Native FGF21 increases energy metabolism, fuel selection, and body weight regulation in both control and iβ1β2AKO mice. (A) timeline of experiment with 45% high fat diet (HFD), in weeks, consisting of a week of tamoxifen (TMX) treatment to induce the deletion of both AMPK beta subunits (β1 and β2) only in adipocytes, and two weeks of native FGF21 administration using implanted osmotic mini-pumps. Mice were maintained on a HFD throughout the illustrated timeline and FGF21 treatment was administered for two weeks. (B–G) oxygen consumption (VO2) normalized to whole body mass (B) and lean body mass (C), energy expenditure normalized to lean body mass (D) respiratory exchange ratio (R.E.R.) (E), food intake (F), and activity levels (G) of control and iβ1β2AKO mice treated with saline or native FGF21 for 14 days (n = 4 per group). Change in body weights (H) and fat percentage (I) of control and iβ1β2AKO mice treated with saline or native FGF21 for 14 days (n = 4–7 per group). Data are means ± SEM with ††† p < 0.001, †† p < 0.01, † p < 0.05 denoting a general treatment effect as determined by a two-way ANOVA.