Acetylcholine‐synthesizing macrophages in subcutaneous fat are regulated by β2‐adrenergic signaling.

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 β2 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. Synopsis: Immune cells secrete acetylcholine to activate beige adipocytes during adaptive thermogenesis, yet the identity of these acetylcholine‐secreting cells is unclear. This study shows that a subpopulation of adipose macrophages—named cholinergic adipose macrophages (ChAMs)—is responsible for β2 adrenergic receptor‐dependent secretion of acetylcholine upon acute cold to stimulate thermogenesis in neighboring beige adipocytes within murine subcutaneous fat. A non‐neuronal cholinergic circuitry consisting of ChAMs and beige adipocytes in subcutaneous adipose tissue influences both thermogenic response to cold and energy homeostasis in mice.Loss of acetylcholine production in macrophages compromises the adaptive thermogenic capacity of subcutaneous fat.The β2 adrenergic receptor mediates cholinergic macrophage activation in subcutaneous fat after cold exposure. [ABSTRACT FROM AUTHOR]