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

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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.

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Abbreviations

α7nAChR:

α7 nicotinic acetylcholine receptor

ACh:

acetylcholine

AChE:

acetylcholinesterase

ANS:

autonomic nervous system

ATM:

adipose tissue macrophage

BCL2:

B cell lymphoma 2

BCM:

beta-cell mass

CAIR:

cholinergic anti-inflammatory reflex

CNS:

central nervous system

CREB:

cAMP response element-binding protein

DIO:

diet-induced obesity

DMV:

dorsal motor nucleus of the vagus

EEC:

enteroendocrine cell

ENS:

enteric nervous system

ER:

endoplasmic reticulum

GABA:

gama aminobutyric acid

GPCR:

G protein-coupled receptor

GLP-1:

glucagon-like peptide-1

GTS-21:

3-(2,4-dimethoxy-benzylidene)anabaseine

HbA1c:

glycated hemoglobin 1c

HFD:

high fat diet

IFN:

interferon

IgG Fc:

immunoglobulin G fragment crystallizable

IκBα:

inhibitor of nuclear factor kappa B alpha

IL:

interleukin

IRE1α :

inositol-requiring enzyme 1α

KO:

knockout

JAK2:

Janus kinase 2

JNK:

c-Jun N-terminal kinase

LPS:

lipopolysaccharide

MCP-1:

chemokine monocyte chemoattractant protein-1

MLDS:

multiple low-dose streptozotocin

MOMP:

mitochondrial outer membrane permeabilization

MyD88:

myeloid differentiation factor 88

mTOR:

mammalian target of rapamycin

NAFLD:

non-alcoholic fatty liver disease

NF-κB:

nuclear factor kappa B

NOS:

nictric oxide synthase

NPY:

neuropeptide Y

NPY2R:

neuropeptide Y2 receptor

NTS:

nucleus tractus solitarius

PAM:

positive allosteric modulator

p70S6K:

ribosomal protein S6 kinase beta-1

PC1/3:

prohormone convertase 1/3

PI3K:

phosphatidylinositol 3-kinase

PKA:

protein kinase A

PKB:

protein kinase B

PNU 282987:

N-(3R)-1-Azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide

POMC:

proopiomelanocortin

PYY:

peptide YY

RNase:

endoribonuclease

SAT:

subcutaneous adipose tissue

siRNA:

small interfering RNA

STAT3:

signal transducer and activator of transcription 3

STZ:

streptozotocin

XBP1s:

spliced X-box binding protein

T1D:

type 1 diabetes

T2D:

type 2 diabetes

TGF:

transforming growth factor

TXNIP :

thioredoxin-interacting protein

TLR4:

Toll-like receptor-4

TNF:

tumor necrosis factor

UCD-T2D:

UC Davis type 2 diabetes model rat

UPR:

unfolded protein response

VAT:

visceral adipose tissue

VIP:

vasoactive intestinal polypeptide

VN:

vagus nerve

ZDF:

Zucker diabetic fatty rat

References

  1. Cornier MA, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, et al. The metabolic syndrome. Endocr Rev. 2008;29(7):777–822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wu J, Jiao ZY, Zhang Z, Tang ZH, Zhang HH, Lu HL, et al. Cross-talk between alpha7 nAChR-mediated cholinergic pathway and acylation stimulating protein signaling in 3T3-L1 adipocytes: role of NFkappaB and STAT3. Biochem Cell Biol. 2015;93(4):335–42.

    Article  CAS  PubMed  Google Scholar 

  3. Cancello R, Zulian A, Maestrini S, Mencarelli M, Della Barba A, Invitti C, et al. The nicotinic acetylcholine receptor alpha7 in subcutaneous mature adipocytes: downregulation in human obesity and modulation by diet-induced weight loss. Int J Obes. 2012;36(12):1552–7.

    Article  CAS  Google Scholar 

  4. Xu TY, Guo LL, Wang P, Song J, Le YY, Viollet B, et al. Chronic exposure to nicotine enhances insulin sensitivity through alpha7 nicotinic acetylcholine receptor-STAT3 pathway. PLoS One. 2012;7(12):e51217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Scabia G, Cancello R, Dallanoce C, Berger S, Matera C, Dattilo A, et al. ICH3, a selective alpha7 nicotinic acetylcholine receptor agonist, modulates adipocyte inflammation associated with obesity. J Endocrinol Investig. 2020;43(7):983–93.

    Article  CAS  Google Scholar 

  6. Wada T, Naito M, Kenmochi H, Tsuneki H, Sasaoka T. Chronic nicotine exposure enhances insulin-induced mitogenic signaling via up-regulation of alpha7 nicotinic receptors in isolated rat aortic smooth muscle cells. Endocrinology. 2007;148(2):790–9.

    Article  CAS  PubMed  Google Scholar 

  7. Zhao J, Park S, Kim JW, Qi J, Zhou Z, Lim CW, et al. Nicotine attenuates concanavalin A-induced liver injury in mice by regulating the alpha7-nicotinic acetylcholine receptor in Kupffer cells. Int Immunopharmacol. 2020;78:106071.

    Article  CAS  PubMed  Google Scholar 

  8. Hiramoto T, Chida Y, Sonoda J, Yoshihara K, Sudo N, Kubo C. The hepatic vagus nerve attenuates Fas-induced apoptosis in the mouse liver via alpha7 nicotinic acetylcholine receptor. Gastroenterology. 2008;134(7):2122–31.

    Article  PubMed  Google Scholar 

  9. Souza CM, do Amaral CL, Souza SC, ACP d S, de Cássia Alves Martins I, Contieri LS, et al. JAK2/STAT3 pathway is required for α7nAChR-dependent expression of POMC and AGRP neuropeptides in male mice. Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology. 2019;53(4):701–12.

