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成为一名独立科学家提供基础。首席研究员(Pi)此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头两年的博士后见习。塞门科维奇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过往记录。拟议的培训计划将不断完善 派的科学技能。PI还将利用华盛顿大学巨大的资源广度。这项拟议的研究试图确定从头脂肪生成在骨骼肌“葡萄糖-脂肪酸循环”中扮演的潜在角色。在过去的几年里，Semenkovich实验室成功地培育出并鉴定了组织特异性脂肪酸合成酶(Fas)缺失的小鼠，并提供了新生的脂类在多种组织中具有不同的信号作用的证据。PI已经产生了骨骼肌特异缺失Fas的小鼠，在没有从头合成脂肪酸的情况下研究骨骼肌代谢，这是永远不可能的情况。初步证据表明，Fas在骨骼肌中产生PPAR配体。在这一应用中，我们将检验Fas参与高脂饮食和运动诱导的骨骼肌对脂肪和葡萄糖代谢的适应性反应的假设，并且这种作用是通过激活PPAR来介导的。

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 two years 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.