Role of Hepatic Fatty Acid Oxidation in Metabolic Homeostasis

肝脏是哺乳动物新陈代谢的中心，在为其他组织提供燃料方面起着关键作用，特别是在食物有限的情况下。线粒体脂肪酸β-氧化具有不同先天性缺陷的人在禁食后表现出危及生命的低酮-低血糖，这是由于脂肪酸氧化对代谢物生成和酮生成的关键作用。为了了解肝脏脂肪酸氧化对全身代谢功能障碍的贡献，我们通过条件性缺失肉毒碱棕榈酰转移酶2（Cpt 2）（由单个基因编码的专性步骤），在肝细胞中特异性地产生了不能通过线粒体β-氧化氧化长链脂肪酸的小鼠。在这里，我们将利用这一模型来了解脂肪酸氧化的贡献，肝脏和肝外调节系统代谢稳态禁食和高脂肪饮食的挑战。在此，我们提出三个具体目标。1.确定禁食期间肝脏脂肪酸氧化的要求。2.确定肝脏脂肪酸氧化在高脂饮食诱导的体重和糖耐量中的作用。3.确定脂肪酸诱导转录的机制。长期目标是了解禁食和高脂喂养期间肝脏脂质代谢的作用和要求。我们的期望是，我们提出的研究将描述禁食时肝脂肪酸氧化的要求以及肥胖和葡萄糖耐受不良的发展。此外，我们还将揭示肝细胞因子和代谢信号在全身代谢生理学控制中的新作用。

The liver is central to mammalian metabolism and plays a critical role in providing fuel to other tissues particularly when food is limiting. People with disparate inborn errors in mitochondrial fatty acid β-oxidation exhibit life-threatening hypoketotic-hypoglycemia following a fast due to the critical role of fatty acid oxidation to gluconeogenesis and ketogenesis. To understand the contribution of hepatic fatty acid oxidation to systemic metabolic dysfunction, we have generated mice that cannot oxidize long chain fatty acids via mitochondrial β-oxidation specifically in hepatocytes by the conditional deletion of Carnitine Palmitoyltransferase 2 (Cpt2), an obligate step encoded by a single gene. Here we will leverage this model to understand the contribution of fatty acid oxidation to hepatic and extrahepatic regulation of systemic metabolic homeostasis during fasting and high fat dietary challenges. Herein we propose three specific aims. 1. Determine the requirements of hepatic fatty acid oxidation during fasting. 2. Determine the role of hepatic fatty acid oxidation in high fat diet- induced body weight and glucose tolerance. 3. Determine the mechanism of fatty acid-induced transcription. The long-term goal is to understand the roles and requirements of hepatic lipid metabolism during fasting and high fat feeding. The expectation is that our proposed studies will describe the requirements of hepatic fatty acid oxidation in fasting and the development of obesity and glucose intolerance. Additionally, we will uncover new rolls for hepatokines and metabolic signaling in the control of systemic metabolic physiology.