    Article  CAS  Google Scholar 

  10. Gupta D, Lacayo AA, Greene SM, Leahy JL, Jetton TL. Beta-cell mass restoration by alpha7 nicotinic acetylcholine receptor activation. J Biol Chem. 2018;293(52):20295–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang D, Meng Q, Leech CA, Yepuri N, Zhang L, Holz GG, et al. alpha7 nicotinic acetylcholine receptor regulates the function and viability of L cells. Endocrinology. 2018;159(9):3132–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Stegemann A, Bohm M. Tropisetron via alpha7 nicotinic acetylcholine receptor suppresses tumor necrosis factor-alpha-mediated cell responses of human keratinocytes. Exp Dermatol. 2019;28(3):276–82.

    Article  CAS  PubMed  Google Scholar 

  13. Marrero MB, Lucas R, Salet C, Hauser TA, Mazurov A, Lippiello PM, et al. An alpha7 nicotinic acetylcholine receptor-selective agonist reduces weight gain and metabolic changes in a mouse model of diabetes. J Pharmacol Exp Ther. 2010;332(1):173–80.

    Article  CAS  PubMed  Google Scholar 

  14. Wang X, Yang Z, Xue B, Shi H. Activation of the cholinergic antiinflammatory pathway ameliorates obesity-induced inflammation and insulin resistance. Endocrinology. 2011;152(3):836–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu RH, Kurose T, Matsukura S. Oral nicotine administration decreases tumor necrosis factor-alpha expression in fat tissues in obese rats. Metabolism. 2001;50(1):79–85.

    Article  CAS  PubMed  Google Scholar 

  16. Pavlov VA, Tracey KJ. The vagus nerve and the inflammatory reflex-linking immunity and metabolism. Nat Rev Endocrinol. 2012;8(12):743–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chang EH, Chavan SS, Pavlov VA. Cholinergic control of inflammation, metabolic dysfunction, and cognitive impairment in obesity-associated disorders: mechanisms and novel therapeutic opportunities. Front Neurosci. 2019;13:263.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Berthoud HR, Neuhuber WL. Vagal mechanisms as neuromodulatory targets for the treatment of metabolic disease. Ann N Y Acad Sci. 2019;1454(1):42–55.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Bonaz B, Sinniger V, Pellissier S. The vagus nerve in the neuro-immune axis: implications in the pathology of the gastrointestinal tract. Front Immunol. 2017;8:1452.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Browning KN, Verheijden S, Boeckxstaens GE. The vagus nerve in appetite regulation, mood, and intestinal inflammation. Gastroenterology. 2017;152(4):730–44.

    Article  PubMed  Google Scholar 

  21. de Lartigue G. Role of the vagus nerve in the development and treatment of diet-induced obesity. J Physiol. 2016;594(20):5791–815.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Kany S, Vollrath JT, Relja B. Cytokines in inflammatory disease. Int J Mol Sci. 2019;20(23).

  23. Johnston GR, Webster NR. Cytokines and the immunomodulatory function of the vagus nerve. Br J Anaesth. 2009;102(4):453–62.

    Article  CAS  PubMed  Google Scholar 

  24. Rosas-Ballina M, Goldstein RS, Gallowitsch-Puerta M, Yang L, Valdés-Ferrer SI, Patel NB, et al. The selective alpha7 agonist GTS-21 attenuates cytokine production in human whole blood and human monocytes activated by ligands for TLR2, TLR3, TLR4, TLR9, and RAGE. Mol Med. 2009;15(7–8):195–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421(6921):384–8.

    Article  CAS  PubMed  Google Scholar 

  26. Yoshikawa H, Kurokawa M, Ozaki N, Nara K, Atou K, Takada E, et al. Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I-kappaB phosphorylation and nuclear factor-kappaB transcriptional activity through nicotinic acetylcholine receptor alpha7. Clin Exp Immunol. 2006;146(1):116–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Masi EB, Valdes-Ferrer SI, Steinberg BE. The vagus neurometabolic interface and clinical disease. Int J Obes. 2018;42(6):1101–11.

    Article  Google Scholar 

  28. Chavan SS, Pavlov VA, Tracey KJ. Mechanisms and therapeutic relevance of neuro-immune communication. Immunity. 2017;46(6):927–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Goehler LE, Gaykema RP, Nguyen KT, Lee JE, Tilders FJ, Maier SF, et al. Interleukin-1beta in immune cells of the abdominal vagus nerve: a link between the immune and nervous systems? J Neurosci. 1999;19(7):2799–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405(6785):458–62.

    Article  CAS  PubMed  Google Scholar 

  31. Rosas-Ballina M, Olofsson PS, Ochani M, Valdes-Ferrer SI, Levine YA, Reardon C, et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 2011;334(6052):98–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Abot A, Cani PD, Knauf C. Impact of intestinal peptides on the enteric nervous system: novel approaches to control glucose metabolism and food intake. Front Endocrinol. 2018;9:328.

    Article  Google Scholar 

  33. Nezami BG, Srinivasan S. Enteric nervous system in the small intestine: pathophysiology and clinical implications. Curr Gastroenterol Rep. 2010;12(5):358–65.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Metz CN, Pavlov VA. Vagus nerve cholinergic circuitry to the liver and the gastrointestinal tract in the neuroimmune communicatome. Am J Physiol Gastrointest Liver Physiol. 2018;315(5):G651–g8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jamal Uddin M, Joe Y, Zheng M, Blackshear PJ, Ryter SW, Park JW, et al. A functional link between heme oxygenase-1 and tristetraprolin in the anti-inflammatory effects of nicotine. Free Radic Biol Med. 2013;65:1331–9.

    Article  CAS  PubMed  Google Scholar 

  36. Ahren B, Taborsky GJ Jr. The mechanism of vagal nerve stimulation of glucagon and insulin secretion in the dog. Endocrinology. 1986;118(4):1551–7.

