- 學位論文
Fibroblast growth factor 21 as a key modulator of glucose uptake and lipolysis in adipocytes: molecular mechanismsand physiological implications
Fibroblast growth factor 21 as a key modulator of glucose uptake and lipolysis in adipocytes: molecular mechanismsand physiological implications
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並列摘要
Fibroblast Growth Factor (FGF) 21 is a liver-derived endocrine factor with multiple metabolic effects on glucose and lipid homeostasis in animals. The adipose tissue has been proposed as a major target of FGF21, where it enhances glucose uptake and modulates lipolysis as well as thermogenesis. However, the molecular mechanisms underlying the pleiotropic effects of FGF21 in adipocytes and the physiological roles of FGF21 in regulating energy homeostasis remain poorly characterized. Therefore, the present study aimed to investigate: 1) the signal transduction pathway whereby FGF21 enhances glucose uptake in white adipocytes; 2) the role of FGF21 in lipolysis in both mouse and human white adipose tissues (WAT) and its underlying mechanisms involved; 3) the phenotypes of FGF21 knockout (KO) mice with respect to energy expenditure and adiposity under both standard chow and high fat diet. Key findings: 1. In vitro studies demonstrated that extracellular signal-regulated kinases (ERK1/2) play an obligatory role in mediating FGF21-induced upregulation of glucose transporter-1 (GLUT1) expression and hence elevation of glucose uptake in 3T3-L1 adipocytes. 2. Chromatin immunoprecipitation assay revealed that Serum Response Factor (SRF) and ETS-like protein-1 (Elk-1), the two transcription factors which are known as the downstream targets of ERK1/2, were recruited to the endogenous GLUT1 promoter in adipocytes. A conserved binding motif for these two transcription factors was also identified in the GLUT1 promoter responsive to FGF21 stimulation in 3T3-L1 adipocytes by site-directed mutagenesis and luciferase assay. 3. In WAT of diet-induced obese mice, FGF21-evoked downstream signaling events, including the phosphorylation of ERK1/2 and SRF/Elk-1, the upregulation of GLUT1, and the increased glucose uptake, were markedly blunted compared to lean controls, suggesting the existence of “FGF21 resistance” in obesity. 4. In vivo and ex vivo studies on fasted wild type and FGF21 KO mice demonstrated that FGF21 acutely suppressed basal and forskolin-stimulated lipolysis in WAT. 5. FGF21-inhibited lipolysis was mediated by Akt-dependent reduction of cyclic adenosine monophosphate (cAMP) levels in both mouse and human WAT. 6. FGF21 KO mice were resistant to diet- and aging-induced obesity, which was attributed to decreased fat mass. The increased lipolysis and fatty acid oxidation in FGF21 KO mice may explain in part the lean phenotype of FGF21 KO mice. Conclusions: These results collectively suggest FGF21 as a key modulator of glucose and lipid metabolism in WAT, by activation of ERK1/2 kinase and Akt respectively. FGF21 and its signaling components may represent potential targets for the future development of new strategies for treating obesity and its medical complications.