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An immune-beige adipocyte communication via nicotinic acetylcholine receptor signaling

Nature Medicine volume 24, pages 814–822 (2018)Cite this article

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Abstract

Beige adipocytes have recently been shown to regulate energy dissipation when activated and help organisms defend against hypothermia and obesity. Prior reports indicate that beige-like adipocytes exist in adult humans and that they may present novel opportunities to curb the global epidemic in obesity and metabolic illnesses. In an effort to identify unique features of activated beige adipocytes, we found that expression of the cholinergic receptor nicotinic alpha 2 subunit (Chrna2) was induced in subcutaneous fat during the activation of these cells and that acetylcholine-producing immune cells within this tissue regulated this signaling pathway via paracrine mechanisms. CHRNA2 functioned selectively in uncoupling protein 1 (Ucp1)-positive beige adipocytes, increasing thermogenesis through a cAMP- and protein kinase A-dependent pathway. Furthermore, this signaling via CHRNA2 was conserved and present in human subcutaneous adipocytes. Inactivation of Chrna2 in mice compromised the cold-induced thermogenic response selectively in subcutaneous fat and exacerbated high-fat diet-induced obesity and associated metabolic disorders, indicating that even partial loss of beige fat regulation in vivo had detrimental consequences. Our results reveal a beige-selective immune–adipose interaction mediated through CHRNA2 and identify a novel function of nicotinic acetylcholine receptors in energy metabolism. These findings may lead to identification of therapeutic targets to counteract human obesity.

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Fig. 1: Chrna2 is induced in subcutaneous adipocytes of mice and humans during beiging.
Fig. 2: CHRNA2 signaling is beige adipocyte-selective.
Fig. 3: Acetylcholine-synthesizing cells of hematopoietic origin reside within inguinal subcutaneous fat tissue.
Fig. 4: Loss of Chrna2 reduces the adaptive thermogenic capacity of inguinal adipose tissue.
Fig. 5: Loss of Chrna2 exacerbates diet-induced obesity.

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Acknowledgements

We thank B. M. Spiegelman and J. D. Lin for their advice and discussion throughout this work, B. Lowell (Beth Israel Deaconess Medical Center) for the β-less mice, J. M. Gimble (Tulane University) for human subcutaneous adipose precursor cells and W. Rainey (University of Michigan) for human perirenal adipose precursor cells. The work was supported by the Human Frontier Science Program (grant no. RGY0082/14; J.W.), the Edward Mallinckrodt Jr. Foundation (J.W.), the American Diabetes Association (grant no. 1-18-IBS-281; J.W.), the US National Institutes of Health (grant no. R01DK107583 (J.W.), P30-DK020572 (J.W.), P30-DK089503 (J.W.), F31DK112625 (M.P.E.), R37EB003320 (R.T.K.) and DK046960 (R.T.K.), R01-AI091627 (I.M.) and T32DA007268 (A.G.Z.)) and a postdoctoral fellowship from the American Heart Association (17POST33060001; D.K.).

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Author notes

  1. Alexander G. Zestos

    Present address: Department of Chemistry, Center for Behavioral Neuroscience, American University, Washington, D.C., USA

  2. Ivan Maillard

    Present address: Division of Hematology–Oncology, Department of Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

Authors and Affiliations

  1. Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA

    Heejin Jun, Hui Yu, Jianke Gong, Juan Jiang, Xiaona Qiao, Dong-il Kim, Margo P. Emont, Jung-Sun Cho, Ivan Maillard, X. Z. Shawn Xu & Jun Wu

  2. Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA

    Hui Yu, Margo P. Emont, X. Z. Shawn Xu & Jun Wu

  3. International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China

    Jianke Gong & Jianfeng Liu

  4. Department of Respiratory Medicine, Key Site of National Clinical Research Center for Respiratory Diseases, Xiangya Hospital, Central South University, Changsha, China

    Juan Jiang

  5. Huashan Hospital, Fudan University, Shanghai, China

    Xiaona Qiao

  6. Center for Stem Cell Biology, Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA

    Eric Perkey

  7. Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA

    Eric Perkey & Ivan Maillard

  8. Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA

    Eric Perkey

  9. Department of Chemistry, University of Michigan, Ann Arbor, MI, USA

    Alexander G. Zestos & Robert T. Kennedy

  10. Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA

    Robert T. Kennedy

  11. Division of Hematology–Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI, USA

    Ivan Maillard

  12. Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA

    Ivan Maillard

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Contributions

H.J., H.Y. and J.W. designed the experiments and wrote the manuscript; H.J., H.Y., J.G., J.J., X.Q., E.P., D.K., M.P.E., A.G.Z., J.-S.C. and J.W. performed the experiments; and H.J., H.Y., J.G., E.P., A.G.Z., J.L., R.T.K., I.M., X.Z.S.X. and J.W. analyzed the data.

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Correspondence to Jun Wu.

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Jun, H., Yu, H., Gong, J. et al. An immune-beige adipocyte communication via nicotinic acetylcholine receptor signaling. Nat Med 24, 814–822 (2018). https://doi.org/10.1038/s41591-018-0032-8

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