    Article  CAS  PubMed  Google Scholar 

  37. Berthoud HR. The vagus nerve, food intake and obesity. Regul Pept. 2008;149(1–3):15–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bugajski AJ, Gil K, Ziomber A, Zurowski D, Zaraska W, Thor PJ. Effect of long-term vagal stimulation on food intake and body weight during diet induced obesity in rats. J Physiol Pharmacol. 2007;58(Suppl 1):5–12.

    PubMed  Google Scholar 

  39. Burneo JG, Faught E, Knowlton R, Morawetz R, Kuzniecky R. Weight loss associated with vagus nerve stimulation. Neurology. 2002;59(3):463–4.

    Article  CAS  PubMed  Google Scholar 

  40. Dai F, Yin J, Chen JDZ. Effects and mechanisms of vagal nerve stimulation on body weight in diet-induced obese rats. Obes Surg. 2020;30(3):948–56.

    Article  PubMed  Google Scholar 

  41. de Lartigue G, Diepenbroek C. Novel developments in vagal afferent nutrient sensing and its role in energy homeostasis. Curr Opin Pharmacol. 2016;31:38–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Li S, Zhai X, Rong P, McCabe MF, Wang X, Zhao J, et al. Therapeutic effect of vagus nerve stimulation on depressive-like behavior, hyperglycemia and insulin receptor expression in Zucker fatty rats. PLoS One. 2014;9(11):e112066.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Malbert CH, Picq C, Divoux JL, Henry C, Horowitz M. Obesity-associated alterations in glucose metabolism are reversed by chronic bilateral stimulation of the abdominal vagus nerve. Diabetes. 2017;66(4):848–57.

    Article  CAS  PubMed  Google Scholar 

  44. Pardo JV, Sheikh SA, Kuskowski MA, Surerus-Johnson C, Hagen MC, Lee JT, et al. Weight loss during chronic, cervical vagus nerve stimulation in depressed patients with obesity: an observation. Int J Obes. 2007;31(11):1756–9.

    Article  CAS  Google Scholar 

  45. Sobocki J, Fourtanier G, Estany J, Otal P. Does vagal nerve stimulation affect body composition and metabolism? Experimental study of a new potential technique in bariatric surgery. Surgery. 2006;139(2):209–16.

    Article  PubMed  Google Scholar 

  46. Val-Laillet D, Biraben A, Randuineau G, Malbert CH. Chronic vagus nerve stimulation decreased weight gain, food consumption and sweet craving in adult obese minipigs. Appetite. 2010;55(2):245–52.

    Article  CAS  PubMed  Google Scholar 

  47. Arterburn DE, Fisher DP. The current state of the evidence for bariatric surgery. Jama. 2014;312(9):898–9.

    Article  CAS  PubMed  Google Scholar 

  48. Ikramuddin S, Blackstone RP, Brancatisano A, Toouli J, Shah SN, Wolfe BM, et al. Effect of reversible intermittent intra-abdominal vagal nerve blockade on morbid obesity: the ReCharge randomized clinical trial. JAMA. 2014;312(9):915–22.

    Article  CAS  PubMed  Google Scholar 

  49. Priest C, Tontonoz P. Inter-organ cross-talk in metabolic syndrome. Nat Metab. 2019;1(12):1177–88.

    Article  PubMed  Google Scholar 

  50. Burcelin R, Gourdy P. Harnessing glucagon-like peptide-1 receptor agonists for the pharmacological treatment of overweight and obesity. Obes Rev. 2017;18(1):86–98.

    Article  CAS  PubMed  Google Scholar 

  51. Müller TD, Finan B, Bloom SR, D'Alessio D, Drucker DJ, Flatt PR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72–130.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Nadkarni P, Chepurny OG, Holz GG. Regulation of glucose homeostasis by GLP-1. Prog Mol Biol Transl Sci. 2014;121:23–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kentish SJ, Vincent AD, Kennaway DJ, Wittert GA, Page AJ. High-fat diet-induced obesity ablates gastric vagal afferent circadian rhythms. J Neurosci. 2016;36(11):3199–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kentish S, Li H, Philp LK, O'Donnell TA, Isaacs NJ, Young RL, et al. Diet-induced adaptation of vagal afferent function. J Physiol. 2012;590(1):209–21.

    Article  CAS  PubMed  Google Scholar 

  55. Daly DM, Park SJ, Valinsky WC, Beyak MJ. Impaired intestinal afferent nerve satiety signalling and vagal afferent excitability in diet induced obesity in the mouse. J Physiol. 2011;589(Pt 11):2857–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kentish SJ, O'Donnell TA, Isaacs NJ, Young RL, Li H, Harrington AM, et al. Gastric vagal afferent modulation by leptin is influenced by food intake status. J Physiol. 2013;591(7):1921–34.

    Article  CAS  PubMed  Google Scholar 

  57. Lee J, Cummings BP, Martin E, Sharp JW, Graham JL, Stanhope KL, et al. Glucose sensing by gut endocrine cells and activation of the vagal afferent pathway is impaired in a rodent model of type 2 diabetes mellitus. Am J Physiol Regul Integr Comp Physiol. 2012;302(6):R657–66.

    Article  CAS  PubMed  Google Scholar 

  58. Bernik TR, Friedman SG, Ochani M, DiRaimo R, Ulloa L, Yang H, et al. Pharmacological stimulation of the cholinergic antiinflammatory pathway. J Exp Med. 2002;195(6):781–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Beinat C, Banister SD, Herrera M, Law V, Kassiou M. The therapeutic potential of alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists for the treatment of the cognitive deficits associated with schizophrenia. CNS Drugs. 2015;29(7):529–42.

    Article  CAS  PubMed  Google Scholar 

  60. Ishikawa M, Hashimoto K. α7 nicotinic acetylcholine receptor as a potential therapeutic target for schizophrenia. Curr Pharm Des. 2011;17(2):121–9.

