title: Activation of AMPKα2 in adipocytes is essential for nicotine-induced insulin resistance in vivo.
abstract: Cigarette smoking promotes body weight reduction in humans while paradoxically also promoting insulin resistance (IR) and hyperinsulinemia. However, the mechanisms behind these effects are unclear. Here we show that nicotine, a major constituent of cigarette smoke, selectively activates AMP-activated protein kinase α2 (AMPKα2) in adipocytes, which in turn phosphorylates MAP kinase phosphatase-1 (MKP1) at serine 334, initiating its proteasome-dependent degradation. The nicotine-dependent reduction of MKP1 induces the aberrant activation of both p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, leading to increased phosphorylation of insulin receptor substrate 1 (IRS1) at serine 307. Phosphorylation of IRS1 leads to its degradation, protein kinase B inhibition, and the loss of insulin-mediated inhibition of lipolysis. Consequently, nicotine increases lipolysis, which results in body weight reduction, but this increase also elevates the levels of circulating free fatty acids and thus causes IR in insulin-sensitive tissues. These results establish AMPKα2 as an essential mediator of nicotine-induced whole-body IR in spite of reductions in adiposity.
authors: 1] Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. [2] Department of Cardiology, Cardiovascular Research Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors: Yue
authors: Y
authors: Wu
authors: Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors: Ping
authors: P
authors: Song
authors: Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors: Wencheng
authors: W
authors: Zhang
authors: Department of Cardiology, Cardiovascular Research Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors: Junhui
authors: J
authors: Liu
authors: Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors: Xiaoyan
authors: X
authors: Dai
authors: Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors: Zhaoyu
authors: Z
authors: Liu
authors: Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors: Qiulun
authors: Q
authors: Lu
authors: 1] Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. [2] Key Laboratory of Hubei Province on Cardio-Cerebral Diseases, Hubei University of Science and Technology, Xianning, Hubei, China.
authors: Changhan
authors: C
authors: Ouyang
authors: Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors: Zhonglin
authors: Z
authors: Xie
authors: Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors: Zhengxing
authors: Z
authors: Zhao
authors: Department of Cardiology, Cardiovascular Research Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors: Xiaozhen
authors: X
authors: Zhuo
authors: 1] INSERM, U1016, Institut Cochin, Paris, France. [2] CNRS, UMR 8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Benoit
authors: B
authors: Viollet
authors: 1] INSERM, U1016, Institut Cochin, Paris, France. [2] CNRS, UMR 8104, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Marc
authors: M
authors: Foretz
authors: Key Laboratory of Hubei Province on Cardio-Cerebral Diseases, Hubei University of Science and Technology, Xianning, Hubei, China.
authors: Jiliang
authors: J
authors: Wu
authors: Department of Cardiology, Cardiovascular Research Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors: Zuyi
authors: Z
authors: Yuan
authors: 1] Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. [2] Key Laboratory of Hubei Province on Cardio-Cerebral Diseases, Hubei University of Science and Technology, Xianning, Hubei, China.
authors: Ming-Hui
authors: MH
authors: Zou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D050154:Adiposity; D000818:Animals; D001823:Body Composition; D001835:Body Weight; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D004789:Enzyme Activation; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D000960:Hypolipidemic Agents / Q000737:chemistry; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009538:Nicotine / Q000737:chemistry*; D010766:Phosphorylation; D011719:Pyrazines / Q000737:chemistry; D051381:Rats; D012694:Serine / Q000737:chemistry; D012907:Smoking
chemical_list: D000960:Hypolipidemic Agents; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D011719:Pyrazines; D012694:Serine; D009538:Nicotine; C534978:Prkaa2 protein, mouse; C526181:PRKAA2 protein, human; D055372:AMP-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; C027696:acipimox