FGF21 is a modulator of lipid metabolism and glucose homeostasis (ref.36). FGF21 attenuates hyperglycemia by increasing energy metabolism in adipose tissues (ref.37); hepatic FGF21 transgenic mice were protected from diet-induced obesity (ref.25). Treatment with FGF21 also acts directly on the liver to modulate hepatic metabolism (ref.37) and FGF21 knockdown caused both hepatic steatosis and hypertriglyceridemia (ref.38). We found that recombinant FGF21 (rFGF21) treatment blunted hypertriglyceridemia induced by alcohol feeding in pparα−/− mice (ref.12), so PPARα regulates lipid metabolism through FGF21. FGF21 is mainly produced in liver and is released from liver into blood. FGF21 can target adipocytes because FGF21 exerts its effect via binding to FGF receptor 1 which is mainly expressed in adipocytes (ref.37 and 39). Thus, interaction between adipose tissue and liver might be mediated by the liver-released FGF21. Because FGF21 is regulated by PPARα (ref.38, ref.40–41), serum FGF21 was much lower in P-/A- mice and P-/A+ mice than in P+/A- mice (Fig.4D). Free fatty acids are endogenous ligands to activate PPARα, but serum free fatty acids from adipose tissue do not activate PPARα, instead, it is de
