Fibroblast growth factor 21 (FGF21) is a recently discovered hormone that regulates energy balance. In diabetic rodents and monkeys, FGF21 has broad metabolic effects that include reducing serum glucose and triglyceride concentrations. We recently discovered that FGF21 expression is markedly induced in liver by peroxisome proliferator-activated receptor (PPAR), a member of the nuclear steroid/thyroid hormone receptor family that is activated by fatty acids. PPAR plays a central role in the fasting response, including the induction of fatty acid catabolism and ketogenesis, and is the molecular target for the fibrate class of dyslipidemia drugs. We have found that administration of recombinant FGF21 to mice recapitulates many of the metabolic actions of PPAR activation including the reduction of circulating triglyceride concentrations and the induction of ketogenesis. In addition, FGF21 reduces physical activity and enhances torpor, an energyconserving state of regulated hypothermia. Based on these data, we hypothesize that FGF21 is a fastinginduced hepatokine that coordinately regulates systemic metabolism and behavior to conserve energy. The studies outlined in this application are designed to directly test specific components of this hypothesis.
In Specific Aim 1, we will examine the role of FGF21 in mediating the physiologic responses to PPAR agonists, fasting and high fat diets.
In Specific Aim 2, the role of FGF21 in the induction of hepatic lipolysis and ketogenesis will be studied.
In Specific Aim 3, we will examine whether the effects of FGF21 on torpor and activity are mediated via the central nervous system. We believe that these studies will provide important insights into the molecular mechanisms governing metabolism and will also yield unexpected insights into the molecular actions of the fibrate class of drugs. Ultimately, manipulation of the FGF21 signaling pathway may provide novel strategies for treating obesity, diabetes, and the metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Linked Research project Grant (RL1)
Project #
5RL1GM084436-05
Application #
8123122
Study Section
Special Emphasis Panel (ZRR1-SRC (99))
Program Officer
Okita, Richard T
Project Start
2007-09-30
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$377,381
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Patel, Rucha; Bookout, Angie L; Magomedova, Lilia et al. (2015) Glucocorticoids regulate the metabolic hormone FGF21 in a feed-forward loop. Mol Endocrinol 29:213-23
Nelson, Bethany T; Ding, Xunshan; Boney-Montoya, Jamie et al. (2013) Metabolic hormone FGF21 is induced in ground squirrels during hibernation but its overexpression is not sufficient to cause torpor. PLoS One 8:e53574
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
Wei, Wei; Dutchak, Paul A; Wang, Xunde et al. (2012) Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor ýý. Proc Natl Acad Sci U S A 109:3143-8
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
Dutchak, Paul A; Katafuchi, Takeshi; Bookout, Angie L et al. (2012) Fibroblast growth factor-21 regulates PPAR? activity and the antidiabetic actions of thiazolidinediones. Cell 148:556-67
Ding, Xunshan; Boney-Montoya, Jamie; Owen, Bryn M et al. (2012) ?Klotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab 16:387-93
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
Kliewer, Steven A; Mangelsdorf, David J (2010) Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr 91:254S-257S

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