Regulation of Metabolism by the Hormone FGF15/19

激素 FGF15/19 对代谢的调节

• 批准号: 8247793
• 负责人: STEVEN A. KLIEWER
• 金额: $ 33.47万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247793
• 关键词: Affect; Bile Acid Biosynthesis Pathway; Bile Acids; Biological; Blood Circulation; Body Weight decreased; CYP7A1 gene; Cell membrane; Cholesterol; Cholesterol 7-alpha-Monooxygenase; Citric Acid Cycle; Clinical; Complex; Data; Diabetes Mellitus; Endocrine; Enzymes; Epidemic; Evaluation; Fasting; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Funding; Gallbladder; Genes; Genetic Transcription; Gluconeogenesis; Glucose Intolerance; Health; Hepatic; Hormones; Human; Hyperinsulinism; In Vitro; Insulin; Intestines; Knock-out; Knockout Mice; Light; Link; Liver; Mediating; Membrane; Metabolic Diseases; Metabolic syndrome; Mixed Function Oxygenases; Modeling; Molecular; Mus; Nuclear; Nutrient; Obesity; Orthologous Gene; Phosphotransferases; Physiological; Physiology; Play; Proteins; Publishing; Refractory; Regulation; Rodent; Rodent Model; Role; Signal Pathway; Signal Transduction; Small Intestines; Testing; Transcription Coactivator; Transcription Repressor/Corepressor; base; carbohydrate metabolism; fatty acid oxidation; feeding; gene repression; glucose metabolism; glucose production; hormone metabolism; human HNF4A protein; impaired glucose tolerance; improved; in vivo; insight; insulin sensitivity; lipid metabolism; novel; novel therapeutics; physiologic model; promoter; receptor; research study; response; uptake

DESCRIPTION (provided by applicant): Recent studies have revealed the importance of gut hormones as principal responders to nutrient status and as potential new therapeutics for treating the escalating obesity epidemic. Under the previous funding period, we discovered that the atypical fibroblast growth factor, FGF15, and its human ortholog, FGF19, are expressed and secreted from intestine as novel endocrine hormones in response to postprandial activation of the bile acid receptor FXR. In turn, FGF15/19 enters the hepatic portal circulation and governs bile acid synthesis and gallbladder filling. Studies have also shown pharmacologic administration of FGF15/19 markedly improves insulin sensitivity in rodent models of metabolic disease, whereas knocking out FGF15 expression in mice results in hyperinsulinemia and glucose intolerance. Together, these findings have linked postprandial uptake of bile acids in the gut with a novel FGF signaling pathway that plays a dual role in resetting key aspects of the digestive machinery and in mediating insulin-like effects in the liver following a meal. In this proposal, we seek to elucidate the molecular mechanisms that underlie these actions of FGF15/19 in the liver and to further characterize the repertoire of physiological effects FGF15/19 has on carbohydrate and lipid metabolism. In Aim 1, we will determine the molecular mechanism by which FGF15/19 regulates bile acid synthesis through its transcriptional repression of the gene encoding cholesterol 71-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis. In Aim 2, we will explore the role the transcriptional coactivator PGC-11 has in mediating the insulin-sensitizing actions of FGF15/19. This aim is based on our unpublished finding that FGF15/19 causes a marked reduction in hepatic expression of PGC-11. In Aim 3 we will characterize the physiologic effects FGF15/19 has on carbohydrate and lipid metabolism by testing the hypothesis that FGF15/19 improves insulin sensitivity by inhibiting gluconeogenesis, thereby decreasing hepatic glucose production. These studies will provide fundamental insights into this newly characterized endocrine signaling pathway and examine its potential utility for the pharmacologic treatment of metabolic syndrome. PUBLIC HEALTH RELEVANCE: This proposal investigates the biological actions of FGF15/19, a relatively unexplored hormone that is secreted from the small intestine after a meal. Among its effects, FGF15/19 resets the digestive machinery, potentiates the actions of insulin, and causes weight loss in rodents. Insights from these studies may provide new clinical strategies for treating obesity, diabetes, and other forms of metabolic disease.

描述（由申请人提供）：最近的研究揭示了肠道激素作为营养状况的主要反应者和治疗不断升级的肥胖流行病的潜在新疗法的重要性。在之前的资助期间，我们发现非典型成纤维细胞生长因子FGF 15及其人类直系同源物FGF 19作为新型内分泌激素从肠道中表达和分泌，以响应胆汁酸受体FXR的餐后激活。反过来，FGF 15/19进入肝门循环并控制胆汁酸合成和胆囊充盈。研究还表明，FGF 15/19的药理学施用显著改善代谢疾病啮齿动物模型中的胰岛素敏感性，而敲除小鼠中的FGF 15表达导致高胰岛素血症和葡萄糖耐受不良。总之，这些发现将肠道中胆汁酸的餐后摄取与新型FGF信号通路联系起来，该信号通路在重新设置消化机制的关键方面和在餐后介导肝脏中的胰岛素样作用方面发挥双重作用。在这个建议中，我们试图阐明这些行动的基础上的FGF 15/19在肝脏的分子机制，并进一步表征的剧目的生理作用FGF 15/19对碳水化合物和脂质代谢。在目的1中，我们将确定FGF 15/19通过其对编码胆固醇71-羟化酶（CYP 7A 1）（胆汁酸合成中的限速酶）的基因的转录抑制来调节胆汁酸合成的分子机制。在目标2中，我们将探讨转录辅激活因子PGC-11在介导FGF 15/19的胰岛素增敏作用中的作用。这一目的是基于我们未发表的发现，即FGF 15/19导致PGC-11的肝脏表达显著降低。在目标3中，我们将通过检验FGF 15/19通过抑制胰岛素生成从而减少肝葡萄糖产生来改善胰岛素敏感性的假设来表征FGF 15/19对碳水化合物和脂质代谢的生理作用。这些研究将提供基本的见解，这一新的特点内分泌信号通路，并检查其潜在的效用，代谢综合征的药物治疗。公共卫生相关性：该提案研究了FGF 15/19的生物学作用，FGF 15/19是一种相对未开发的激素，在饭后从小肠分泌。在其作用中，FGF 15/19重置消化机制，增强胰岛素的作用，并导致啮齿动物体重减轻。这些研究的见解可能会为治疗肥胖、糖尿病和其他形式的代谢疾病提供新的临床策略。