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Review
. 2020 Dec;21(4):431-447.
doi: 10.1007/s11154-020-09584-3. Epub 2020 Aug 26.

Therapeutic potential of α7 nicotinic acetylcholine receptor agonists to combat obesity, diabetes, and inflammation

Han Xie  1 , Natesh Yepuri  1 , Qinghe Meng  1 , Ravi Dhawan  1 , Colin A Leech  1 , Oleg G Chepurny  2 , George G Holz  2 , Robert N Cooney  3
Affiliations
Review

Therapeutic potential of α7 nicotinic acetylcholine receptor agonists to combat obesity, diabetes, and inflammation

Han Xie et al. Rev Endocr Metab Disord. 2020 Dec.

Abstract

The cholinergic anti-inflammatory reflex (CAIR) represents an important homeostatic regulatory mechanism for sensing and controlling the body's response to inflammatory stimuli. Vagovagal reflexes are an integral component of CAIR whose anti-inflammatory effects are mediated by acetylcholine (ACh) acting at α7 nicotinic acetylcholine receptors (α7nAChR) located on cells of the immune system. Recently, it is appreciated that CAIR and α7nAChR also participate in the control of metabolic homeostasis. This has led to the understanding that defective vagovagal reflex circuitry underlying CAIR might explain the coexistence of obesity, diabetes, and inflammation in the metabolic syndrome. Thus, there is renewed interest in the α7nAChR that mediates CAIR, particularly from the standpoint of therapeutics. Of special note is the recent finding that α7nAChR agonist GTS-21 acts at L-cells of the distal intestine to stimulate the release of two glucoregulatory and anorexigenic hormones: glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). Furthermore, α7nAChR agonist PNU 282987 exerts trophic factor-like actions to support pancreatic β-cell survival under conditions of stress resembling diabetes. This review provides an overview of α7nAChR function as it pertains to CAIR, vagovagal reflexes, and metabolic homeostasis. We also consider the possible usefulness of α7nAChR agonists for treatment of obesity, diabetes, and inflammation.

Keywords: Cholinergic anti-inflammatory reflex; Diabetes; GLP-1; Obesity; PYY; α7nAChR.

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Conflict of interest statement

Conflicts of Interest: The authors have no financial interests to disclose.

Figures

Fig. 1
Fig. 1
Neurocircuitry of vagovagal reflexes underlying CAIR and mediated by α7nAChR with consequent engagement of multiple organ systems including the central nervous system (CNS) brainstem nucleus tractus solitarius (NTS) and the dorsal motor nucleus (DMN) of the vagus nerve so that TNFα proinflammatory cytokine production is inhibited in cells of the immune system. Black arrows indicate stimulatory effects, whereas red boxes indicate inhibitory effects
Fig. 2
Fig. 2
Growth factor-like signal transduction pathways under the control of α7nAChR and relevant to CAIR, proinflammatory cytokine production, cell growth/survival, inflammation, apoptosis, and pancreatic β-cell survival. For additional details concerning α7nAChR and β-cell survival, see Gupta et al. [152].
Fig. 3
Fig. 3
Dual role of α7nAChR to promote enteroendocrine L-cell GLP-1 and PYY secretion, and to also enhance L-cell viability under conditions of hyperglycemic stress. For additional details see Wang et al. [130].
Fig. 4
Fig. 4
The nicotinic α7nAChR mediates actions of ACh to counteract endoplasmic reticulum stress and to protect against apoptosis in pancreatic β-cells. However, Ca2+ entry through α7nAChR fails to stimulate β-cell insulin secretion. Instead, ACh action at muscarinic M3 receptors promotes insulin secretion through the mobilization of intracellular Ca2+, while also upregulating protein kinase C (PKC) activity. Abbreviations: A-UPR, adaptive unfolded protein response; T-UPR, terminal unfolded protein response; IRE1α, inositol-requiring enzyme 1α.
Fig. 5
Fig. 5
α7nAChR agonist GTS-21 participates in the control of GLP-1 and PYY release from L-cells, while also protecting β-cells from apoptosis. Note that GLP-1 released from L-cells initiates vagovagal reflexes that transmit through CNS and ANS to influence whole-body metabolism, whereas PYY crosses the blood brain barrier to suppress appetite. Dipeptidylpeptidase-4 (DPP-4) inhibitors enhance the glycemic action of GLP-1 by slowing its normally fast metabolic inactivation. It is presently uncertain whether levels of circulating GLP-1 are sufficiently high to stimulate the β-cell GLP-1 receptor even when T2D patients are administered DPP-4 inhibitors. Instead, DPP-4 inhibitors may primarily enhance GLP-1 action at the GLP-1R located on VN afferents. For additional details see Burcelin et al. [133].
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