Fibroblast growth factor-21 (FGF21) decreases hepatic triglycerides when administered to obese animals and humans, and thus has gained attention as a novel drug target for nonalcoholic fatty liver disease (NAFLD). However, its mechanism of action remains unclear. Furthermore, although NAFLD pathology is well known to be sexually dimorphic, studies of FGF21 have skewed toward males without sufficient consideration of sex as a biological variable. Here we report that FGF21 administration to diet-induced obese mice decreased hepatic triglycerides in a weight loss-independent manner in obese male mice, but this effect was blunted in female littermates (p(treatment x sex)<0.001). Adiponectin, a key mediator of FGF21’s therapeutic effects, was increased by FGF21 in males but not females (p(treatment x sex)<0.01). In agreement with this, FGF21 elicited an increase in hepatic adenosine monophosphate, known to be downstream of adiponectin signaling, and decreased the expression of lipogenic genes Pparg, Cidea, and Cd36 in males but not females (p(treatment x sex)<0.05, <0.0001, <0.05, <0.01, respectively). Finally, we investigated whether the metabolic benefits of FGF21 observed in males are restored in ovariectomized (OVX) females. OVX females did not phenocopy males, as FGF21 did not significantly decrease hepatic triglycerides, increase plasma adiponectin, or decrease lipogenic gene expression in OVX females. These data have immediate clinical implications, and highlight the importance of both sex and reproductive status as a biological variable in ongoing development of FGF21-based therapeutics for NAFLD.


A. T. B. Chaffin: None. K. R. Larson: None. K. Huang: None. K. K. Ryan: None.


National Institutes of Health (R01DK121035, F31DK124080)

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