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 novo synthesized fatty acids that activate PPARα (ref.42). Fatty acid synthase (FAS) is elevated in cyp2a5−/− mice (ref.11). Thus, in cyp2a5−/− mice fatty acids de novo synthesized by FAS may activate the already elevated PPARα. Therefore, serum FGF21 were still higher in P+A- mice than in P-/A- mice and P-/A+ mice even though serum free fatty acids (mainly derived from adipose lipolysis) were lower in P+/A- mice than in P-/A- mice and P-/A+ mice. FGF21 may exert effect via adiponectin (ref.26–27). However, no difference in serum adiponectin between P-A- and P+A- mice was observed. Instead, serum leptin was dramatically induced by HFD in P+/A- mice but not in P-/A- mice and P-/A+ mice, which is similar to changes of serum FGF21. In fact, leptin is a potential regulator of FGF21 (ref.43) and FGF21 can promote metabolic homeostasis via leptin (ref.44). In addition, another adipokine CTRP3 also protected against hepatic steatosis (ref.45). It is possible that PPARα regulates interaction between liver
