Fibroblast growth factor 21 (FGF21) is a recently discovered hormone that regulates energy balance. Indiabetic rodents and monkeys, FGF21 has broad metabolic effects that include reducing serum glucose andtriglyceride concentrations. We recently discovered that FGF21 expression is markedly induced in liver byperoxisome proliferator-activated receptor (PPAR), a member of the nuclear steroid/thyroid hormonereceptor family that is activated by fatty acids. PPAR plays a central role in the fasting response, includingthe induction of fatty acid catabolism and ketogenesis, and is the molecular target for the fibrate class ofdyslipidemia drugs. We have found that administration of recombinant FGF21 to mice recapitulates many ofthe metabolic actions of PPAR activation including the reduction of circulating triglyceride concentrations andthe induction of ketogenesis. In addition, FGF21 reduces physical activity and enhances torpor, an energyconservingstate of regulated hypothermia. Based on these data, we hypothesize that FGF21 is a fastinginducedhepatokine that coordinately regulates systemic metabolism and behavior to conserve energy. Thestudies 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 andketogenesis will be studied.
In Specific Aim 3, we will examine whether the effects of FGF21 on torpor andactivity are mediated via the central nervous system. We believe that these studies will provide importantinsights into the molecular mechanisms governing metabolism and will also yield unexpected insights intothe molecular actions of the fibrate class of drugs. Ultimately, manipulation of the FGF21 signaling pathwaymay provide novel strategies for treating obesity, diabetes, and the metabolic syndrome.
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