FGF15/19 is required for adipose tissue plasticity in response to thermogenic adaptation.

Abstract Objective To determine the role of the enterokine, FGF15/19, in adipose tissue thermogenic adaptations. Methods Circulating FGF19 and gene expression (qRT-PCR) levels were assessed in subcutaneous adipose tissue from human patients with obesity. Effects of experimentally increased FGF15 and FGF19 levels in vivo were determined in mice using adenoviral and adeno-associated vectors. Adipose tissues were characterized in FGF15-null mice under distinct cold-related thermogenic challenges. The analyses performed spanned metabolic profiling, tissue characterization, histology, gene expression and immunoblot assays. Results In humans, FGF19 levels are directly associated with UCP1 gene expression in subcutaneous adipose tissue. Experimental increases of FGF15 or FGF19 induced white fat browning in mice, as evidence by the appearance of multilocular beige cells and markers indicative of a beige phenotype, including increased UCP1 protein levels. Mice lacking FGF15 showed markedly impaired white adipose tissue browning and a mild reduction in parameters indicative of BAT activity in response to cold-induced environmental thermogenic challenges. This was concomitant with signs of altered systemic metabolism, such as reduced glucose tolerance and impaired cold-induced insulin sensitization. Conclusions The enterokine FGF15/19 is a key factor required for adipose tissue plasticity in response to thermogenic adaptations.