A PPARgamma-FGF1 axis is required for adaptive adipose remodeling

We identify fibroblast growth factor 1 (FGF1) as a critical transducer in adipose tissue remodeling and link its regulation to peroxisome proliferator activated-receptor gamma (PPARgamma), the adipocyte master regulator and target of the thiazolidinedione (TZD) class of insulin sensitizing drugs. We show that FGF1 is highly induced in adipose tissue in response to high-fat diet (HFD) and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with HFD. Mechanistically, we show that transcription of FGF1 is directly regulated by an adipocyte-selective proximal PPAR response element, and that this PPARgamma-FGF1 axis is evolutionarily conserved in mammals. This work describes the first phenotype of the FGF1 knockout mouse and establishes FGF1 as a new member of the NR-FGF axis critical for maintaining metabolic homeostasis and insulin sensitization. Total RNA was obtained from epidydimal white adipose tissue (eWAT) and livers from 6 month old wild-type and FGF1-/- mice after 16 weeks on normal chow or high-fat diets.本研究鉴定成纤维细胞生长因子1（fibroblast growth factor 1, FGF1）为脂肪组织重塑过程中的关键转导因子，并将其调控通路与过氧化物酶体增殖物激活受体γ（peroxisome proliferator activated-receptor gamma, PPARγ）建立关联——PPARγ作为脂肪细胞的核心调控因子，同时也是噻唑烷二酮类（thiazolidinedione, TZD）胰岛素增敏药物的作用靶点。研究显示，高脂饮食（high-fat diet, HFD）刺激可显著诱导FGF1在脂肪组织中表达；而FGF1基因敲除小鼠在高脂饮食造模后，会出现侵袭性糖尿病表型，并伴随异常脂肪组织扩张。机制研究证实，FGF1的转录直接受脂肪细胞特异性近端过氧化物酶体增殖物应答元件调控，且该PPARγ-FGF1通路在哺乳动物中具有进化保守性。本研究首次报道了FGF1基因敲除小鼠的表型，并确立FGF1为核受体-成纤维细胞生长因子（NR-FGF）轴的新成员，该轴对于维持代谢稳态与胰岛素增敏至关重要。本研究的总RNA提取自经16周普通饲料或高脂饮食喂养的6月龄野生型与FGF1基因敲除（FGF1-/-）小鼠的附睾白色脂肪组织（epidydimal white adipose tissue, eWAT）与肝脏。