Our finding that adipose tissue transplantation completely restored FGF21 responsiveness was of significant interest. The extent of the improvement in fat-transplanted Tg mice treated with FGF21 surpassed the typical effect observed with FGF21 administration in WT mice (Figure 4H. vs. 4F respectively), raising the possibility that the transplanted tissue not only restored WT amounts of adipose but also restored physiological functions itself. This perhaps is of most interest when comparing to a lack of restoration of TZD efficacy in WAT-transplanted A-ZIP/F-1 mice [25]. TZDs operate directly on WAT to improve insulin sensitivity and possibly implantation process leaves the tissue refractory to those direct actions (due to graft complications) whereas FGF21 co-operates with WAT to improve insulin sensitivity and glucose homeostasis, indeed we observed that adiponectin levels as a marker of insulin sensitity was only increased in WT and Tg–tx mice treated with FGF21. Additionally, the combination therapy of leptin and FGF21 improved all glucose and insulin measures (Figures 6A–D). The incremented effect in the GTT bore resemblance to that of the transplant + FGF21 group in the transplantation study (Figures