    Article  CAS  PubMed  Google Scholar 

  61. Pohanka M. Alpha7 nicotinic acetylcholine receptor is a target in pharmacology and toxicology. Int J Mol Sci. 2012;13(2):2219–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Terry AV Jr, Callahan PM. α7 nicotinic acetylcholine receptors as therapeutic targets in schizophrenia: update on animal and clinical studies and strategies for the future. Neuropharmacology. 2020;170:108053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chini B, Raimond E, Elgoyhen AB, Moralli D, Balzaretti M, Heinemann S. Molecular cloning and chromosomal localization of the human alpha 7-nicotinic receptor subunit gene (CHRNA7). Genomics. 1994;19(2):379–81.

    Article  CAS  PubMed  Google Scholar 

  64. Orr-Urtreger A, Seldin MF, Baldini A, Beaudet AL. Cloning and mapping of the mouse alpha 7-neuronal nicotinic acetylcholine receptor. Genomics. 1995;26(2):399–402.

    Article  CAS  PubMed  Google Scholar 

  65. Peng X, Katz M, Gerzanich V, Anand R, Lindstrom J. Human alpha 7 acetylcholine receptor: cloning of the alpha 7 subunit from the SH-SY5Y cell line and determination of pharmacological properties of native receptors and functional alpha 7 homomers expressed in Xenopus oocytes. Mol Pharmacol. 1994;45(3):546–54.

    CAS  PubMed  Google Scholar 

  66. Séguéla P, Wadiche J, Dineley-Miller K, Dani JA, Patrick JW. Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium. J Neurosci. 1993;13(2):596–604.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Changeux JP. The nicotinic acetylcholine receptor: the founding father of the pentameric ligand-gated ion channel superfamily. J Biol Chem. 2012;287(48):40207–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kalamida D, Poulas K, Avramopoulou V, Fostieri E, Lagoumintzis G, Lazaridis K, et al. Muscle and neuronal nicotinic acetylcholine receptors. Structure, function and pathogenicity. FEBS J. 2007;274(15):3799–845.

    Article  CAS  PubMed  Google Scholar 

  69. Andersen N, Corradi J, Sine SM, Bouzat C. Stoichiometry for activation of neuronal alpha7 nicotinic receptors. Proc Natl Acad Sci U S A. 2013;110(51):20819–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Nielsen BE, Minguez T, Bermudez I, Bouzat C. Molecular function of the novel alpha7beta2 nicotinic receptor. Cellular and Molecular Life Sciences : CMLS. 2018;75(13):2457–71.

    Article  CAS  PubMed  Google Scholar 

  71. Wu J, Lukas RJ. Naturally-expressed nicotinic acetylcholine receptor subtypes. Biochem Pharmacol. 2011;82(8):800–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Uteshev VV. alpha7 nicotinic ACh receptors as a ligand-gated source of Ca2+ ions: the search for a Ca2+ optimum. Adv Exp Med Biol. 2012;740:603–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Corradi J, Bouzat C. Understanding the bases of function and modulation of α7 nicotinic receptors: implications for drug discovery. Mol Pharmacol. 2016;90(3):288–99.

    Article  CAS  PubMed  Google Scholar 

  74. King JR, Ullah A, Bak E, Jafri MS, Kabbani N. Ionotropic and metabotropic mechanisms of allosteric modulation of α7 nicotinic receptor intracellular calcium. Mol Pharmacol. 2018;93(6):601–11.

    Article  CAS  PubMed  Google Scholar 

  75. Liu Q, Berg DK. Actin filaments and the opposing actions of CaM kinase II and calcineurin in regulating alpha7-containing nicotinic receptors on chick ciliary ganglion neurons. J Neurosci. 1999;19(23):10280–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. King JR, Nordman JC, Bridges SP, Lin MK, Kabbani N. Identification and characterization of a G protein-binding cluster in α7 nicotinic acetylcholine receptors. J Biol Chem. 2015;290(33):20060–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Grady SR, Wageman CR, Patzlaff NE, Marks MJ. Low concentrations of nicotine differentially desensitize nicotinic acetylcholine receptors that include alpha5 or alpha6 subunits and that mediate synaptosomal neurotransmitter release. Neuropharmacology. 2012;62(5–6):1935–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Mao D, Yasuda RP, Fan H, Wolfe BB, Kellar KJ. Heterogeneity of nicotinic cholinergic receptors in rat superior cervical and nodose ganglia. Mol Pharmacol. 2006;70(5):1693–9.

    Article  CAS  PubMed  Google Scholar 

  79. Simeone X, Karch R, Ciuraszkiewicz A, Orr-Urtreger A, Lemmens-Gruber R, Scholze P, et al. The role of the nAChR subunits α5, β2, and β4 on synaptic transmission in the mouse superior cervical ganglion. Physiol Rep. 2019;7(6):e14023.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Orr-Urtreger A, Göldner FM, Saeki M, Lorenzo I, Goldberg L, De Biasi M, et al. Mice deficient in the alpha7 neuronal nicotinic acetylcholine receptor lack alpha-bungarotoxin binding sites and hippocampal fast nicotinic currents. J Neurosci. 1997;17(23):9165–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Gulsevin A, Papke RL, Horenstein N. In silico modeling of the α7 nicotinic acetylcholine receptor: new pharmacological challenges associated with multiple modes of signaling. Mini Rev Med Chem. 2020;20(10):841–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kem WR. The brain alpha7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease: studies with DMXBA (GTS-21). Behav Brain Res. 2000;113(1–2):169–81.

