Metabolic Regulation by Fibroblast Growth Factor 21

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Title: Metabolic Regulation by Fibroblast Growth Factor 21
Author: Dutchak, Paul Anthony
Abstract: Fibroblast growth factor 21 (FGF21 ) is a secreted hormone that can beneficially regulate glucose and lipid homeostasis . Through a reverse endocrinology approach , we uncovered that FGF21 expression is transcriptionally regulated by the peroxisome proliferator activated -receptor alpha (PPARa ) in liver . PPARa is a member of the nuclear hormone receptor superfamily that is physiologically activated by increased fatty acid mobilization to liver during fasting , and regulates the genetic program whereby lipids are converted to ketone bodies through a process known as ketogenesis . Here , I show the effects of FGF21 as a fasting hormone that is expressed in liver and contributes to the regulation of adipose tissue and hepatic ketogenesis during the fasted state . Using in vitro and in vivo methods to investigate the effects of FGF21 , a model whereby FGF21 stimulates lipolysis in adipose tissue was generated . Intriguingly , using our FGF21 transgenic mice , I observed the expression of many genes involved in lipogenesis was highly induced in adipose tissue in an FGF21 -dependent manner . Moreover , many of these lipogenic genes were found to be down -regulated in adipose of the FGF21 knockout mouse . The inhibition of lipogenic genes in adipose tissue was associated with increased SUMOylation of PPARg protein in this tissue . Using a feeding -fasting paradigm , I found that FGF21 expression in the liver and adipose tissue was rhythmic , peaking in liver prior to feeding and peaking in the adipose after feeding . Furthermore , the induction of FGF21 by PPARg ligands suggested a unique function for this protein in adipose , independent from its role in the fasted state . To assess the contribution of FGF21 to the anti -diabetic properties of PPARg agonists (ie . thiazolidinediones ) , diet -induced obese wild type and Fgf21 - / - mice were treated with the TZD rosiglitazone . Rosiglitazone produced a significant increase in adipose FGF21 expression , but decreased hepatic FGF21 mRNA and circulating FGF21 protein . These data suggest that FGF21 functions as an autocrine factor within adipose tissue . Moreover , the therapeutic effects of rosiglitazone as an insulin sensitizer were lost in the Fgf21 - / - mouse , as assessed by glucose and insulin tolerance tests . Several other effects of rosiglitazone were lost in the Fgf21 - / - mice , including increased adipose mass , edema , and PPARg target gene expression in the adipose . These data indicated that PPARg can control the expression of FGF21 , which functions as a feed -forward mechanism to stimulate PPARg target genes and PPARg dependent physiology . Since PPARg can be modified by SUMO on two different sites on the protein , in vitro experiments were performed to show that PPARg is SUMOylated at Lysine -107 , a previously identified negative regulator of its transcriptional activity . Importantly , I found that treatment of Fgf21 - / - adipocytes with FGF21 reduced the amount of SUMOylated PPARg , thereby allowing it to be it an active state . Collectively , these data reveal that FGF21 has two independent roles in regulating metabolism in vivo : as a hepatic endocrine hormone that is induced during the fasting response through PPARa , and as an adipose autocrine /paracrine factor that is induced in a feed -forward loop to stimulate PPARg activity .
URI: http : / /hdl .handle .net /2152 .5 /935
Date: 2011-12-12


Metabolic Regulation by Fibroblast Growth Factor 21. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /935 .

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