FGF21 signals to leptin receptor-expressing cells to promote weight loss. (A) Representative immunofluorescence imaging for pSTAT3 in the medial preoptic area (mPOA), lateral hypothalamus (LH), ventromedial hypothalamus (VMH), dorsomedial hypothalamus (DMH), arcuate nucleus (ARC) and ventral premammillary nucleus (PMv) of KLB-Cre; tdTomato mice administered leptin (i.p., 100 μg) following an overnight fast. 3 V = 3rd ventricle. (B–C) 16–18 week old diet-induced obese (DIO) WT and KLBLepR−KO mice were administered vehicle or FGF21 daily (i.p., 1 mg/kg) for 3 weeks (n = 6–8/group). (B) Daily percent change in body weight and (c) final percent chance in body weight. (D–E) Plasma glucose levels during an insulin tolerance test (ITT) in DIO WT and KLBLepR−KO mice at baseline and after 3 weeks of daily FGF21 injections (i.p, 1 mg/kg) (n = 6/group). (E) Quantification of the area under the curve for ITT in (D).