animals also showed a higher metabolic rate, greater heat production, more effective control of blood glucose after oral administration of glucose, and increased sensitivity to insulin. Adiopocytes secrete regulatory peptides (adipokines) and, similar to their effects on cytokine production in the immune system, the NFAT proteins appeared to regulate expression of genes encoding adipokines in adipocytes. Chromatin immunoprecipitation experiments showed association of NFATc2 with the promoter of the gene encoding the adipokine resistin. Pharmacological blockade of NFAT activation also reduced expression of resistin mRNA. NFAT has been previously implicated in roles outside the immune system, including heart development and neural pathfinding. The new work shows an even broader repertoire for the NFAT proteins that includes key roles in metabolic pathogenesis and expression of adipokine genes.

T. T. C. Yang, H. Y. Suk, X. Y. Yang, O. Olabisi, R. Y. L. Yu, J. Durand, L. A. Jelicks, J.-Y. Kim, P. E. Scherer, Y. Wang, Y. Feng, L. Rossetti, I. A. Graef, G. R. Crabtree, C.-W. Chow, Role of transcription factor NFAT in glucose and insulin homeostasis. Mol. Cell. Biol. 26, 7372-7387 (2006). [Abstract] [Full Text]