ORPHAN RECEPTOR COUP-TFII IN ADIPOCYTE DIFFERENTIATION

Baylor College Of Medicine, Houston TX

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Abstract

A major public health issue in obesity is that obesity enhances the risk of developing type II diabetes[unreadable] and cardiovascular diseases. To reduce the prevalence of obesity, we need to understand the underlying[unreadable] mechanism of adipogenesis such that effective preventive and treatment strategies could be[unreadable] implemented to overcome these metabolic disorders. COUP-TFII is a member of the nuclear receptor[unreadable] superfamily and is highly expressed in mesenchymal cells during development. Ablation of COUP-TFII in[unreadable] mice results in early embryonic lethality due to defects in angiogenesis and heart development. During[unreadable] the course of analyzing the phenotypes of COUP-TFII heterozygous mice, we noted that the mutant mice[unreadable] are leaner and their adipose tissue mass is reduced in comparison to the control littermates. In addition,[unreadable] the abdominal white adipose tissues appear more like brown adipose tissues by expressing UCP-1, a[unreadable] marker of brown adipocytes important for adaptive thermogenesis. Consistent with the increase in brown[unreadable] fat-like tissues, the COUP-TFII heterozygous mutant is more insulin sensitive and glucose tolerant. Using[unreadable] 3T3L1cell culture models, we demonstrated that COUP-TFII is highly induced during the expansion[unreadable] phase of adipocyte differentiation. Knockdown of COUP-TFII expression during the early phase of 3T3L1[unreadable] adipocyte differentiation disrupts the differentiation program and impairs the accumulation of triglycerides.[unreadable] These findings suggest that COUP-TFII is likely an important but yet unexplored regulator of adipocyte[unreadable] differentiation. To understand the role of COUP-TFII, we will use both tissue specific and conditional[unreadable] knockout as well as in vitro cell culture differentiation system to dissect COUP-TFII's role in adipogenesis.[unreadable] To accomplish these goals, three Specific Aims are proposed: Aim 1: Determine the in vivo role of[unreadable] COUP-TFII during adipogenesis; Aim 2: Investigate the mechanism by which COUP-TFII regulates[unreadable] adipocyte differentiation; Aim 3: Analyze COUP-TFII target genes in adipocytes. Our studies are[unreadable] timely and will reveal new information on COUP-TFII as a regulator of adipogenesis as well as provide[unreadable] additional targets for obesity intervention.