Functional Interactions of SRC-2 and COUP-TFII in Muscle Energy Metabolism

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Metabolic syndromes are major health hazards of the modern society. These syndromes, including obesity, diabetes, kidney dysfunction, neuropathy and cardiovascular diseases, have reached epidemic proportions in the United States. In the last funding period, we showed that loss of an allele of COUP-TFII in mice enhanced energy expenditure and protected the heterozygous mice from high fat diet induced obesity, suggesting that COUP-TFII plays a pivotal role in modulating energy homeostasis. SRC-2 null mutant mice exhibit similar energy metabolism phenotypes as COUP-TFII heterozygous mice. Our preliminary results show that mice over-expressing SRC-2 switch fuel usage from lipid to carbohydrate in cardiac muscle Dysregulation of lipids is also shown in skeletal muscle-specific SRC-2 knockout mice, suggesting that SRC 2 plays a role in lipid metabolism in cardiac and skeletal muscles. Intriguingly, mice overexpressing COUP- TFII in cardiac muscle exhibit similar phenotypes as SRC-2 overexpressing mice, implicating that these two factors functionally interact to regulate energy expenditure in the muscle. Since skeletal muscle is one of the major tissues dissipating energy and inefficient usage of fatty acids in the skeletal muscle is a hallmark of insulin resistance, we will focus our study on the role of SRC-2 and COUP-TFII in energy expenditure using skeletal specific SRC-2 and COUP-TFII over- and under- expression mouse lines. We will first determine the phenotypes and key molecules impacted by these two factors in the regulation of energy expenditure. To understand the underlying mechanisms, we will identify the direct downstream target genes and signaling pathways impacted by SRC-2 and COUP-TFII to control energy metabolism using microarray and ChlP-seq analysis. These studies will increase our understanding of how SRC-2 and COUP-TFII jointly regulate transcriptional networks in cell types that are pivotal in the regulation of metabolic pathways that govern energy homeostasis in vivo. Thus, our studies are highly significant and accomplishment of the proposed studies will provide new insights into future development of therapeutic interventions for metabolic disorders. RELEVANCE (See instructions): The rising incidence of diabetes and its associated metabolic syndromes are major health hazards for modern society. The enhanced energy expenditure and the resistance to high fat diet induced obesity exhibited by COUP-TFII and SRC-2 mutant mice suggest that these two factors are major regulators of energy metabolism. Understanding how COUP-TFII and SRC-2 act in concert to regulate energy metabolism in the muscle are likely to lead to the timely discovery of new treatment approaches for these debilitating diseases.