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Research ArticleNEUROPHARMACOLOGY

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 and Merouane Bencherif
Journal of Pharmacology and Experimental Therapeutics January 2010, 332 (1) 173-180; DOI: https://doi.org/10.1124/jpet.109.154633
Mario B. Marrero
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Rudolf Lucas
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Christina Salet
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Terry A. Hauser
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Anatoly Mazurov
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Patrick M. Lippiello
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Merouane Bencherif
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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.

Footnotes

  • This work was supported by Targacept, Inc., Winston-Salem, North Carolina.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.109.154633

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    IL-6
    interleukin 6
    TNF-α
    tumor necrosis factor-α
    CNS
    central nervous system
    ACh
    acetylcholine
    nAChR
    nicotinic acetylcholine receptor
    LPS
    lipopolysaccharide
    TC-7020
    5-methyl-N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide
    Compound A
    (R,E)-5-(2-pyrrolidin-3-ylvinyl)-pyrimidine
    MLA
    methyllycaconitine
    JAK2
    Janus kinase 2
    AG-490
    α-cyano-(3,4-dihydroxy)-N-benzylcinnamide
    HbA1c
    glycosylated hemoglobin
    STAT3
    signal transducer and activator of transcription 3.

    • Received April 2, 2009.
    • Accepted September 25, 2009.
  • © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 332 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 332, Issue 1
1 Jan 2010
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Research ArticleNEUROPHARMACOLOGY

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 and Merouane Bencherif
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 173-180; DOI: https://doi.org/10.1124/jpet.109.154633

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Research ArticleNEUROPHARMACOLOGY

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 and Merouane Bencherif
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 173-180; DOI: https://doi.org/10.1124/jpet.109.154633
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