beta(2) Adrenergic receptors ((beta(2)ARs) are G protein-coupled receptors (GPCRs) that are expressed in major insulin target tissues. beta(2)ARs play an important role in the regulation of lipid metabolism during aging; however, little is known about the significance of beta(2)ARs in the pathogenesis of hepatic fat accumulation in high-fat diet (HFD) mice. This study aims to examine the role of beta(2)AR in the development of nonalcoholic fatty liver disease (NAFLD) induced by HFD and the underlying mechanisms. Surprisingly, we found that genetic deletion of beta(2)AR significantly increased the liver weight of mice fed a HFD for 20 weeks compared to that of wild-type (WT) mice. Moreover, genetic deletion of beta(2)AR could aggravate HFD-induced liver lipid accumulation and liver injury in mice. Mechanistically, we demonstrated that beta(2)AR deletion significantly activated PPAR gamma/CD36 signaling via inactivation of the cAMP response element-binding (CREB) protein to facilitate hepatocellular lipid deposition in HFD mice. Together, our results identify beta(2)AR as a plausible therapeutic target for preventing or treating NAFLD. (C) 2019 Elsevier Inc. All rights reserved.