    Article  CAS  PubMed  Google Scholar 

  83. Papke RL, Lindstrom JM. Nicotinic acetylcholine receptors: conventional and unconventional ligands and signaling. Neuropharmacology. 2020;168:108021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Williams DK, Wang J, Papke RL. Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations. Biochem Pharmacol. 2011;82(8):915–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Meyer EM, Kuryatov A, Gerzanich V, Lindstrom J, Papke RL. Analysis of 3-(4-hydroxy, 2-Methoxybenzylidene)anabaseine selectivity and activity at human and rat alpha-7 nicotinic receptors. J Pharmacol Exp Ther. 1998;287(3):918–25.

    CAS  PubMed  Google Scholar 

  86. Bodnar AL, Cortes-Burgos LA, Cook KK, Dinh DM, Groppi VE, Hajos M, et al. Discovery and structure-activity relationship of quinuclidine benzamides as agonists of alpha7 nicotinic acetylcholine receptors. J Med Chem. 2005;48(4):905–8.

    Article  CAS  PubMed  Google Scholar 

  87. Wishka DG, Walker DP, Yates KM, Reitz SC, Jia S, Myers JK, et al. Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an agonist of the alpha7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: synthesis and structure--activity relationship. J Med Chem. 2006;49(14):4425–36.

    Article  CAS  PubMed  Google Scholar 

  88. Acker BA, Jacobsen EJ, Rogers BN, Wishka DG, Reitz SC, Piotrowski DW, et al. Discovery of N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide as an agonist of the alpha7 nicotinic acetylcholine receptor: in vitro and in vivo activity. Bioorg Med Chem Lett. 2008;18(12):3611–5.

    Article  CAS  PubMed  Google Scholar 

  89. Dallanoce C, Magrone P, Matera C, Frigerio F, Grazioso G, De Amici M, et al. Design, synthesis, and pharmacological characterization of novel spirocyclic quinuclidinyl-Delta2-isoxazoline derivatives as potent and selective agonists of alpha7 nicotinic acetylcholine receptors. ChemMedChem. 2011;6(5):889–903.

    Article  CAS  PubMed  Google Scholar 

  90. Matera C, Dondio G, Braida D, Ponzoni L, De Amici M, Sala M, et al. In vivo and in vitro ADMET profiling and in vivo pharmacodynamic investigations of a selective alpha7 nicotinic acetylcholine receptor agonist with a spirocyclic Delta(2)-isoxazoline molecular skeleton. Eur J Pharmacol. 2018;820:265–73.

    Article  CAS  PubMed  Google Scholar 

  91. Di Cesare ML, Pacini A, Matera C, Zanardelli M, Mello T, De Amici M, et al. Involvement of alpha7 nAChR subtype in rat oxaliplatin-induced neuropathy: effects of selective activation. Neuropharmacology. 2014;79:37–48.

    Article  CAS  Google Scholar 

  92. Briggs CA, Gronlien JH, Curzon P, Timmermann DB, Ween H, Thorin-Hagene K, et al. Role of channel activation in cognitive enhancement mediated by alpha7 nicotinic acetylcholine receptors. Br J Pharmacol. 2009;158(6):1486–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Bristow LJ, Easton AE, Li YW, Sivarao DV, Lidge R, Jones KM, et al. The novel, nicotinic alpha7 receptor partial agonist, BMS-933043, improves cognition and sensory processing in preclinical models of schizophrenia. PLoS One. 2016;11(7):e0159996.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Godin JR, Roy P, Quadri M, Bagdas D, Toma W, Narendrula-Kotha R, et al. A silent agonist of alpha7 nicotinic acetylcholine receptors modulates inflammation ex vivo and attenuates EAE. Brain Behav Immun. 2020;87:286–300.

    Article  CAS  PubMed  Google Scholar 

  95. Gronlien JH, Hakerud M, Ween H, Thorin-Hagene K, Briggs CA, Gopalakrishnan M, et al. Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes. Mol Pharmacol. 2007;72(3):715–24.

    Article  PubMed  CAS  Google Scholar 

  96. Gurley DA, Lanthorn TH. Nicotinic agonists competitively antagonize serotonin at mouse 5-HT3 receptors expressed in Xenopus oocytes. Neurosci Lett. 1998;247(2–3):107–10.

    Article  CAS  PubMed  Google Scholar 

  97. Gault J, Robinson M, Berger R, Drebing C, Logel J, Hopkins J, et al. Genomic organization and partial duplication of the human alpha7 neuronal nicotinic acetylcholine receptor gene (CHRNA7). Genomics. 1998;52(2):173–85.

    Article  CAS  PubMed  Google Scholar 

  98. Riley B, Williamson M, Collier D, Wilkie H, Makoff A. A 3-Mb map of a large segmental duplication overlapping the alpha7-nicotinic acetylcholine receptor gene (CHRNA7) at human 15q13-q14. Genomics. 2002;79(2):197–209.

    Article  CAS  PubMed  Google Scholar 

  99. Araud T, Graw S, Berger R, Lee M, Neveu E, Bertrand D, et al. The chimeric gene CHRFAM7A, a partial duplication of the CHRNA7 gene, is a dominant negative regulator of alpha7*nAChR function. Biochem Pharmacol. 2011;82(8):904–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. de Lucas-Cerrillo AM, Maldifassi MC, Arnalich F, Renart J, Atienza G, Serantes R, et al. Function of partially duplicated human α77 nicotinic receptor subunit CHRFAM7A gene: potential implications for the cholinergic anti-inflammatory response. J Biol Chem. 2011;286(1):594–606.

    Article  PubMed  CAS  Google Scholar 

  101. Baez-Pagan CA, Delgado-Velez M, Lasalde-Dominicci JA. Activation of the macrophage alpha7 nicotinic acetylcholine receptor and control of inflammation. J NeuroImmune Pharmacol. 2015;10(3):468–76.

    Article  PubMed  PubMed Central  Google Scholar 

  102. de Jonge WJ, van der Zanden EP, The FO, Bijlsma MF, van Westerloo DJ, Bennink RJ, et al. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol. 2005;6(8):844–51.

