An α7 nicotinic acetylcholine receptor-selective agonist reduces weight gain and metabolic changes in a mouse model of diabetes

Mario B Marrero, Rudolf Lucas, Christina Salet, Terry A. Hauser, Anatoly Mazurov, Patrick M. Lippiello, Merouane Bencherif

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Type 2 diabetes has become a pervasive public health problem. The etiology of the disease has not been fully defined but appears to involve abnormalities in peripheral and central nervous system pathways, as well as prominent inflammatory components. Because nicotinic acetylcholine receptors (nAChRs) are known to interact with anti-inflammatory pathways and have been implicated in control of appetite and body weight, as well as lipid and energy metabolism, we examined their role in modulating biological parameters associated with the disease. In a model of type 2 diabetes, the homozygous leptin-resistant db/db obese mouse, we measured the effects of a novel α7 nAChR-selective agonist [5-methyl-N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2- carboxamide (TC-7020)] on body mass, glucose and lipid metabolism, and proinflammatory cytokines. Oral administration of TC-7020 reduced weight gain and food intake, reduced elevated glucose and glycated hemoglobin levels, and lowered elevated plasma levels of triglycerides and the proinflammatory cytokine tumor necrosis factor-α. These changes were reversed by the α7-selective antagonist methyllycaconitine, confirming the involvement of α7 nAChRs. Prevention of weight gain, decreased food intake, and normalization of glucose levels were also blocked by the Janus kinase 2 (JAK2) inhibitor α-cyano-(3,4-dihydroxy)-N-benzylcinnamide (AG-490), suggesting that these effects involve linkage of α7 nAChRs to the JAK2-signal transducer and activator of transcription 3 signaling pathway. The results show that α7 nAChRs play a central role in regulating biological parameters associated with diabetes and support the potential of targeting these receptors as a new therapeutic strategy for treatment.

Original languageEnglish (US)
Pages (from-to)173-180
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume332
Issue number1
DOIs
StatePublished - Jan 1 2010

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Nicotinic Receptors
Weight Gain
Janus Kinase 2
Lipid Metabolism
Glucose
Type 2 Diabetes Mellitus
Eating
Cytokines
STAT3 Transcription Factor
Obese Mice
Peripheral Nervous System
Glycosylated Hemoglobin A
Appetite
Leptin
Energy Metabolism
Oral Administration
Triglycerides
Anti-Inflammatory Agents
Central Nervous System
Public Health

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Medicine(all)

Cite this

An α7 nicotinic acetylcholine receptor-selective agonist reduces weight gain and metabolic changes in a mouse model of diabetes. / Marrero, Mario B; Lucas, Rudolf; Salet, Christina; Hauser, Terry A.; Mazurov, Anatoly; Lippiello, Patrick M.; Bencherif, Merouane.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 332, No. 1, 01.01.2010, p. 173-180.

Research output: Contribution to journalArticle

Marrero, Mario B ; Lucas, Rudolf ; Salet, Christina ; Hauser, Terry A. ; Mazurov, Anatoly ; Lippiello, Patrick M. ; Bencherif, Merouane. / An α7 nicotinic acetylcholine receptor-selective agonist reduces weight gain and metabolic changes in a mouse model of diabetes. In: Journal of Pharmacology and Experimental Therapeutics. 2010 ; Vol. 332, No. 1. pp. 173-180.
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