Globular adiponectin controls insulin-mediated vasoreactivity in muscle through AMPKα2

Research output: Contribution to journalJournal articlepeer-review

  • Michiel P de Boer
  • Rick I Meijer
  • Richter, Erik A.
  • Geerten P van Nieuw Amerongen
  • Pieter Sipkema
  • Erik M van Poelgeest
  • Jurjan Aman
  • Tom J A Kokhuis
  • Pieter Koolwijk
  • Victor W M van Hinsbergh
  • Yvo M Smulders
  • Erik H Serné
  • Etto C Eringa

Decreased tissue perfusion increases the risk of developing insulin resistance and cardiovascular disease in obesity, and decreased levels of globular adiponectin (gAdn) have been proposed to contribute to this risk. We hypothesized that gAdn controls insulin's vasoactive effects through AMP-activated protein kinase (AMPK), specifically its α2 subunit, and studied the mechanisms involved. In healthy volunteers, we found that decreased plasma gAdn levels in obese subjects associate with insulin resistance and reduced capillary perfusion during hyperinsulinemia. In cultured human microvascular endothelial cells (HMEC), gAdn increased AMPK activity. In isolated muscle resistance arteries gAdn uncovered insulin-induced vasodilation by selectively inhibiting insulin-induced activation of ERK1/2, and the AMPK inhibitor compound C as well as genetic deletion of AMPKα2 blunted insulin-induced vasodilation. In HMEC deletion of AMPKα2 abolished insulin-induced Ser(1177) phosphorylation of eNOS. In mice we confirmed that AMPKα2 deficiency decreases insulin sensitivity, and this was accompanied by decreased muscle microvascular blood volume during hyperinsulinemia in vivo. This impairment was accompanied by a decrease in arterial Ser(1177) phosphorylation of eNOS, which closely related to AMPK activity. In conclusion, globular adiponectin controls muscle perfusion during hyperinsulinemia through AMPKα2, which determines the balance between NO and ET-1 activity in muscle resistance arteries. Our findings provide a novel mechanism linking reduced gAdn-AMPK signaling to insulin resistance and impaired organ perfusion.

Original languageEnglish
JournalVascular Pharmacology
Volume78
Pages (from-to)24-35
Number of pages12
ISSN1537-1891
DOIs
Publication statusPublished - 2016

ID: 144416581