title: Perivascular adipose tissue control of insulin-induced vasoreactivity in muscle is impaired in db/db mice.
abstract: Microvascular recruitment in muscle is a determinant of insulin sensitivity. Whether perivascular adipose tissue (PVAT) is involved in disturbed insulin-induced vasoreactivity is unknown, as are the underlying mechanisms. This study investigates whether PVAT regulates insulin-induced vasodilation in muscle, the underlying mechanisms, and how obesity disturbs this vasodilation. Insulin-induced vasoreactivity of resistance arteries was studied with PVAT from C57BL/6 or db/db mice. PVAT weight in muscle was higher in db/db mice compared with C57BL/6 mice. PVAT from C57BL/6 mice uncovered insulin-induced vasodilation; this vasodilation was abrogated with PVAT from db/db mice. Blocking adiponectin abolished the vasodilator effect of insulin in the presence of C57BL/6 PVAT, and adiponectin secretion was lower in db/db PVAT. To investigate this interaction further, resistance arteries of AMPKα2(+/+) and AMPKα2(-/-) were studied. In AMPKα2(-/-) resistance arteries, insulin caused vasoconstriction in the presence of PVAT, and AMPKα2(+/+) resistance arteries showed a neutral response. On the other hand, inhibition of the inflammatory kinase Jun NH(2)-terminal kinase (JNK) in db/db PVAT restored insulin-induced vasodilation in an adiponectin-dependent manner. In conclusion, PVAT controls insulin-induced vasoreactivity in the muscle microcirculation through secretion of adiponectin and subsequent AMPKα2 signaling. PVAT from obese mice inhibits insulin-induced vasodilation, which can be restored by inhibition of JNK.
authors.affiliation: Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Rick I
authors.initials: RI
authors.lastname: Meijer
authors.forename: Wineke
authors.initials: W
authors.lastname: Bakker
authors.forename: Caro-Lynn A F
authors.initials: CL
authors.lastname: Alta
authors.forename: Pieter
authors.initials: P
authors.lastname: Sipkema
authors.forename: John S
authors.initials: JS
authors.lastname: Yudkin
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Erik A
authors.initials: EA
authors.lastname: Richter
authors.forename: Yvo M
authors.initials: YM
authors.lastname: Smulders
authors.forename: Victor W M
authors.initials: VW
authors.lastname: van Hinsbergh
authors.forename: Erik H
authors.initials: EH
authors.lastname: Serné
authors.forename: Etto C
authors.initials: EC
authors.lastname: Eringa
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology; D052242:Adiponectin / Q000037:antagonists & inhibitors / Q000378:metabolism; D000273:Adipose Tissue / Q000098:blood supply / Q000502:physiology*; D000818:Animals; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects; D009765:Obesity / Q000503:physiopathology*; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D054419:Receptors, Adiponectin / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D007328:Insulin; C525168:L-JNKI-1; D010446:Peptide Fragments; D010455:Peptides; D054419:Receptors, Adiponectin; C534978:Prkaa2 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases