FGF21 increases energy expenditure and improves glucose homeostasis in a BAT-independent fashion. Vo2 (A), Vco2 (B), and energy expenditure per body weight (C) were significantly higher in FGF21-treated mice (n = 8/group). Plasma glucose during the intraperitoneal glucose tolerance test (D) and the AUC (E) were significantly lower in FGF21-treated mice. Plasma insulin during the intraperitoneal glucose tolerance test (F) and the AUC (G) were significantly lower in FGF21-treated mice (n = 8/group). These experiments were performed in mice that underwent BAT lipectomy and were fed a HFD. Data are presented as mean ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001.