title: Globular adiponectin controls insulin-mediated vasoreactivity in muscle through AMPKα2.
abstract: 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.
authors.affiliation: Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Michiel P
authors.initials: MP
authors.lastname: de Boer
authors.affiliation: Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Rick I
authors.initials: RI
authors.lastname: Meijer
authors.affiliation: Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Richter
authors.affiliation: Laboratory for Physiology, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Geerten P
authors.initials: GP
authors.lastname: van Nieuw Amerongen
authors.affiliation: Laboratory for Physiology, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Sipkema
authors.affiliation: Laboratory for Physiology, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Erik M
authors.initials: EM
authors.lastname: van Poelgeest
authors.affiliation: Laboratory for Physiology, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Jurjan
authors.initials: J
authors.lastname: Aman
authors.affiliation: Department of Biomedical Engineering, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Tom J A
authors.initials: TJ
authors.lastname: Kokhuis
authors.affiliation: Laboratory for Physiology, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Koolwijk
authors.affiliation: Laboratory for Physiology, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Victor W M
authors.initials: VW
authors.lastname: van Hinsbergh
authors.affiliation: Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Yvo M
authors.initials: YM
authors.lastname: Smulders
authors.affiliation: Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Erik H
authors.initials: EH
authors.lastname: Serné
authors.affiliation: Laboratory for Physiology, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands. Electronic address: e.eringa@vumc.nl.
authors.forename: Etto C
authors.initials: EC
authors.lastname: Eringa
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism*; D000328:Adult; D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014664:Vasodilation / Q000502:physiology
chemical_list: D052242:Adiponectin; D019332:Endothelin-1; D007328:Insulin; D009569:Nitric Oxide; C526181:PRKAA2 protein, human; D055372:AMP-Activated Protein Kinases
keywords: 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), AMPK agonist; Animal models of human disease; Compound C, AMPK antagonist; Endothelium; Globular adiponectin (gAdn); Human; Insulin; Insulin resistance; Intracellular signaling; Microcirculation; Nitric oxide; Obesity; PD-142893, non-selective endothelin receptor antagonist; l-NA, NO synthase inhibitor