We found separable features of efficacy following FGF21 therapy in the Tg mice, notably anti-diabetic vs. cholesterol lowering. Concomitant with a lack of improvement in insulin sensitivity, we continued to observe that FGF21 lowered plasma cholesterol levels (Figures 1J & 4K). Taken together with maintained FGF21 liver signaling in Tg mice (Figure 3D), it is possible that the liver is the target tissue for the cholesterol efficacy. Triglyceride levels were not coordinately lowered alongside cholesterol levels; in fact, Tg mice were resistant to FGF21-induced triglyceride lowering. It is possible that adipose tissue is required for triglyceride lowering efficacy. To support this, is the observation that FGF21 treatment in Tg-tx mice lead to a small (but non-significant) triglyceride reduction compared to vehicle-treated controls. Although this may indicate possible restoration of FGF21 responsiveness in non-WAT tissue, it highlights a dependence of WAT for FGF21 function.
