In conclusion, our data show that lipodystrophic mice are resistant to FGF21’s effect on glucose homeostasis and adipose transplantation or supraphysiological leptin treatment can correct this impairment. It remains to be determined if leptin restores FGF21 anti-diabetic efficacy at the adipocyte, or whether other tissues/organs become FGF21-sensitive (such as the liver or BAT). Furthermore, the lipodystrophic mice provide a useful tool for elucidating the tissue-specific metabolic action of FGF21; the liver governs FGF21-induced cholesterol lowering, whereas the adipose tissue governs the FGF21-induced effects on triglyceride and glucose homeostasis. Together, these data have implications for the pharmacological additivity and interaction of FGF21 and leptin, and help to further understand the physiological mechanism of action of FGF21.
