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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
da Costa, Rafael Menezes ; Neves, Karla Bianca ; Mestriner, Fabiola Leslie ; Louzada-Junior, Paulo ; Bruder-Nascimento, Thiago ; Tostes, Rita C.
Total Authors: 6
Document type: Journal article
Source: CARDIOVASCULAR DIABETOLOGY; v. 15, AUG 25 2016.
Web of Science Citations: 15
Abstract

Background: High fat diet (HFD) induces insulin resistance in various tissues, including the vasculature. HFD also increases plasma levels of TNF-alpha, 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-alpha, reduces Akt signaling and, consequently, nitric oxide (NO) production, we hypothesized that PTEN contributes to TNF-alpha-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-alpha KO mice submitted to control or HFD diet for 18 weeks to assess molecular mechanisms by which TNF-alpha 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-alpha. TNF-alpha receptors deficiency and TNF-alpha blockade with infliximab abolished the effects of HFD and TNF-alpha 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-alpha receptor deletion restored PTEN expression/activity and Akt/eNOS/NO signaling in HFD-fed mice. Conclusion: TNF-alpha induces vascular insulin resistance by mechanisms that involve positive modulation of PTEN and inhibition of Akt/eNOS/NO signaling. Our findings highlight TNF-alpha and PTEN as potential targets to limit insulin resistance and vascular complications associated with obesity-related conditions. (AU)

FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
Grantee:Fernando de Queiroz Cunha
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC