Unexpectedly, the entire FGFR/β-klotho cell signaling cascade was altered in WAT from Tg mice. Proximally, β-klotho and FGFR1 mRNA were expressed normally in lipodystrophy WAT. Interestingly, pY-FRS2 (Figure 3B) and pY-SHP2 (Figure 3C) were increased and decreased respectively when compared to WT WAT. Furthermore this phosphorylation pattern in lipodystrophic WAT was unchanged in response to recombinant FGF21 (Figure 3B), collectively suggesting that FGFR1/FRS2 signaling was basally activated in WAT and cellular FGF21 resistance was observed in these mice. Adipose inflammation in this mouse model could account for the noted basal activation [22]. Indeed, we observed macrophage infiltration in lipodystrophic WAT (Figure S6) and thus the heterogeneous nature of this adipose could obscure the precise signaling events such that the observations are not reflective of adipocytes. Alternatively, if the changes observed in FGFR signaling are solely restricted to adipocytes, these data 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
