The miR-182-5p/FGF21/acetylcholine axis mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis

Abstract

A dynamically regulated microenvironment, which is mediated by crosstalks between adipocytes and neighboring cells, is critical for adipose tissue homeostasis and function. However, information on key molecules and/or signaling pathways regulating the crosstalks remains limited. In this study, we identify adipocyte miR-182-5p as a crucial anti-obesity molecule that stimulates beige fat thermogenesis by promoting the crosstalk between adipocytes and macrophages. miR-182-5p is highly enriched in thermogenic adipocytes and its expression is markedly stimulated by cold exposure in mice. In contrast, miR-182-5p expression is significantly reduced in adipose tissues of obese humans and mice. Knockout of miR-185-5p decreased cold-induced beige fat thermogenesis whereas overexpression of miR-185-5p increased beiging and thermogenesis in mice. Mechanistically, miR-182-5p promotes FGF21 expression and secretion in adipocytes by suppressing Nr1d1 at 5'UTR, which in turn stimulates acetylcholine synthesis and release in macrophages. Increased acetylcholine expression activates the nicotine acetylcholine receptor in adipocytes, which stimulates PKA signaling and consequent thermogenic gene expression. Our study reveals a key role of the miR-182-5p/FGF21/acetylcholine/acetylcholine receptor axis that mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis. Activation of the miR-182-5p-induced signaling pathway in adipose tissue may be an effective approach to ameliorate obesity and associated metabolic diseases.

The Adipose Tissue Macrophages Central to Adaptive Thermoregulation

“…ChAMs are the only ATM subset so far known to target a non-canonical thermogenic pathway, CHRNA2 signaling, in beige adipocytes among the four thermogenic ATMs. In addition, ChAMs responded to β2-AR agonist or fibroblast growth factor 21 mediated by miRNA-182-5p from beige adipocytes to induce acetylcholine secretion in a cold environment ( 15 , 97 ). The other three ATM subpopulations are linked to the canonical β-AR mechanism in thermogenic adipocytes via regulating local noradrenergic tone.…”

Reciprocal signaling between adipose tissue depots and the central nervous system

“…Furthermore, β2-AR stimulation in macrophages promotes thermogenesis via the production and secretion of acetylcholine, which acts on adipocytes via acetylcholine receptors, stimulating the PKA pathway and subsequently inducing thermogenic gene expression ( Figure 2A ) ( Knights et al, 2021 ; Meng et al, 2021 ).…”

“… Sympathetic regulation of adipose tissue macrophages. (A) Beta-2 adrenergic receptor (β2-AR) stimulation in macrophages promotes the production and secretion of acetylcholine, which acts on adipocytes via acetylcholine receptors, stimulating thermogenesis through the PKA pathway and consequently inducing thermogenic gene expression ( Knights et al, 2021 ; Meng et al, 2021 ). Additionally, β2-AR stimulation is essential for maintaining low tumor necrosis factor -alpha (TNFα) levels ( Wang et al, 2003 ).…”

miR-375 is cold exposure sensitive and drives thermogenesis in visceral adipose tissue derived stem cells

“…Recent studies also suggest that miRNAs are associated with the regulation of thermogenesis. However, these studies were performed mainly in mice or cell culture and have not been confirmed in human intervention studies 17 – 20 .…”