Regulation of Metabolism by the Hormone FGF15/19

描述(由申请人提供)：最近的研究表明，肠道激素作为营养状况的主要反应因素以及作为治疗不断升级的肥胖症的潜在新疗法的重要性。在之前的资助期间，我们发现非典型的成纤维细胞生长因子FGF15及其人类同源基因FGF19作为一种新的内分泌激素从肠道表达和分泌，以响应餐后胆汁酸受体FXR的激活。进而，FGF15/19进入肝门循环，调控胆汁酸的合成和胆囊壁的充盈。研究还表明，在代谢性疾病的啮齿动物模型中，给予FGF15/19的药理作用显著改善了胰岛素敏感性，而敲除FGF15在小鼠中的表达会导致高胰岛素血症和葡萄糖耐量异常。总之，这些发现将餐后胆汁酸在肠道中的摄取与一种新的成纤维细胞生长因子信号通路联系在一起，该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。在这项建议中，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对碳水化合物和脂肪代谢的生理影响。在目标1中，我们将确定FGF15/19通过转录抑制胆汁酸合成中的限速酶--胆固醇71-羟基酶基因(CYP7A1)来调节胆汁酸合成的分子机制。在目标2中，我们将探讨转录辅活化子PGC-11在介导FGF15/19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FGF15/19导致肝脏PGC-11的表达显著减少。在目标3中，我们将通过验证FGF15/19通过抑制糖异生从而降低肝脏葡萄糖生成来改善胰岛素敏感性的假设，来表征FGF15/19对碳水化合物和脂肪代谢的生理影响。这些研究将提供对这一新表征的内分泌信号通路的基本见解，并检验其在代谢综合征药物治疗中的潜在用途。公共卫生相关性：这项提案调查了FGF15/19的生物学作用，FGF15/19是一种相对未被探索的荷尔蒙，在餐后从小肠分泌。在其作用中，FGF15/19重置消化机械，增强胰岛素的作用，并使啮齿类动物体重减轻。来自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性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.