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This aim i s based on our unpublished finding that FGF15/19 causes a marked reduction in hepatic expression of PGC-11.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.
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.
| Patton, John B; Bonne-Année, Sandra; Deckman, Jessica et al. (2018) Methylprednisolone acetate induces, and ?7-dafachronic acid suppresses, Strongyloides stercoralis hyperinfection in NSG mice. Proc Natl Acad Sci U S A 115:204-209 |
| Song, Parkyong; Zechner, Christoph; Hernandez, Genaro et al. (2018) The Hormone FGF21 Stimulates Water Drinking in Response to Ketogenic Diet and Alcohol. Cell Metab 27:1338-1347.e4 |
| Katafuchi, Takeshi; Holland, William L; Kollipara, Rahul K et al. (2018) PPAR?-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice. Proc Natl Acad Sci U S A 115:12102-12111 |
| Lan, Tian; Morgan, Donald A; Rahmouni, Kamal et al. (2017) FGF19, FGF21, and an FGFR1/?-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia. Cell Metab 26:709-718.e3 |
| Coate, Katie C; Hernandez, Genaro; Thorne, Curtis A et al. (2017) FGF21 Is an Exocrine Pancreas Secretagogue. Cell Metab 25:472-480 |
| Albarqi, Mennatallah M Y; Stoltzfus, Jonathan D; Pilgrim, Adeiye A et al. (2016) Regulation of Life Cycle Checkpoints and Developmental Activation of Infective Larvae in Strongyloides stercoralis by Dafachronic Acid. PLoS Pathog 12:e1005358 |
| Youm, Yun-Hee; Horvath, Tamas L; Mangelsdorf, David J et al. (2016) Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. Proc Natl Acad Sci U S A 113:1026-31 |
| Talukdar, Saswata; Owen, Bryn M; Song, Parkyong et al. (2016) FGF21 Regulates Sweet and Alcohol Preference. Cell Metab 23:344-9 |
| Katafuchi, Takeshi; Esterházy, Daria; Lemoff, Andrew et al. (2015) Detection of FGF15 in plasma by stable isotope standards and capture by anti-peptide antibodies and targeted mass spectrometry. Cell Metab 21:898-904 |
| Kliewer, Steven A; Mangelsdorf, David J (2015) Bile Acids as Hormones: The FXR-FGF15/19 Pathway. Dig Dis 33:327-31 |
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