{"doi":"10.1016/j.tcb.2021.11.009","title":"CHRNA2: a new paradigm in beige thermoregulation and metabolism","abstract":"Non-neuronal cholinergic signaling via the choline acetyltransferase (ChAT)– cholinergic receptor nicotinic α2 subunit (CHRNA2) axis is present in subcutaneous fat and mediates beige fat function, glucose homeostasis, systemic energy metabolism, and whole-body health. Functional CHRNA2 signaling in adipose tissue is a unique feature of beige adipocytes in both mice and humans. CHRNA2 signaling regulates both canonical and glycolytic beige fat function. Upon cold exposure, acetylcholine secreted from cholinergic macrophages within the subcutaneous fat depot activates CHRNA2 signaling in beige adipocytes. CHRNA2 signaling mediates thermogenesis through both uncoupling protein 1 (UCP1)- and creatine-dependent pathways. The contribution of thermogenic adipocytes to maintain systemic metabolic homeostasis has been increasingly appreciated in recent years. It is now recognized that different types (e.g., brown, beige) and subtypes of thermogenic adipocytes may arise from various developmental origins. In addition to the adrenergic pathway, other signals can activate thermogenesis, including paracrine communication between immune cells within the adipose tissue niche and thermogenic adipocytes. In this opinion article we highlight the recently discovered beige-selective signaling between acetylcholine from immune cells and cholinergic receptor nicotinic alpha 2 subunit (CHRNA2) in activated beige adipocytes. We present our current knowledge of how this previously unrecognized adipose non-neuronal cholinergic signaling pathway mediates beige thermoregulation, and discuss its impact on whole-body fitness and its therapeutic potential as a novel target for combating metabolic disease. The contribution of thermogenic adipocytes to maintain systemic metabolic homeostasis has been increasingly appreciated in recent years. It is now recognized that different types (e.g., brown, beige) and subtypes of thermogenic adipocytes may arise from various developmental origins. In addition to the adrenergic pathway, other signals can activate thermogenesis, including paracrine communication between immune cells within the adipose tissue niche and thermogenic adipocytes. In this opinion article we highlight the recently discovered beige-selective signaling between acetylcholine from immune cells and cholinergic receptor nicotinic alpha 2 subunit (CHRNA2) in activated beige adipocytes. We present our current knowledge of how this previously unrecognized adipose non-neuronal cholinergic signaling pathway mediates beige thermoregulation, and discuss its impact on whole-body fitness and its therapeutic potential as a novel target for combating metabolic disease. an organic chemical that is released by neurons or other non-neuronal cells, including T cells and macrophages. Acetylcholine functions as a neurotransmitter and plays an essential role in regulating nervous system function. Acetylcholine from non-neuronal sources regulates a spectrum of physiological functions, including anti-inflammation and energy homeostasis. a family of G protein-coupled receptors whose ligands are catecholamines, such as norepinephrine secreted from sympathetic nerves. There are several subtypes of β-ARs, including β1, β2, and β3. In particular, β3-adrenergic receptors are mainly expressed in differentiated thermogenic adipocytes. a technique that optically measures the concentration of calcium in cultured cells or cells in situ by analyzing fluorescence intensity changes using either chemical indicators (e.g., Fura-2AM) or genetically encoded calcium indicators (GECIs). the rate-limiting enzyme in the synthesis of acetylcholine in neurons and other non-neuronal cells, including T cells and macrophages. ChAT catalyzes the transfer of an acetyl group from acetyl-CoA to choline. a subunit of the nicotinic acetylcholine receptor (nAChR) family which forms pentameric, ligand-gated ion channels. CHRNA2-containing ion channels respond to both acetylcholine and nicotine. CHRNA2 sig","journal":"Trends in Cell Biology","year":2021,"id":192525,"datarank":0.38474240361923057,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.0,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9506,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":467865,"name":"Shanshan Liu","orcid":"0000-0002-7301-5196","position":1,"is_corresponding":false},{"id":467864,"name":"Heejin Jun","orcid":"0000-0001-6440-9997","position":2,"is_corresponding":false},{"id":467868,"name":"Jun Wu","orcid":"0000-0003-4493-5820","position":3,"is_corresponding":false},{"id":468686,"name":"Yingxu Ma","orcid":null,"position":0,"is_corresponding":true}],"reference_count":95,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:49:43.496702Z","pmid":"34952750","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}