Fibroblast Growth Factor-9 Regulates Adaptive Brown Adipose Tissue Mass Expansion

Brown adipose tissue (BAT) plays an essential role in adaptive thermogenesis in response to environmental changes, such as cold and diet. Targeting BAT and modulating its mass and/or energy-dissipating capacity hold great promise for treatment of metabolic disorders. Expansion of BAT mass through increased cellular proliferation is a fundamental mechanism of cold adaptation. We have recently discovered Fibroblast Growth Factor 9 (FGF-9) as a cold-induced adipokine produced by BAT that regulates BAT mass. Adeno-associated virus (AAV)-mediated overexpression of FGF-9 in vivo increased BAT mass and improved glucose metabolism in obese mice. Additionally, using double thymidine analogue labeling we demonstrated that FGF-9 overexpression in BAT increased cellular proliferation and enhanced cold-induced BAT expansion. Using an adipose tissue-specific Cas9 knock-in mouse model coupled with the AAV-mediated delivery of gRNAs targeting FGF-9, we specifically deleted FGF-9 in BAT and demonstrated that loss of FGF-9 resulted in reduction of cold-induced proliferation of brown adipocyte progenitors, and led to impaired thermogenic capacity. Therefore, FGF-9 is essential for cold-induced formation of new brown adipocytes and long term cold adaptation. Combining the results from these gain- and loss-of-function studies, we conclude that FGF-9 acts as a growth factor for brown adipocyte progenitors to promote BAT expansion in response to cold. These findings provide a novel regulatory mechanism modulating BAT mass, and may ultimately contribute to the development of novel therapeutic strategies to combat obesity and its comorbidities.