The beneficial effects of native FGF21 in control and iβ1β2AKO mice are not driven by the upregulation of a thermogenic program in vivo. A and B: tissue weights of BAT (A) and iWAT (B) of control and iβ1β2AKO mice treated with saline or native FGF21 for 14 days (n = 4–7 per group). (C) representative H&E stains (10x) of BAT from control and iβ1β2AKO mice fed a high fat diet (45%) for 10 weeks and treated with saline or native FGF21 for 14 days. D and E: mRNA expression of mitochondrial and browning markers (Hadh, MT-CO2, Cox8b, Cpt1b, Ppargc1α, Pparα, Cidea, Ucp1) in BAT (D) and iWAT (F) (n = 4–7 per group). (E) mitochondrial COX activity in whole tissue BAT lysates from control and iβ1β2AKO mice treated with FGF21 (n = 4–7 per group). G–H: representative UCP1 and β-tubulin immunoblotting (G) with quantification in BAT (H) and iWAT (I) of high fat diet-fed and two week treated (saline or native FGF21) control and iβ1β2AKO mice (n = 4–7 per group). Data are means ± SEM with ††† p < 0.001, †† p < 0.01, † p < 0.05 denoting a general treatment effect and * p < 0.05 denoting a general genotype effect as determined by a two-way ANOVA.