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Activation of AMPKα2 in adipocytes is essential for nicotine-induced insulin resistance in vivo

Nature Medicine volume 21, pages 373–382 (2015)Cite this article

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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.

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Figure 1: Nicotine (Nic) perfusion induces IR and lowers adiposity.
Figure 2: Inhibition of lipolysis blocks nicotine-induced IR and adiposity reduction.
Figure 3: Deletion of Ampkα2, but not Ampkα1, blocks nicotine-induced IR and inhibition of weight gain in mice.
Figure 4: Adipose Ampkα2 is required for the nicotine-dependent inhibitory effects on weight gain and insulin signaling in mice.
Figure 5: Nicotine treatment results in greater pMkp1-Ser334 levels and subsequent degradation through Ampk.
Figure 6: MKP1 reduction is required for nicotine-mediated IR and lipolysis.

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Acknowledgements

We thank L. Yu for helpful discussions and D. Wang and Y. Du for technical support. Prkaa1flox/flox and Prkaa2flox/flox mice were provided by B. Viollet (INSERM, U1016, Institut Cochin, Paris, France). This study was supported by grants from the US National Institutes of Health (HL079584, HL080499, HL074399, HL089920, HL096032, HL105157, HL110488, and AG047776 to M.-H.Z.) and (HL128014 to Z.X.). This study was also supported in part by grants from the National Natural Science Foundation of China (81100209, 81025002 and 91339116 to Z.Y. and 81270355 to J.W.), the Scientist Development Grant of American Heart Association (11SDG5560036 to P.S.), and the Oklahoma Center for the Advancement of Science and Technology (HR12-061 to P.S.).

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  1. Ming-Hui Zou

    Present address: Present address: The Center for Molecular and Translational Medicine, Georgia State University, Atlanta, Georgia, USA.,

Authors and Affiliations

  1. Department of Medicine, Section of Molecular Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

    Yue Wu, Ping Song, Wencheng Zhang, Xiaoyan Dai, Zhaoyu Liu, Qiulun Lu, Changhan Ouyang, Zhonglin Xie, Zhengxing Zhao & Ming-Hui Zou

  2. Department of Cardiology, Cardiovascular Research Center, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.,

    Yue Wu, Junhui Liu, Xiaozhen Zhuo & Zuyi Yuan

  3. Key Laboratory of Hubei Province on Cardio-Cerebral Diseases, Hubei University of Science and Technology, Xianning, Hubei, China.,

    Changhan Ouyang, Jiliang Wu & Ming-Hui Zou

  4. INSERM, U1016, Institut Cochin, Paris, France

    Benoit Viollet & Marc Foretz

  5. CNRS, UMR 8104, Paris, France

    Benoit Viollet & Marc Foretz

  6. Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    Benoit Viollet & Marc Foretz

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Contributions

Y.W. designed and performed the experiments, analyzed data, and drafted the manuscript. P.S., W.Z., X.D., Z.L., C.O., Z.X. and X.Z. performed a part of the animal experiments. J.L. and Z.Y. performed the human experiments. Z.Z. and J.W. partially performed the in vitro experiments, W.Z. and Q.L. generated series mutants. B.V. and M.F. provided the Ampk knockout mice. M.-H.Z. conceived the projects, designed the experiments, analyzed data, and wrote the manuscript.

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Correspondence to Zuyi Yuan or Ming-Hui Zou.

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Wu, Y., Song, P., Zhang, W. et al. Activation of AMPKα2 in adipocytes is essential for nicotine-induced insulin resistance in vivo. Nat Med 21, 373–382 (2015). https://doi.org/10.1038/nm.3826

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