Skeletal Muscle De Novo Lipogenesis and the Glucose-Fatty Acid Cycle

描述（由申请人提供）：本提案旨在为申请人作为独立科学家做好准备提供基础。主要研究者（PI）之前曾接受过肌肉和运动生理学领域的博士培训，并在Clay Semenkovich博士的指导下完成了第一年的博士后培训。Semenkovich博士是生理学和新陈代谢领域公认的领导者，在培养成功的科学家方面有着良好的记录。拟议的培训计划将不断完善PI的科学技能。PI还将利用华盛顿大学广泛的资源。 这项研究旨在确定从头脂肪生成在骨骼肌“葡萄糖-脂肪酸循环”中的潜在作用。在过去的几年里，Semenkovich实验室成功地产生和表征了脂肪酸合酶（FAS）组织特异性缺失的小鼠，并提供了证据表明新生脂质在多种组织中具有不同的信号传导作用。PI已经产生了骨骼肌特异性缺失FAS的小鼠，以研究在不存在从头合成脂肪酸的情况下的骨骼肌代谢，这种情况从未发生过。初步证据表明FAS在骨骼肌中产生PPAR配体。在本申请中，我们将检验FAS参与高脂饮食和运动诱导的骨骼肌脂质和葡萄糖代谢适应性反应的假设，并且这种作用是通过激活PPARs介导的。 公共卫生相关性：肥胖及其相关的共病是主要的公共卫生问题，仅在美国就影响大约7250万人。这些研究的结果可能会导致新的治疗方法来治疗肥胖相关疾病。

DESCRIPTION (provided by applicant): This proposal aims to provide a foundation to prepare the applicant as an independent scientist. The principal investigator (PI) has previously undergone PhD training in the field of muscle and exercise physiology and completed the first year as a postdoctoral trainee under the mentorship of Dr. Clay Semenkovich. Dr. Semenkovich is a recognized leader in physiology and metabolism and has a track record for training successful scientists. The proposed training plan will provide continual refinement of the PI's scientific skills. The PI will also take advantage of the enormous breadth of resources at Washington University. The proposed research seeks to identify the potential roles that de novo lipogenesis plays in skeletal muscle "glucose-fatty acid cycle". In the past few years, the Semenkovich laboratory successfully generated and characterized mice with tissue-specific deletion of fatty acid synthase (FAS) and provided evidence that de novo-generated lipids have distinct signaling roles in multiple tissues. The PI has generated mice with skeletal muscle specific deletion of FAS to study skeletal muscle metabolism in the absence of de novo synthesized fatty acids, a situation that has never been possible. The preliminary evidence suggests that FAS generates PPAR ligands in skeletal muscle. In this application, we will test the hypothesis that FAS is involved in high fat diet- and exercise-induced skeletal muscle adaptive responses in lipid and glucose metabolism and that this effect is mediated through the activation of PPARs. PUBLIC HEALTH RELEVANCE: Obesity and its associated co-morbidities are major public health problems affecting approximately 72.5 million individuals in United States alone. Findings from these studies may lead to novel therapeutic approaches to the treatment of the obesity-related diseases.