    Article  PubMed  CAS  Google Scholar 

  103. Marrero MB, Bencherif M. Convergence of alpha 7 nicotinic acetylcholine receptor-activated pathways for anti-apoptosis and anti-inflammation: central role for JAK2 activation of STAT3 and NF-kappaB. Brain Res. 2009;1256:1–7.

    Article  CAS  PubMed  Google Scholar 

  104. Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology. 2007;132(6):2169–80.

    Article  CAS  PubMed  Google Scholar 

  105. Han JM, Levings MK. Immune regulation in obesity-associated adipose inflammation. J Immunol. 2013;191(2):527–32.

    Article  CAS  PubMed  Google Scholar 

  106. Sutherland JP, McKinley B, Eckel RH. The metabolic syndrome and inflammation. Metab Syndr Relat Disord. 2004;2(2):82–104.

    Article  CAS  PubMed  Google Scholar 

  107. Phosat C, Panprathip P, Chumpathat N, Prangthip P, Chantratita N, Soonthornworasiri N, et al. Elevated C-reactive protein, interleukin 6, tumor necrosis factor alpha and glycemic load associated with type 2 diabetes mellitus in rural Thais: a cross-sectional study. BMC Endocr Disord. 2017;17(1):44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. de Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett. 2008;582(1):97–105.

    Article  PubMed  CAS  Google Scholar 

  109. Rehman K, Akash MS. Mechanisms of inflammatory responses and development of insulin resistance: how are they interlinked? J Biomed Sci. 2016;23(1):87.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Tzanavari T, Giannogonas P, Karalis KP. TNF-alpha and obesity. Curr Dir Autoimmun. 2010;11:145–56.

    Article  CAS  PubMed  Google Scholar 

  111. Coelho M, Oliveira T, Fernandes R. Biochemistry of adipose tissue: an endocrine organ. Arch Med Sci: AMS. 2013;9(2):191–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Jiao ZY, Wu J, Liu C, Wen B, Zhao WZ, Du XL. Nicotinic α7 receptor inhibits the acylation stimulating protein-induced production of monocyte chemoattractant protein-1 and keratinocyte-derived chemokine in adipocytes by modulating the p38 kinase and nuclear factor-κB signaling pathways. Mol Med Rep. 2016;14(4):2959–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Chau YY, Bandiera R, Serrels A, Martínez-Estrada OM, Qing W, Lee M, et al. Visceral and subcutaneous fat have different origins and evidence supports a mesothelial source. Nat Cell Biol. 2014;16(4):367–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hasan MK, Friedman TC, Sims C, Lee DL, Espinoza-Derout J, Ume A, et al. alpha7-nicotinic acetylcholine receptor agonist ameliorates nicotine plus high-fat diet-induced hepatic steatosis in male mice by inhibiting oxidative stress and stimulating AMPK signaling. Endocrinology. 2018;159(2):931–44.

    Article  CAS  PubMed  Google Scholar 

  115. Li DJ, Zhao T, Xin RJ, Wang YY, Fei YB, Shen FM. Activation of alpha7 nicotinic acetylcholine receptor protects against oxidant stress damage through reducing vascular peroxidase-1 in a JNK signaling-dependent manner in endothelial cells. Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology. 2014;33(2):468–78.

    Article  CAS  Google Scholar 

  116. Costa SO, Souza CM, Lanza PG, Sartori JO, Ignacio-Souza LM, Candreva T, et al. Maternal high fat diet consumption reduces liver alpha7 nicotinic cholinergic receptor expression and impairs insulin signalling in the offspring. Sci Rep. 2020;10(1):48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Zhu Z, Cao F, Li X. Epigenetic programming and fetal metabolic programming. Front Endocrinol. 2019;10:764.

    Article  Google Scholar 

  118. Lilienfeld S. Galantamine--a novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer’s disease. CNS Drug Rev. 2002;8(2):159–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Consolim-Colombo FM, Sangaleti CT, Costa FO, Morais TL, Lopes HF, Motta JM, et al. Galantamine alleviates inflammation and insulin resistance in patients with metabolic syndrome in a randomized trial. JCI Insight. 2017;2(14).

  120. Mucke HA. The case of galantamine: repurposing and late blooming of a cholinergic drug. Future Sci OA. 2015;1(4):Fso73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Maelicke A, Samochocki M, Jostock R, Fehrenbacher A, Ludwig J, Albuquerque EX, et al. Allosteric sensitization of nicotinic receptors by galantamine, a new treatment strategy for Alzheimer’s disease. Biol Psychiatry. 2001;49(3):279–88.

    Article  CAS  PubMed  Google Scholar 

  122. Texidó L, Ros E, Martín-Satué M, López S, Aleu J, Marsal J, et al. Effect of galantamine on the human alpha7 neuronal nicotinic acetylcholine receptor, the Torpedo nicotinic acetylcholine receptor and spontaneous cholinergic synaptic activity. Br J Pharmacol. 2005;145(5):672–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Satapathy SK, Ochani M, Dancho M, Hudson LK, Rosas-Ballina M, Valdes-Ferrer SI, et al. Galantamine alleviates inflammation and other obesity-associated complications in high-fat diet-fed mice. Mol Med. 2011;17(7–8):599–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Jo YH, Talmage DA, Role LW. Nicotinic receptor-mediated effects on appetite and food intake. J Neurobiol. 2002;53(4):618–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Winders SE, Grunberg NE. Effects of nicotine on body weight, food consumption and body composition in male rats. Life Sci. 1990;46(21):1523–30.

