The objective of this proposal is to elucidate the physiological relevancy of transcription factor NFAT in adipocyte differentiation. We hypothesize that regulation of NFAT expression and activity accounts for the positive role of NFAT in adipocyte differentiation Obesity is a rising health concern in the United States because of its association with diabetes, heart failure, and certain cancers. Obesity is a consequence of energy imbalance, which increases adipocyte cell number and/or cell size to accommodate the elevated lipid load. Molecular analysis indicates that transcription factors play an important role in adipocyte differentiation. Increased expression of members of the CCAAT/enhancer binding protein (C/EBP) and nuclear factor peroxisome proliferator-activated receptor gamma (PPAR gamma) family is required to commit adipocyte differentiation. Four members (NFATc1-NFATc4) of the NFAT group of transcription factors exhibit high sequence homology and similar regulatory mechanisms mediated by the calcineurin phosphatase. We have demonstrated that the expression levels of NFATc2 and NFATc4 are modulated during adipocyte differentiation. In addition, expression of a gain-of-function NFATc4 protein promotes adipocyte differentiation, in part, by formation of an NFAT:C/EBP composite complex on the PPARgamma2 gene promoter. However, several questions remain to be addressed for the role of NFAT in adipocyte differentiation. What is the role of NFATc2 and/or NFATc4 ? When is NFAT activated ? What regulates the NFAT expression ? The following aims are proposed to address these questions.
Aim 1) To determine the role of NFATc2 and NFATc4 in adipocyte differentiation.
Aim 2) To assess the activation profile of NFAT during adipocyte differentiation.
Aim 3) To elucidate the molecular basis of NFAT induction during adipocyte differentiation. Completion of these studies will provide physiological relevancy and mechanistic insights into the role of NFAT in adipocyte differentiation. This information will also offer new understanding of the regulation of NFAT gene expression. Knowledge obtained will shed new light on the biological functions of the NFAT group of transcription factors and their relationships to obesity and diabetes. ? ?
| Yang, Teddy T C; Ung, Peter M U; Rincon, Mercedes et al. (2006) Role of the CCAAT/enhancer-binding protein NFATc2 transcription factor cascade in the induction of secretory phospholipase A2. J Biol Chem 281:11541-52 |
