Acetylcholine‐synthesizing macrophages in subcutaneous fat are regulated by β ₂ ‐adrenergic signaling

Abstract

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 b 2 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.

The Adipose Tissue Macrophages Central to Adaptive Thermoregulation

“…Besides sympathetic innervation or denervation, the local noradrenergic tone within thermogenic adipose tissues has been proposed to be mediated by adipose resident immune cells, such as subpopulations of ATM synthesizing or degrading catecholamine ( 17 , 19 ). Intriguingly, recent studies also identified cholinergic adipose macrophages (ChAMs) that secrete acetylcholine to selectively activate beige fat thermogenesis under cold exposure ( 15 ). Hence, the regulation and function of thermogenic fat need to be understood considering its heterogeneity and complexity stemming from the tissue microenvironment as a bona fide platform for developing thermogenic fat-targeting therapeutic interventions.…”

“…Jun et al. recently identified ChAMs responsible for acetylcholine secretion and adaptive thermogenesis in subcutaneous WAT where parasympathetic innervation is absent ( 15 , 92 , 93 ). Using ChAT reporter mice to monitor functional ChAT-expressing cells in vivo , acetylcholine-producing cell populations were defined as CD45 + hematopoietic immune cells, not neurons, and they were composed mainly of B cells, T cells and macrophages ( 92 ).…”

“…Using ChAT reporter mice to monitor functional ChAT-expressing cells in vivo , acetylcholine-producing cell populations were defined as CD45 + hematopoietic immune cells, not neurons, and they were composed mainly of B cells, T cells and macrophages ( 92 ). Among the ChAT + immune subsets, macrophages were the only population to show induction in ChAT abundance and acetylcholine secretion in response to cold stress ( 15 ). Macrophage-specific ChAT deleted mice showed impaired cold-induced thermogenesis in subcutaneous WAT.…”

“…Intriguingly, recent studies identified and highlighted the non-canonical roles of ATMs found in thermogenic adipose niches. Certain ATM subsets are specialized to mediate thermogenic programs of brown or beige adipocytes through driving local noradrenergic or cholinergic tone ( 15 – 20 ). This review covers the roles of ATMs in thermogenic adipose tissues, emphasizing distinct macrophage subpopulations central to adaptive thermoregulation.…”

Immune Cells in Thermogenic Adipose Depots: The Essential but Complex Relationship

“…More recently, a study pointed out CX3CR1 + SAMs as a potential source of IL-27, which has been shown to contribute to thermogenesis and energy expenditure ( 75 ). Besides, a novel study proposed a subpopulation termed cholinergic adipose macrophages (ChAMs) to secrete acetylcholine and regulate thermogenic activation of beige fat ( 41 ), adding another layer of complexity to the global contribution of macrophages to sympathetic activation. The sufficiency of M2 macrophages in promoting browning independently of sympathetic neuron involvement was described in a Fasn -/- mouse model ( 76 ).…”