They appear to mediate many of the systemic and local effects of FGF21 (50, 51). Reduction of effects of a lipotoxic environment and oxidative stress is a common feature of adiponectin in liver, muscle, heart, kidney, pancreas, and endothelium (52). Thus, both the regulation of fatty acid metabolism and modifications of adipokine profile by FGF21 are favorable for the relief of liver’s steatotic burden that, when extreme and chronic, causes irreversible hepatic damage (Figure 1). Similarly, these FGF21-induced adipocyte responses are favorable for reduction of lipid overload and lipotoxicity in stressed or diseased muscle and possibly other tissues when autophagy/mitophagy, the mitochondria-ER-Golgi network or homeostasis in insulin function and glucose, lipid, and energy metabolic networks is compromised (34, 53).
