Widberg C H, Newell F S, Bachmann A W, Ramnoruth S N, Spelta M C, Whitehead J P, Hutley L J, Prins J B
Diamantina Institute for Cancer, Immunology, and Metabolic Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
Am J Physiol Endocrinol Metab. 2009 Jan;296(1):E121-31. doi: 10.1152/ajpendo.90602.2008. Epub 2008 Oct 21.
Cell number is an important determinant of adipose tissue mass, and the coordinated proliferation and differentiation of preadipocytes into mature lipid-laden adipocytes underpins the increased adipose tissue mass associated with obesity. Despite this, the molecular cues governing such adipose tissue expansion are poorly understood. We previously reported that fibroblast growth factor-1 (FGF-1) promotes both proliferation and differentiation of human preadipocytes and that the major adipogenic effect of FGF-1 occurs during proliferation, priming the cells for adipose conversion. In the current study, we examined whether this effect was linked to the mitogenic action of FGF-1 by investigating the mitogenic and adipogenic potential of other growth factors, platelet-derived growth factor (PDGF; AA and BB) and vascular endothelial growth factor. Although PDGF-AA and PDGF-BB showed comparable mitogenic potential to FGF-1, only FGF-1 treatment resulted in priming and subsequent differentiation. Pharmacological inhibition of FGF receptor (FGFR) tyrosine kinase activity, using the FGFR-specific inhibitors PD-173074 and SU-5402, revealed an obligate requirement for FGFR activity in these processes. A combination of biochemical and genetic approaches revealed an important role for FGFR1. Knock down of FGFR1 expression by small-interfering RNA reduced FGF-1-stimulated signaling events, proliferation, and priming. Together these data highlight the unique nature of the role of FGF-1 during the earliest stages of adipogenesis and establish a role for FGFR1 in human adipogenesis, identifying FGFR1 as a potential therapeutic target to reduce obesity.
细胞数量是脂肪组织质量的一个重要决定因素，前脂肪细胞向成熟的充满脂质的脂肪细胞的协同增殖和分化是肥胖相关脂肪组织质量增加的基础。尽管如此，调控这种脂肪组织扩张的分子线索仍知之甚少。我们之前报道过，成纤维细胞生长因子-1（FGF-1）可促进人前脂肪细胞的增殖和分化，且FGF-1的主要促脂肪生成作用发生在增殖过程中，使细胞为脂肪转化做好准备。在本研究中，我们通过研究其他生长因子——血小板衍生生长因子（PDGF；AA和BB）和血管内皮生长因子的促有丝分裂和促脂肪生成潜力，来检验这种作用是否与FGF-1的促有丝分裂作用有关。尽管PDGF-AA和PDGF-BB显示出与FGF-1相当的促有丝分裂潜力，但只有FGF-1处理能引发并随后促进分化。使用FGFR特异性抑制剂PD-173074和SU-5402对FGF受体（FGFR）酪氨酸激酶活性进行药理学抑制，揭示了这些过程中FGFR活性的绝对必要性。生化和遗传学方法相结合揭示了FGFR1的重要作用。通过小干扰RNA敲低FGFR1表达可减少FGF-1刺激的信号转导事件、增殖和起始作用。这些数据共同凸显了FGF-1在脂肪生成最早阶段作用的独特性质，并确立了FGFR1在人脂肪生成中的作用，将FGFR1确定为减轻肥胖的潜在治疗靶点。
