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

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.