TNF-α induces vascular insulin resistance via positive modulation of PTEN and decreased Akt/eNOS/NO signaling in high fat diet-fed mice

da Costa, Rafael Menezes and Neves, Karla Bianca and Mestriner, Fabíola Leslie and Louzada-Junior, Paulo and Bruder-Nascimento, Thiago and Tostes, Rita C. (2016) TNF-α induces vascular insulin resistance via positive modulation of PTEN and decreased Akt/eNOS/NO signaling in high fat diet-fed mice. Cardiovascular Diabetology, 15 (1). 119. ISSN 1475-2840 (https://doi.org/10.1186/s12933-016-0443-0)

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Abstract

Background: High fat diet (HFD) induces insulin resistance in various tissues, including the vasculature. HFD also increases plasma levels of TNF-α, a cytokine that contributes to insulin resistance and vascular dysfunction. Considering that the enzyme phosphatase and tension homologue (PTEN), whose expression is increased by TNF-α, reduces Akt signaling and, consequently, nitric oxide (NO) production, we hypothesized that PTEN contributes to TNF-α-mediated vascular resistance to insulin induced by HFD. Mechanisms underlying PTEN effects were determined. Methods: Mesenteric vascular beds were isolated from C57Bl/6J and TNF-α KO mice submitted to control or HFD diet for 18 weeks to assess molecular mechanisms by which TNF-α and PTEN contribute to vascular dysfunction. Results: Vasodilation in response to insulin was decreased in HFD-fed mice and in ex vivo control arteries incubated with TNF-α. TNF-α receptors deficiency and TNF-α blockade with infliximab abolished the effects of HFD and TNF-α on insulin-induced vasodilation. PTEN vascular expression (total and phosphorylated isoforms) was increased in HFD-fed mice. Treatment with a PTEN inhibitor improved insulin-induced vasodilation in HFD-fed mice. TNF-α receptor deletion restored PTEN expression/activity and Akt/eNOS/NO signaling in HFD-fed mice. Conclusion: TNF-α induces vascular insulin resistance by mechanisms that involve positive modulation of PTEN and inhibition of Akt/eNOS/NO signaling. Our findings highlight TNF-α and PTEN as potential targets to limit insulin resistance and vascular complications associated with obesity-related conditions.

ORCID iDs

da Costa, Rafael Menezes, Neves, Karla Bianca ORCID logoORCID: https://orcid.org/0000-0001-5158-9263, Mestriner, Fabíola Leslie, Louzada-Junior, Paulo, Bruder-Nascimento, Thiago and Tostes, Rita C.;
  • Item type:Article
    ID code:82736
    Dates:
    Date
    Event
    25 August 2016
    Published
    18 August 2016
    Accepted
    Notes:Funding Information: This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2013/08216‑2‑CRID), Coordenação de Aper‑ feiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil. Publisher Copyright: © 2016 The Author(s).
    Subjects:Medicine
    Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Depositing user: Pure Administrator
    Date deposited:13 Oct 2022 09:23
    Last modified:26 Oct 2024 08:24
    Related URLs:
    URI:https://strathprints.strath.ac.uk/id/eprint/82736
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