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This aim i s based on our unpublished finding that FGF15/19 causes a marked reduction in hepatic expression of PGC-11.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.

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067158-10
Application #
8448350
Study Section
Special Emphasis Panel (ZRG1-EMNR-H (02))
Program Officer
Margolis, Ronald N
Project Start
2004-03-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$322,966
Indirect Cost
$117,255
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Owen, Bryn M; Ding, Xunshan; Morgan, Donald A et al. (2014) FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab 20:670-7
Evans, Ronald M; Mangelsdorf, David J (2014) Nuclear Receptors, RXR, and the Big Bang. Cell 157:255-66
Bookout, Angie L; de Groot, Marleen H M; Owen, Bryn M et al. (2013) FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat Med 19:1147-52
Owen, Bryn M; Bookout, Angie L; Ding, Xunshan et al. (2013) FGF21 contributes to neuroendocrine control of female reproduction. Nat Med 19:1153-6
Goetz, Regina; Ohnishi, Mutsuko; Ding, Xunshan et al. (2012) Klotho coreceptors inhibit signaling by paracrine fibroblast growth factor 8 subfamily ligands. Mol Cell Biol 32:1944-54
Potthoff, Matthew J; Kliewer, Steven A; Mangelsdorf, David J (2012) Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev 26:312-24
Kir, Serkan; Beddow, Sara A; Samuel, Varman T et al. (2011) FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science 331:1621-4
Li, Tingting; Holmstrom, Sam R; Kir, Serkan et al. (2011) The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling. Mol Endocrinol 25:1066-71
Potthoff, Matthew J; Boney-Montoya, Jamie; Choi, Mihwa et al. (2011) FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1ýý pathway. Cell Metab 13:729-38
Fon Tacer, Klementina; Bookout, Angie L; Ding, Xunshan et al. (2010) Research resource: Comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol 24:2050-64

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