A primary target of the pleiotropic metabolic hormone FGF21 is adipose tissue, where it initiates a gene expression program to enhance energy expenditure, an effect presumed to be centered on augmented UCP1 expression and activity. In UCP1 null (UCP1KO) mice, we show that the effect of FGF21 to increase the metabolic rate is abolished. However, in contrast to prior expectations, we found that increased UCP1-dependent thermogenesis is only partially required to achieve the beneficial effects of FGF21 treatment. In UCP1KO mice, there appears to be an underlying reduction in food intake following FGF21 administration, facilitating weight loss equal to that observed in wild-type animals. Furthermore, we show that UCP1-dependent thermogenesis is not required for FGF21 to improve glycemic control or to reduce circulating cholesterol or free fatty acids. These data indicate that several important metabolic endpoints of FGF21 are UCP1 independent; however, the contribution of UCP1-dependent thermogenesis to other discrete aspects of FGF21 biology requires further study.
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