Adipose tissue is required for normal metabolic function, but abnormal proliferation of adipocytes results in obesity. Although retinoic acid (RA) promotes differentiation of a variety of cell types, RA inhibits adipose conversion of 3T3-L1 preadipocytes. In contrast, activators of peroxisome proliferator activated receptors (PFARs), which are highly related to nuclear retinoid receptors, induce adipose conversion. The goal of this research is to understand the molecular basis of nuclear hormone receptor actions and interactions in this system. The first specific aim of this proposal is to determine the role of specific RAR subtypes and isoforms in adipocyte differentiation. 3T3-L1 preadipocytes express multiple retinoic acid receptors (RARs). RARgamma1 is down-regulated early and correlates with the effects of RA. Moreover, constitutive expression of RARgamma1 prevents adipocyte differentiation. Thus, RARgamma1 has a particularly important role in adipocyte differentiation and its mechanism of action will be determined. The second specific aim is to determine the role of specific retinoid X receptor (RXR) subtypes in adipocyte differentiation. RXRs are retinoid receptors which heterodimerize with RARs. RXRalpha is induced shortly after exposure to differentiating conditions, and preliminary data suggest that its expression causes preadipocytes to differentiate. The mechanism by which RXRalpha exerts these effects will be determined. RXR also heterodimerizes with PPAR. The third specific aim is to determine the role of specific forms of PPAR in adipocyte differentiation. Three PPAR subtypes are induced during adipocyte differentiation, but PPARgamma is most interesting because its expression is fat-specific and induced early in the course of adipogenesis. Each of the specific aims will be accomplished by creating 3T3-L1 cell lines which constitutively express different receptor subtypes, then studying the differentiation of these cells in the presence or absence of RA or peroxisome proliferators. Inducible promoters and antisense approaches will also be used to generate cell lines and analyze the effects of specific receptors. In addition, the mechanism of subtype- specific effects will be studied using deletion mutants and chimeric receptors. The fourth specific aim is to understand the hierarchical roles of RAR, RXR, and PPAR during adipocyte differentiation. It is hypothesized that the changes in expression of the nuclear hormone receptors reflect temporal and causal hierarchies of gene expression and regulation. To test this, the phenotypic dominance of cell lines which stable co-express two receptors involved in adipogenesis (e.g., RARgamma1 and RXRalpha will be determined. Together, the proposed studies will provide insight into the role of nuclear receptors and ligands in fat cell growth and differentiation. This knowledge may lead to rational new approaches to the prevention and treatment of human obesity, which is an endemic and costly cause of morbidity and mortality in the U. S.
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