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.