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

代谢综合征是现代社会的主要健康危害。这些症状，包括肥胖， 糖尿病、肾功能障碍、神经病变和心血管疾病已经达到流行的程度 在美国。在上一个资助阶段，我们在小鼠中发现了COUP-TFII等位基因的缺失 增加能量消耗，保护杂合子小鼠免受高脂饮食诱导的肥胖， 提示COUP-TFII在调节能量动态平衡中起着关键作用。SRC-2缺失突变小鼠 表现出与COUP-TFII杂合子小鼠相似的能量代谢表型。我们的初步结果 显示过度表达SRC-2的小鼠在心肌中将燃料的使用从脂肪转换为碳水化合物 在骨骼肌特异的SRC-2基因敲除小鼠中也显示出脂质调节失调，这表明SRC 2在心肌和骨骼肌脂代谢中起作用。有趣的是，老鼠过度表达政变- 心肌中的TFII与SRC-2过表达的小鼠表现出相似的表型，这意味着这两者 这些因素在功能上相互作用，调节肌肉中的能量消耗。由于骨骼肌是 主要组织消耗能量和骨骼肌中脂肪酸的低效利用是 对于胰岛素抵抗，我们将重点研究SRC-2和COUP-TFII在能量消耗中的作用 骨骼特异性SRC-2和COUP-TFII高表达和低表达小鼠系。我们将首先确定 这两个因素在能量消耗调节中对表型和关键分子的影响。至 了解潜在的机制，我们将确定直接下游的靶基因和信号转导 SRC-2和COUP-TFII调控能量代谢途径的基因芯片和ChlP-seq研究 分析。这些研究将增加我们对SRC-2和COOP-TFII如何联合调控的理解 细胞类型中的转录网络，在控制代谢途径的调节中起关键作用 体内能量动态平衡。因此，我们的研究是非常有意义的，并完成了提出的 研究将为代谢紊乱治疗干预措施的未来发展提供新的见解。 相关性(请参阅说明)： 糖尿病发病率的上升及其相关的代谢综合征是对 现代社会。能量消耗增加与高脂饮食诱导肥胖的抵抗力 COUP-TFII和SRC-2突变小鼠的实验结果表明，这两个因素是 能量代谢。了解COUP-TFII和SRC-2如何协同作用调节能量代谢 可能会导致及时发现这些衰弱的新的治疗方法 疾病。

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.