suggest increased FGFR1 in lipodystrophic adipocytes increases receptor phosphorylation and manifests in a unique pattern of FRS phosphorylation that impairs typical FGF21-induced signaling. The increase in plasma FGF21 is of interest and corresponds to the dramatic increase in Fgf21 expression in liver, BAT and WAT. It has been reported that the liver accounts for most of circulating FGF21 [23], [24]. Despite the increase in Fgf21 expression in these 3 tissues it appears that the circulating levels are mostly governed by the liver expression, since transplantation decreased the elevated FGF21 levels in Tg mice (Figure S5C) and correlates to a ≈75% reduction in Fgf21 expression in liver only. The recent findings [23] that PPARγ mediates FGF21’s action promoted our investigation of Pparg expression in adipose tissues and liver in our mice. We observed that indeed Tg tissues exhibit differences in Pparg expression; levels of Pparg in WAT and BAT were reduced in Tg mice and this profile is consistent with the lack of efficacy of rmuFGF21, suggesting that PPARγ may play a role FGF21’s effects [23]. An important observation was that Pparg was increased only in transplanted WAT treated with FGF21– corresponding to the group of animals with restored efficacy.
