FUNCTIONAL ANALYSIS OF SMAF1, AN OBESITY CANDIDATE GENE

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Obesity is on the rise in the United States where it affects one-third of the population. The impact of increased adipose mass on human health is wide-ranging with increased risk of cardiovascular disease, diabetes and some forms of cancer. Studies in human lipodystrophy and in mouse models have demonstrated that a dearth of adipose tissue also carries health risks, most notably diabetes. To achieve and maintain optimal health, the genes that impact this balance between health and disease in adipose tissue must be identified and their mechanisms of function determined. Recent DNA microarray studies have revealed that in addition to the long-standing role of PPARgamma and C/EBP proteins in adipose biology, a variety of other genes are modulated during adipogenesis. A central principle that has been highly productive in defining details of adipogenesis is the study of those genes showing specific and unique patterns of expression in adipose tissue; they are most likely to offer key molecular insights unique to adipose tissue regulation. We have recently cloned a novel adipocyte-specific gene, small activating factor -SMAF1. SMAF1 is enriched in murine intra-abdominal WAT tissue compared with subcutaneous WAT. Furthermore, SMAF1 shows differential regulation in obesity and by hormones and cytokines central to adipose physiology. The SMAF1 gene maps to a chromosomal region containing a novel obesity quantitative trait locus. SMAF1 transcript encodes a wholly novel molecule of 80 amino acids. SMAF1 does not belong to any type of known protein family but possesses a canonical nuclear hormone receptor LXXLL interaction motif. Preliminary data indicate that when fused to a Gal4 DNA binding domain SMAF1 is a strong transcriptional activator and that SMAF1 can potentiate PPAR?-mediated transcriptional signals. It is proposed that SMAF1 has a key role in adipose biology. The role of SMAF1 in adipocyte signaling, differentiation and function will be determined in this R21 application through three specific aims: 1.) The impact of ectopic SMAF1 in the 3T3-L1 in vitro model of adipogenesis; 2.) The impact of SMAF1 on PPARgamma transcriptional signals; and 3.) Identification of SMAF1 binding partners.