Nicotinic Cholinergic Signaling in Adipose Tissue and Pancreatic Islets Biology: Revisited Function and Therapeutic Perspectives

Abstract

Nicotinic acetylcholine receptors (nAChRs) are membrane ligand-gated cation channels whose activation is triggered by the binding of the endogenous neurotransmitter acetylcholine or other biologic compounds including nicotine. Their roles in synaptic transmission in the central and peripheral nervous system as well as in the neuromuscular junction have been extensively studied. Recent implications of nAChRs in intracellular signaling and their detection in peripheral nonneural cells (including epithelial cells and immune cells) have renewed the interest for this class of ionotropic receptors. In the present review, we focus our attention on the potential use of nicotinic cholinergic signaling in the treatment of metabolic diseases (such as obesity and diabetes) in browsing functions of nAChRs in adipose tissue and pancreatic islet biology. In fact, different nAChR subunits can be detected in these metabolic tissues, as well as in immune cells interacting with them. Various rodent models of obesity and diabetes benefit from stimulation of the nicotinic cholinergic pathway, whereas mice deficient for some nAChRs, in particular the a7 nAChR subunit, harbor a worsened metabolic phenotype. In contrast to potential therapeutic applications in metabolic diseases, an overstimulation of this signaling pathway during the early stage of development (typically through nicotine exposure during fetal life) presents deleterious consequences on ontogeny and functionality of adipose tissue and the endocrine pancreas which persist throughout life.

Smoking and the risk of type 2 diabetes

“…Nicotine is an alkaloid naturally produced by the tobacco plant that binds nicotinic acetylcholine receptors, found throughout neuronal and non-neuronal or visceral organs. These receptors participate in signaling within the central and peripheral nervous system and in a number of metabolic tissues, including pancreatic islets, adipose tissue, macrophages, liver, and skeletal muscle [14–17]. Nicotine has been shown to directly alter glucose homeostasis [18], suggesting an important role for this additive in the development of T2D.…”

Key Residues in the Nicotinic Acetylcholine Receptor β2 Subunit Contribute to α-Conotoxin LvIA Binding

“…nAChRs are found in the neuromuscular junction, and in peripheral and central nervous systems throughout the animal kingdom, and play important roles in regulating synaptic transmission (3)(4)(5)(6)(7)(8)(9). Neuronal nAChRs are pentameric membrane-bound proteins, which are made up of ␣ (␣2-␣10) and ␤ (␤2-␤4) subunits (10).…”

Nicotinic acetylcholine receptor signaling regulates inositol‐requiring enzyme 1α activation to protect β‐cells against terminal unfolded protein response under irremediable endoplasmic reticulum stress

“…We also preliminarily confirmed the expression of the α2, α5 and β2 subunits, as well as the α7 subunit (Figure ; Table ). The α7 subunit is the most common subunit in the previous islet studies, and its specific agonist has recently been shown to have a protective effect against cytokine‐induced β‐cell apoptosis and eventual diabetes in vivo . On the basis of these findings, we investigated the α7 subunit‐specific effect on T‐UPR and apoptosis under ER stress.…”

“…Interestingly, recent reports emphasize the importance of nAChR signaling by showing that although cholinergic innervation of human islets is limited, ‐cells can substitute to secrete ACh to stimulate surrounding endocrine cells in a paracrine manner. Supporting an important role of nAChR signaling in glucose metabolism, in vivo , it was reported that nicotine ameliorates the diabetic phenotype in db / db mice, Zucker fatty rats, streptozotocin‐induced diabetic mice and even NOD mice. Furthermore, stimulation of nAChR by nicotine increases insulin secretion in rodent β‐cells, and decreases cytokine‐induced apoptosis in human and rodent islets at least through the α7 nAChR subunit.…”