FGF21 is efficacious in leptin null ob/ob mice and indicates that leptin is not required for FGF21’s anti-diabetic actions. In fact normal FGF21-induced signaling is observed in ob/ob adipose [24], [28], whereas we observe impaired FGF21 signaling in lipodystrophy WAT. Possibly, in Tg mice, not only does leptin exert additive effects to FGF21 on glucose and body weight lowering but also restores FGF21 resistance. It remains to be determined if leptin is responsible for the full restoration of FGF21 efficacy in Tg mice, or merely contributes to it; for example transplantation leads to mild increases in leptin levels, whereas leptin injections delivered supraphysiological doses. A worthwhile future experiment would involve the transplantation of ob/ob WAT into Tg mice to investigate whether leptin is required for the WAT rescue of efficacy.
