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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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.).
The authors declare no competing interests.
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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) doi:10.1038/s41591-018-0032-8
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