FGF9 promotes healthy expansion of subcutaneous adipose tissue and prevents insulin resistance

Aging is associated with the redistribution of body fat, including the relative loss of subcutaneous white fat tissue (sWAT). The hyperplastic expansion of sWAT in obesity is beneficial for metabolism; however, aging, which leads to the exhaustion of adipocyte progenitor cell (APC) pools, impairs adipogenesis. FGF9 was markedly induced in sWAT during obesity and declined during aging; however, it remained relatively unchanged in epididymal adipose tissue. Single-cell RNA-sequencing identified a unique subset of MGP-positive (MGP+) APCs that respond to FGF9 in sWAT. In vitro differentiation and in vivo transplantation experiments demonstrated that MGP+ cells possess high cell-autonomous adipogenic capacity, suggesting that they serve as developmental precursors for mature adipocytes during obesity. Mechanistically, FGF9 mediates MGP+ cell proliferation by binding to FGFR1 and activating the mitogen-activated protein kinase pathway. Genetic manipulation of FGF9 revealed that it is crucial for MGP+ cell adipogenesis and subdermal adipose expansion, and FGF9 deficiency causes obesity-induced insulin resistance. Moreover, specific increases in FGF9 levels in sWAT significantly induced the hyperplastic expansion of sWAT and improved insulin sensitivity in obese aged mice. Notably, a nucleic acid backbone was used to stabilize recombinant human FGF9 (rFGF9), and chronic pharmacological treatment with rFGF9 improved insulin sensitivity, resulting in a whole-body glucose-lowering effect. In conclusion, this study reveals an unexpected insulin-sensitizing effect of FGF9 that has therapeutic potential for the treatment of diabetes.衰老与体脂的重新分布密切相关，其中包括皮下白色脂肪组织（subcutaneous white fat tissue, sWAT）的相对丢失。肥胖状态下皮下白色脂肪组织的增生性扩张对代谢有益；然而，衰老会导致脂肪细胞祖细胞（adipocyte progenitor cell, APC）库耗竭，进而损伤脂肪生成过程。成纤维细胞生长因子9（FGF9）在肥胖过程中于皮下白色脂肪组织内被显著诱导，而在衰老进程中其表达水平下降，但在附睾脂肪组织中相对保持稳定。单细胞RNA测序（single-cell RNA-sequencing）鉴定出一群独特的MGP阳性（MGP+）脂肪细胞祖细胞，该类细胞可在皮下白色脂肪组织中响应FGF9信号。体外分化实验与体内移植实验证实，MGP+细胞具备极强的细胞自主性脂肪生成能力，表明它们在肥胖过程中可作为成熟脂肪细胞的发育前体。从机制层面而言，FGF9通过结合成纤维细胞生长因子受体1（FGFR1）并激活丝裂原活化蛋白激酶通路（mitogen-activated protein kinase pathway），介导MGP+细胞的增殖。对FGF9进行基因操作的实验表明，其对于MGP+细胞的脂肪生成以及皮下脂肪扩张至关重要，而FGF9缺乏会引发肥胖诱导的胰岛素抵抗。此外，在皮下白色脂肪组织中特异性升高FGF9水平，可显著诱导肥胖衰老小鼠的皮下白色脂肪组织增生性扩张，并改善其胰岛素敏感性。值得注意的是，本研究采用核酸骨架稳定重组人FGF9（rFGF9），并通过长期药理学给药方式施用rFGF9，最终改善了机体胰岛素敏感性，产生了全身性降糖效应。综上，本研究揭示了FGF9此前未被发现的胰岛素增敏作用，该作用具备治疗糖尿病的潜在临床价值。