Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
EMBO J. 2021 Dec 15;40(24):e106061. doi: 10.15252/embj.2020106061. Epub 2021 Aug 30.
Non-neuronal cholinergic signaling, mediated by acetylcholine, plays important roles in physiological processes including inflammation and immunity. Our group first discovered evidence of non-neuronal cholinergic circuitry in adipose tissue, whereby immune cells secrete acetylcholine to activate beige adipocytes during adaptive thermogenesis. Here, we reveal that macrophages are the cellular protagonists responsible for secreting acetylcholine to regulate thermogenic activation in subcutaneous fat, and we term these cells cholinergic adipose macrophages (ChAMs). An adaptive increase in ChAM abundance is evident following acute cold exposure, and macrophage-specific deletion of choline acetyltransferase (ChAT), the enzyme for acetylcholine biosynthesis, impairs the cold-induced thermogenic capacity of mice. Further, using pharmacological and genetic approaches, we show that ChAMs are regulated via adrenergic signaling, specifically through the β adrenergic receptor. These findings demonstrate that macrophages are an essential adipose tissue source of acetylcholine for the regulation of adaptive thermogenesis, and may be useful for therapeutic targeting in metabolic diseases.
非神经元胆碱能信号转导由乙酰胆碱介导，在包括炎症和免疫在内的生理过程中发挥重要作用。我们的研究小组首次在脂肪组织中发现了非神经元胆碱能通路的证据，即免疫细胞在适应性产热过程中分泌乙酰胆碱以激活米色脂肪细胞。在这里，我们揭示了巨噬细胞是负责分泌乙酰胆碱以调节皮下脂肪产热激活的细胞，我们将这些细胞称为胆碱能脂肪巨噬细胞（ChAMs）。急性冷暴露后，ChAM 丰度明显增加，而巨噬细胞特异性敲除乙酰胆碱合成酶胆碱乙酰转移酶（ChAT）则会损害小鼠的冷诱导产热能力。此外，我们通过药理学和遗传学方法表明，ChAMs 通过肾上腺素能信号转导调控，特别是通过β肾上腺素能受体。这些发现表明，巨噬细胞是脂肪组织中乙酰胆碱的重要来源，可用于调节适应性产热，并且可能对代谢性疾病的治疗靶向具有重要意义。
