Two major effects of FGF21 directly on adipose tissue stand out that may contribute to relief of metabolic stress on liver and muscle. Activation of the adipocyte FGFR1-KLB complex modulates the rate of adipocyte lipolysis and fatty acid oxidation that indirectly relieves hepatocyte steatosis or muscular lipid overload. Upregulation of expression of genes involved in fatty acid oxidation, browning of white fat and thermogenesis is also thought to collectively contribute to the anti-obesogenic effects (1, 29, 40, 49) in the obese. In contrast, activation of the adipocyte FGFR1-KLB complex during starvation dampens the rate of adipocyte lipolysis, which may help to extend energy usage. Secondly, recent studies show that FGF21 regulates the endocrine function of adipocytes including the secretion of adipokines that act on diverse tissues throughout the body. Notably the adipokine adiponectin is upregulated and leptin downregulated by FGF21. 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).
