FGF21 Regulates Metabolism Through Adipose-Dependent and -Independent Mechanisms

• Published in: Cell metabolism 2017-04, Vol.25 (4), p.935-944.e4
• Main Authors: BonDurant, Lucas D., Ameka, Magdalene, Naber, Meghan C., Markan, Kathleen R., Idiga, Sharon O., Acevedo, Michael R., Walsh, Susan A., Ornitz, David M., Potthoff, Matthew J.
• Format: Article
• Language: English
• Subjects: Adipocytes, Brown - metabolism; adiponectin; Adiponectin - metabolism; adipose; Adipose Tissue - metabolism; Animals; betaklotho; brown; Energy Metabolism; FGF21; Fibroblast Growth Factors - metabolism; glucose; homeostasis; insulin; Insulin - metabolism; Mice, Inbred C57BL; Mice, Knockout; sensitivity; Signal Transduction; Weight Loss; white
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2017.03.005

FGF21 is an endocrine hormone that regulates energy homeostasis and insulin sensitivity. The mechanism of FGF21 action and the tissues responsible for these effects have been controversial, with both adipose tissues and the central nervous system having been identified as the target site mediating FGF21-dependent increases in insulin sensitivity, energy expenditure, and weight loss. Here we show that, while FGF21 signaling to adipose tissue is required for the acute insulin-sensitizing effects of FGF21, FGF21 signaling to adipose tissue is not required for its chronic effects to increase energy expenditure and lower body weight. Also, in contrast to previous studies, we found that adiponectin is dispensable for the metabolic effects of FGF21 in increasing insulin sensitivity and energy expenditure. Instead, FGF21 acutely enhances insulin sensitivity through actions on brown adipose tissue. Our data reveal that the acute and chronic effects of FGF21 can be dissociated through adipose-dependent and -independent mechanisms. [Display omitted] •FGF21 signaling to adipose tissues is required for acute insulin sensitization•Adiponectin is dispensable for the metabolic effects of FGF21•FGF21 reduces body weight by signaling to nonadipose tissues•FGF21 signals to brown adipocytes to mediate its acute glucose-lowering effects Pharmacological administration of FGF21 increases insulin sensitivity and promotes weight loss. BonDurant et al. show that FGF21 signaling to adipose tissues is essential for the acute insulin-sensitizing effects of FGF21, but not for its effects on body weight. Importantly, loss of FGF21 signaling specifically to brown adipocytes disrupts FGF21-mediated glucose disposal.