    Article  CAS  PubMed  Google Scholar 

  126. McFadden KL, Cornier MA, Tregellas JR. The role of alpha-7 nicotinic receptors in food intake behaviors. Front Psychol. 2014;5:553.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Tuesta LM, Chen Z, Duncan A, Fowler CD, Ishikawa M, Lee BR, et al. GLP-1 acts on habenular avoidance circuits to control nicotine intake. Nat Neurosci. 2017;20(5):708–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Barrea L, Pugliese G, Muscogiuri G, Laudisio D, Colao A, Savastano S. New-generation anti-obesity drugs: naltrexone/bupropion and liraglutide. An update for endocrinologists and nutritionists. Minerva Endocrinol. 2020;45(2):127–37.

    Article  PubMed  Google Scholar 

  129. Khalil H, Ellwood L, Lord H, Fernandez R. Pharmacological treatment for obesity in adults: an umbrella review. Ann Pharmacother. 2020;54(7):691–705.

    Article  PubMed  Google Scholar 

  130. Montan PD, Sourlas A, Olivero J, Silverio D, Guzman E, Kosmas CE. Pharmacologic therapy of obesity: mechanisms of action and cardiometabolic effects. Ann Transl Med. 2019;7(16):393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Greenway FL, Fujioka K, Plodkowski RA, Mudaliar S, Guttadauria M, Erickson J, et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2010;376(9741):595–605.

    Article  CAS  PubMed  Google Scholar 

  132. Hollander P, Gupta AK, Plodkowski R, Greenway F, Bays H, Burns C, et al. Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes. Diabetes Care. 2013;36(12):4022–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Borner T, Workinger JL, Tinsley IC, Fortin SM, Stein LM, Chepurny OG, et al. Corrination of a GLP-1 receptor agonist for glycemic control without emesis. Cell Rep. 2020;31(11):107768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Mietlicki-Baase EG, Liberini CG, Workinger JL, Bonaccorso RL, Borner T, Reiner DJ, et al. A vitamin B12 conjugate of exendin-4 improves glucose tolerance without associated nausea or hypophagia in rodents. Diabetes Obes Metab. 2018;20(5):1223–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Gribble FM, Reimann F. Enteroendocrine cells: chemosensors in the intestinal epithelium. Annu Rev Physiol. 2016;78:277–99.

    Article  CAS  PubMed  Google Scholar 

  136. Gribble FM, Reimann F. Function and mechanisms of enteroendocrine cells and gut hormones in metabolism. Nat Rev Endocrinol. 2019;15(4):226–37.

    Article  CAS  PubMed  Google Scholar 

  137. Mace OJ, Tehan B, Marshall F. Pharmacology and physiology of gastrointestinal enteroendocrine cells. Pharmacol Res Perspect. 2015;3(4):e00155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Reimann F, Habib AM, Tolhurst G, Parker HE, Rogers GJ, Gribble FM. Glucose sensing in L cells: a primary cell study. Cell Metab. 2008;8(6):532–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Ye L, Liddle RA. Gastrointestinal hormones and the gut connectome. Curr Opin Endocrinol Diabetes Obes. 2017;24(1):9–14.

    PubMed  PubMed Central  Google Scholar 

  140. De Silva A, Bloom SR. Gut hormones and appetite control: a focus on PYY and GLP-1 as therapeutic targets in obesity. Gut Liver. 2012;6(1):10–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Sandoval D, Dunki-Jacobs A, Sorrell J, Seeley RJ, D’Alessio DD. Impact of intestinal electrical stimulation on nutrient-induced GLP-1 secretion in vivo. Neurogastroenterol Motil. 2013;25(8):700–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Yin J, Ji F, Gharibani P, Chen JD. Vagal nerve stimulation for glycemic control in a rodent model of type 2 diabetes. Obes Surg. 2019;29:2869–77.

    Article  PubMed  Google Scholar 

  143. Rocca AS, Brubaker PL. Role of the vagus nerve in mediating proximal nutrient-induced glucagon-like peptide-1 secretion. Endocrinology. 1999;140(4):1687–94.

    Article  CAS  PubMed  Google Scholar 

  144. Jorsal T, Rhee NA, Pedersen J, Wahlgren CD, Mortensen B, Jepsen SL, et al. Enteroendocrine K and L cells in healthy and type 2 diabetic individuals. Diabetologia. 2018;61(2):284–94.

    Article  CAS  PubMed  Google Scholar 

  145. Cabou C, Burcelin R. GLP-1, the gut-brain, and brain-periphery axes. Rev Diabet Stud. 2011;8(3):418–31.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Burcelin R, Gourdy P, Dalle S. GLP-1-based strategies: a physiological analysis of differential mode of action. Physiology (Bethesda). 2014;29(2):108–21.

    CAS  Google Scholar 

  147. Smith EP, An Z, Wagner C, Lewis AG, Cohen EB, Li B, et al. The role of β cell glucagon-like peptide-1 signaling in glucose regulation and response to diabetes drugs. Cell Metab. 2014;19(6):1050–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. O'Malley TJ, Fava GE, Zhang Y, Fonseca VA, Wu H. Progressive change of intra-islet GLP-1 production during diabetes development. Diabetes Metab Res Rev. 2014;30(8):661–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Donath MY, Burcelin R. GLP-1 effects on islets: hormonal, neuronal, or paracrine? Diabetes Care. 2013;36(Suppl 2):S145–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Urusova IA, Farilla L, Hui H, D'Amico E, Perfetti R. GLP-1 inhibition of pancreatic islet cell apoptosis. Trends Endocrinol Metab. 2004;15(1):27–33.

    Article  CAS  PubMed  Google Scholar 

  151. Farilla L, Bulotta A, Hirshberg B, Li Calzi S, Khoury N, Noushmehr H, et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology. 2003;144(12):5149–58.

    Article  CAS  PubMed  Google Scholar 

  152. Leech CA, Dzhura I, Chepurny OG, Kang G, Schwede F, Genieser HG, et al. Molecular physiology of glucagon-like peptide-1 insulin secretagogue action in pancreatic β cells. Prog Biophys Mol Biol. 2011;107(2):236–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Holz GG IV, Kühtreiber WM, Habener JF. Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37). Nature. 1993;361(6410):362–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Holz GG, Chepurny OG. Diabetes outfoxed by GLP-1? Sci STKE 2005;2005(268):pe2.

