Regulation of Metabolism by the Hormone FGF15/19

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的重要性，以及作为治疗不断升级的肥胖流行病的潜在新疗法。在之前的资助期内，我们发现非典型成纤维细胞生长因子FGF15及其人类同源物FGF19作为一种新的内分泌激素，在餐后胆汁酸受体FXR激活的反应中从肠道中表达和分泌。反过来，FGF15/19进入肝门静脉循环，控制胆汁酸合成和胆囊充盈。研究还表明，FGF15/19的药理学管理可显著改善代谢性疾病啮齿动物模型中的胰岛素敏感性，而敲除小鼠中FGF15的表达会导致高胰岛素血症和葡萄糖耐受不良。总之，这些发现将肠道餐后胆汁酸的摄取与一种新的FGF信号通路联系起来，该信号通路在重置消化机制的关键方面和在餐后肝脏中介导胰岛素样效应方面发挥双重作用。在本提案中，我们试图阐明FGF15/19在肝脏中这些作用的分子机制，并进一步表征FGF15/19对碳水化合物和脂质代谢的生理影响。在Aim 1中，我们将确定FGF15/19通过转录抑制编码胆固醇71-羟化酶（CYP7A1）的基因调控胆汁酸合成的分子机制，CYP7A1是胆汁酸合成的限速酶。在Aim 2中，我们将探讨转录辅激活因子PGC-11在介导FGF15/19胰岛素增敏作用中的作用。这一目标是基于我们未发表的发现，即FGF15/19导致PGC-11在肝脏中的表达显著降低。在Aim 3中，我们将通过测试FGF15/19通过抑制糖异生从而降低肝脏葡萄糖生成从而改善胰岛素敏感性的假设来表征FGF15/19对碳水化合物和脂质代谢的生理影响。这些研究将为这一新特征的内分泌信号通路提供基本见解，并检查其在代谢综合征药物治疗中的潜在效用。公共卫生相关性：本提案调查FGF15/19的生物学作用，FGF15/19是一种相对未被探索的激素，在饭后从小肠分泌。在其作用中，FGF15/19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。

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.