Nobiletin attenuates body weight and adiposity and normalizes adipocyte morphology in both HFHC diet-fed iβ1β2AKO and WT mice. WT and iβ1β2AKO mice were fed a HFHC diet (HF) alone or a HFHC diet plus nobiletin (+Nob) for 12 weeks, n = 8–9 per group. A: Immunoblot of pAMPK, AMPK, pACC, and ACC in liver lysates from WT and iβ1β2AKO mice fed a HFHC diet (HF) or a HFHC diet + nobiletin (N). Lysates were run on the same immunoblot. B: Adipose tissue (iWAT) Ampkb1 mRNA. C: Adipose tissue (iWAT) Ampkb2 mRNA. D: Body weight measured weekly. * or # indicates a statistical difference from nobiletin-treated mice within the same genotype, determined by two-way ANOVA with repeated measures analyses, P < 0.05. E: Mean daily caloric intake measured weekly. F: Adiposity assessed as inguinal fat pad weight/total body weight. G: Adiposity assessed as epididymal fat pad weight/total body weight. H: Representative images of iWAT, eWAT, and BAT stained with H&E. Scale bar is 100 μm. I: Frequency distribution of adipocyte area in eWAT. J: Mean adipocyte area in eWAT. K: Total adipocyte number in eWAT calculated as the mean number of cells per field of view X weight of eWAT. L–O: Adipose tissue (iWAT) Ucp1, Tbx1, Serca2b, and Cd137 mRNA. Data represent the mean ± SEM. Different letters indicate statistical differences by ANOVA with post hoc Tukey’s test (P < 0.05). N.S.; no significant difference.