The non-neuronal cholinergic system in the inflamed adipose tissue of obese mice

Abstract

A key feature of morbid obesity is white adipose tissue (WAT) inflammation. In obese ani- mals and humans WAT is infiltrated by macrophages that are mainly found at sites where adi- pocytes die by pyroptosis [1]. Here, macrophages sequester and digest adipocyte debris, form- ing distinctive crown-like structures [2]. Acetylcholine (ACh) was the first neurotransmitter to be discovered. However, within the past decades increasing experimental evidence has shown that ACh is also produced by non-neuronal cells and tissues, including the immune cells, where it acts as a secreted messenger. Here we evaluated whether the non-neuronal cholinergic sys- tem occurs in obese and inflamed fat. By RT-qPCR, we found that all the components of the non-neuronal cholinergic system molecular machinery significantly increased in subcutane- ous and visceral WAT from high-fat diet obese mice compared with mice fed a normal diet. By immunohistochemistry and confocal microscopy, we found that about 40-50% of macrophages infiltrating obese WAT expressed choline acetyltransferase (ChAT), choline transporter-1 (ChT- 1) and the vesicular ACh transporter (VAChT), whereas the white adipocytes expressed the butyrylcholinesterase (BChE). In vitro studies showed that white adipocytes differentiated from human multipotent adipose-derived stem cells not only produced BChE but also, and to a larg- er amount, acetylcholinesterase (AChE). Collectively, these data suggest that a consistent pro- portion of macrophages infiltrating obese WAT produce and secrete ACh that may act on ACh receptor-bearing adipocytes; diffusion of this potent molecule is prevented by ACh re-uptake by macrophages (through VAChT) or by adipocyte degradation of ACh (through BChE and AChE) into acetate and choline, which is quickly taken up by the macrophages (through ChT- 1). Promoting the anti-inflammatory effect [3] of the non-neuronal cholinergic system present in obese fat could represent a novel and effective therapeutic approach to obesity and associated diseases.