FGF21 Mediates Alcohol‐Induced Adipose Tissue Lipolysis by Activation of Systemic Release of Catecholamine in Mice

Abstract

Alcohol consumption leads to adipose tissue lipoatrophy and mobilization of free fatty acids (FFA), which contributes to hepatic fat accumulation in alcoholic liver disease (ALD). Fibroblast growth factor 21 (FGF21) is a metabolic regulator and plays an important role in glucose and lipid homeostasis in various diseases. Here, we demonstrate that FGF21 knockout (KO) mice are resistant to chronic‐binge alcohol exposure‐induced epididymal white adipose tissue lipolysis. Alcohol consumption increases FGF21 expression both in the liver and adipose tissue. Alcohol exposure causes adipose intracellular cAMP elevation, and lipolytic enzymes and coating protein activation, leading to FFA mobilization in both wild type and FGF21 KO mice. However, alcohol‐induced systemic elevation of catecholamine release, which is known to be a major player in adipose lipolysis by binding to the β‐adrenergic receptor and subsequently PKA activation, was markedly inhibited in KO mice. Supplementation with recombinant human FGF21 to alcohol‐exposed KO mice caused increased fat loss in parallel with an increase of circulating norepinephrine concentration. Furthermore, alcohol consumption‐induced fatty liver is blunted in the KO mice, indicating an inhibition of fatty acid reverse transport from adipose to the liver in the KO mice. In conclusion: FGF21 deficient mice are protected from alcohol‐induced adipose tissue excess‐lipolysis through a mechanism involving sympathetic nervous system (SNS) activation and catecholamine release. Strategies targeting the SNS activation to block FGF21‐mediated excess‐adipose lipolysis might be developed to prevent/treat alcohol‐induced fatty liver disease.