  155. Chepurny OG, Hussain MA, Holz GG. Exendin-4 as a stimulator of rat insulin I gene promoter activity via bZIP/CRE interactions sensitive to serine/threonine protein kinase inhibitor Ro 31-8220. Endocrinology. 2002;143(6):2303–13.

    Article  CAS  PubMed  Google Scholar 

  156. Li W, Yu G, Liu Y, Sha L. Intrapancreatic ganglia and neural regulation of pancreatic endocrine secretion. Front Neurosci. 2019;13:21.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Gilon P, Henquin JC. Mechanisms and physiological significance of the cholinergic control of pancreatic beta-cell function. Endocr Rev. 2001;22(5):565–604.

    CAS  PubMed  Google Scholar 

  158. Moullé VS, Tremblay C, Castell AL, Vivot K, Ethier M, Fergusson G, et al. The autonomic nervous system regulates pancreatic β-cell proliferation in adult male rats. Am J Physiol Endocrinol Metab. 2019;317(2):E234–e43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Ahrén B, Holst JJ. The cephalic insulin response to meal ingestion in humans is dependent on both cholinergic and noncholinergic mechanisms and is important for postprandial glycemia. Diabetes. 2001;50(5):1030–8.

    Article  PubMed  Google Scholar 

  160. Ahrén B. Autonomic regulation of islet hormone secretion--implications for health and disease. Diabetologia. 2000;43(4):393–410.

    Article  PubMed  Google Scholar 

  161. Rodriguez-Diaz R, Abdulreda MH, Formoso AL, Gans I, Ricordi C, Berggren PO, et al. Innervation patterns of autonomic axons in the human endocrine pancreas. Cell Metab. 2011;14(1):45–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Rodriguez-Diaz R, Dando R, Jacques-Silva MC, Fachado A, Molina J, Abdulreda MH, et al. Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans. Nat Med. 2011;17(7):888–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Yoshikawa H, Hellström-Lindahl E, Grill V. Evidence for functional nicotinic receptors on pancreatic beta cells. Metabolism. 2005;54(2):247–54.

    Article  CAS  PubMed  Google Scholar 

  164. Somm E, Guérardel A, Maouche K, Toulotte A, Veyrat-Durebex C, Rohner-Jeanrenaud F, et al. Concomitant alpha7 and beta2 nicotinic AChR subunit deficiency leads to impaired energy homeostasis and increased physical activity in mice. Mol Genet Metab. 2014;112(1):64–72.

    Article  CAS  PubMed  Google Scholar 

  165. Ganic E, Singh T, Luan C, Fadista J, Johansson JK, Cyphert HA, et al. MafA-controlled nicotinic receptor expression is essential for insulin secretion and is impaired in patients with type 2 diabetes. Cell Rep. 2016;14(8):1991–2002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Duttaroy A, Zimliki CL, Gautam D, Cui Y, Mears D, Wess J. Muscarinic stimulation of pancreatic insulin and glucagon release is abolished in m3 muscarinic acetylcholine receptor-deficient mice. Diabetes. 2004;53(7):1714–20.

    Article  CAS  PubMed  Google Scholar 

  167. Bokvist K, Eliasson L, Ammälä C, Renström E, Rorsman P. Co-localization of L-type Ca2+ channels and insulin-containing secretory granules and its significance for the initiation of exocytosis in mouse pancreatic β-cells. EMBO J. 1995;14(1):50–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. King AJ. The use of animal models in diabetes research. Br J Pharmacol. 2012;166(3):877–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Ishibashi T, Morita S, Kishimoto S, Uraki S, Takeshima K, Furukawa Y, et al. Nicotinic acetylcholine receptor signaling regulates inositol-requiring enzyme 1α activation to protect β-cells against terminal unfolded protein response under irremediable endoplasmic reticulum stress. J Diabetes Investig. 2020;11(4):801–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334(6059):1081–6.

    Article  CAS  PubMed  Google Scholar 

  171. Klee P, Bosco D, Guerardel A, Somm E, Toulotte A, Maechler P, et al. Activation of nicotinic acetylcholine receptors decreases apoptosis in human and female murine pancreatic islets. Endocrinology. 2016;157(10):3800–8.

    Article  CAS  PubMed  Google Scholar 

  172. Shikora S, Toouli J, Herrera MF, Kulseng B, Zulewski H, Brancatisano R, et al. Vagal blocking improves glycemic control and elevated blood pressure in obese subjects with type 2 diabetes mellitus. J Obes. 2013;2013:245683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Kitagawa H, Takenouchi T, Azuma R, Wesnes KA, Kramer WG, Clody DE, et al. Safety, pharmacokinetics, and effects on cognitive function of multiple doses of GTS-21 in healthy, male volunteers. Neuropsychopharmacology. 2003;28(3):542–51.

    Article  CAS  PubMed  Google Scholar 

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Funding

Supported in part by 1R01DK122332 (GGH, RNC) and 5R01DK069575 (GGH).

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Authors and Affiliations

  1. Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA

    Han Xie, Natesh Yepuri, Qinghe Meng, Ravi Dhawan, Colin A. Leech & Robert N. Cooney

  2. Departments of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, NY, USA

    Oleg G. Chepurny & George G. Holz

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  1. Han Xie
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All co-authors participated in the literature search, writing, and editing of this review. Figures and Tables prepared by CAL and GGH.

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Xie, H., Yepuri, N., Meng, Q. et al. Therapeutic potential of α7 nicotinic acetylcholine receptor agonists to combat obesity, diabetes, and inflammation. Rev Endocr Metab Disord 21, 431–447 (2020). https://doi.org/10.1007/s11154-020-09584-3

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