Role of FGF21 as a Hormonal Mediator of PPARalpha Actions, Project 4 of 10

FGF21 作为 PPARalpha 作用的激素调节剂的作用，项目 4（共 10 个）

• 批准号: 8123122
• 负责人: DAVID J MANGELSDORF
• 金额: $ 37.74万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8123122
• 关键词: Adipocytes; Agonist; Behavior; Behavioral; Body Temperature; Catabolism; Data; Diabetes Mellitus; Diet; Dyslipidemias; Family; Fasting; Fatty Acids; Fatty acid glycerol esters; Fibrates; Glucose; Hepatic; Homeostasis; Hormonal; Hormones; Human; Lipolysis; Liver; Mediating; Mediator of activation protein; Metabolic; Metabolic syndrome; Metabolism; Modeling; Molecular; Molecular Target; Monkeys; Mus; Neuraxis; Nuclear; Nuclear Receptors; Obesity; PPAR alpha; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Physical activity; Physiological; Play; Receptor Activation; Recombinant Fibroblast Growth Factor; Rodent; Role; Serum; Signal Pathway; Steroids; Stress; Testing; Thyroid Hormone Receptor; Triglycerides; base; design; diabetic; energy balance; fibroblast growth factor 21; insight; ketogenesis; member; natural hypothermia; novel strategies; receptor; response

Fibroblast growth factor 21 (FGF21) is a recently discovered hormone that regulates energy balance. In diabetic rodents and monkeys, FGF21 has broad metabolic effects that include reducing serum glucose and triglyceride concentrations. We recently discovered that FGF21 expression is markedly induced in liver by peroxisome proliferator-activated receptor (PPAR), a member of the nuclear steroid/thyroid hormone receptor family that is activated by fatty acids. PPAR plays a central role in the fasting response, including the induction of fatty acid catabolism and ketogenesis, and is the molecular target for the fibrate class of dyslipidemia drugs. We have found that administration of recombinant FGF21 to mice recapitulates many of the metabolic actions of PPAR activation including the reduction of circulating triglyceride concentrations and the induction of ketogenesis. In addition, FGF21 reduces physical activity and enhances torpor, an energyconserving state of regulated hypothermia. Based on these data, we hypothesize that FGF21 is a fastinginduced hepatokine that coordinately regulates systemic metabolism and behavior to conserve energy. The studies outlined in this application are designed to directly test specific components of this hypothesis. In Specific Aim 1, we will examine the role of FGF21 in mediating the physiologic responses to PPAR agonists, fasting and high fat diets. In Specific Aim 2, the role of FGF21 in the induction of hepatic lipolysis and ketogenesis will be studied. In Specific Aim 3, we will examine whether the effects of FGF21 on torpor and activity are mediated via the central nervous system. We believe that these studies will provide important insights into the molecular mechanisms governing metabolism and will also yield unexpected insights into the molecular actions of the fibrate class of drugs. Ultimately, manipulation of the FGF21 signaling pathway may provide novel strategies for treating obesity, diabetes, and the metabolic syndrome.

成纤维细胞生长因子21（FGF21）是一种调节能量平衡的最近发现的激素。在 糖尿病啮齿动物和猴子，FGF21具有广泛的代谢作用，包括减少血清葡萄糖和 甘油三酸酯的浓度。我们最近发现，FGF21表达在肝脏中明显诱导 过氧化物酶体增殖物激活受体（PPAR），核类固醇/甲状腺激素的成员 被脂肪酸激活的受体家族。 PPAR在禁食响应中起着核心作用，包括 诱导脂肪酸分解代谢和生酮发生，是纤维化类别的分子靶标 血脂血症药物。我们发现，重组FGF21给小鼠的给药概括了许多 PPAR激活的代谢作用，包括减少循环甘油三酸酯浓度和 诱导生酮发生。此外，FGF21减少了体育锻炼并增强了Torpor，这是一种能量的人 受管制体温过低的状态。基于这些数据，我们假设FGF21是一个禁食诱导的 协调调节系统性的代谢和行为以节省能量的肝素。这 本应用中概述的研究旨在直接检验该假设的特定组成部分。在 具体目标1，我们将研究FGF21在介导对PPAR激动剂的生理反应中的作用， 禁食和高脂饮食。在特定的目标2中，FGF21在肝脂解和 将研究生酮的发生。在特定目标3中，我们将检查FGF21对Torpor和 活动是通过中枢神经系统介导的。我们认为这些研究将提供重要的 洞悉有关代谢的分子机制，还将产生意外的见解 纤维化药物类别的分子作用。最终，操纵FGF21信号通路 可以提供治疗肥胖，糖尿病和代谢综合征的新型策略。

项目成果

Metabolic hormone FGF21 is induced in ground squirrels during hibernation but its overexpression is not sufficient to cause torpor.

地松鼠在冬眠期间会诱导代谢激素 FGF21，但其过度表达不足以导致冬眠。

• DOI: 10.1371/journal.pone.0053574
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Nelson,BethanyT;Ding,Xunshan;Boney-Montoya,Jamie;Gerard,RobertD;Kliewer,StevenA;Andrews,MatthewT
• 通讯作者: Andrews,MatthewT