Fibroblast growth factor 21 is critically involved in alcohol‐induced hepatic lipid metabolism and adipose tissue lipolysis in mice

Purpose Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator produced primarily in the liver that regulates hepatic fat metabolism in various models of metabolic syndromes. Alcoholic liver disease (ALD) is characterized by hepatic lipid accumulation. Here, we sought to determine the role of FGF21 in mice exposed to alcohol and to discern underlying mechanisms. Methods Male FGF21 knockout (KO) and control (WT) mice were fed either the Lieber DeCarli diet containing 5% alcohol (AF) or an isocaloric diet (PF). For the chronic alcohol exposure, mice were fed for 4 weeks. For the chronic‐binge alcohol exposure, mice were fed for 12 days, followed by a single dose of alcohol (5g/kg) or isocaloric maltose dextrin treatment by gavage. Mice were sacrificed 6 hours later. One group of AF mice were administered with recombinant human FGF21 (rhFGF21) for the last 5 days. Liver steatosis and inflammation and epididymal white adipose tissue (eWAT) lipolysis were investigated. Results Alcohol exposure induced plasma FGF21 elevation. FGF21 knockout exacerbated chronic alcohol‐induced hepatic steatosis and liver injury, which was associated with increased activation of genes involved in lipogenesis mediated by SREBP1c and decreased expression of genes involved in fatty acid (FA) β‐oxidation mediated by PGC1α. Chronic alcohol exposure induced a moderate adipose tissue lipolysis in eWAT. rhFGF21 administration reduced alcohol‐induced hepatic steatosis and inflammation in WT mice. Surprisingly, in the chronic‐binge model, alcohol consumption‐induced fatty liver is blunted in the KO mice. Chronic‐binge alcohol exposure‐induced in situ hepatic lipogenesis and FA β‐oxidation were comparable to that in chronic alcohol‐exposed mice. However, FGF21 deficiency markedly reduced chronic‐binge alcohol exposure‐induced eWAT lipolysis, which may contribute to hepatic FA uptake. Further analysis showed that in the KO mice alcohol induced significant elevation in systemic catecholamine, which is known to promote adipose lipolysis. rhFGF21 administration increased alcohol‐ induced fat loss in parallel with an increase of circulating norepinephrine concentration in KO mice. Conclusion Our results demonstrated that the role of FGF21 in ALD is alcohol exposure model dependent. Lack of FGF21 exacerbates chronic alcohol exposure‐induced fatty liver, and this exaggeration is overridden in chronic‐binge alcohol exposed mice through a reduction of adipose lipolysis mediated by systemic catecholamine release involving sympathetic nervous system activation. Pharmacologic strategies targeting hepatic FGF21 elevation and reduction in adipose tissue lipolysis are warranted. Support or Funding Information Supported by the NIH and Veterans Administration