Steroid receptors regulate the expression of myriad target genes involved in metabolism, development, and reproduction. Nuclear receptors (NRs) are activated, usually by ligands, and relocate to specific DMA binding sites at target gene promoters where they accumulate an array of coactivators (or corepressors) that carry out the series of transcriptional substeps required for modulating gene expression. The SRC/p160 family of coactivators appears to play a fundamental role in this latter regard. We hypothesize that NRs and their attendant coactivators have evolved as the primary regulators of adipocyte development and of metabolic pathways in fat cells and other metabolic tissues. Toward the goal of elucidating these pathways that control lipid and carbohydrate metabolism, we plan to carry out investigations of the genetic, structural, regulatory and metabolic fingerprints of COUP-TFs and SRC family coactivators in cell extracts, in cells and in animals. We intend to: (1) elucidate the mechanisms by which COUP-TFII regulates adipocyte differentiation;(2) define the role by which SRC-3 controls the onset of the chain of transcriptional events leading to adipocyte developmental function;(3) define the roles of SRC coactivators in coordinately activating (or repressing) their target genes to effect spatiotemporal regulation of metabolic pathways in liver, muscle and fat cells;and (4) define the functional phenotypic effects of the SRC coactivators in controlling lipid and carbohydrate functions in the whole animal and examine the mechanism by which animal genotype modifies such coactivator phenotypic functional diversity. We will employ an integrative methodological approach to prove our hypothesis which uses cellular biology, biochemistry, physical chemistry, microscopy, nucleic acid and transgenic biology, bioinformatics, genetics and animal physiology in 4 Projects and 2 Core Labs. This information will lead to a much greater understanding of nuclear receptor and coactivator biology that would uncover new intervention points to aid in the design of novel therapies for metabolic disorders.
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