Perivascular adipose tissue control of insulin-induced vasoreactivity in muscle is impaired in db/db mice

TY - JOUR

T1 - Perivascular adipose tissue control of insulin-induced vasoreactivity in muscle is impaired in db/db mice

AU - Meijer, Rick I

AU - Bakker, Wineke

AU - Alta, Caro-Lynn A F

AU - Sipkema, Pieter

AU - Yudkin, John S

AU - Viollet, Benoit

AU - Richter, Erik

AU - Smulders, Yvo M

AU - van Hinsbergh, Victor W M

AU - Serné, Erik H

AU - Eringa, Etto C

N1 - CURIS 2013 NEXS 005

PY - 2013/2

Y1 - 2013/2

N2 - 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 NH2-terminal kinase (JNK) in db/db PVAT restored insulin-induced vasodilation in an adiponectindependent 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.

AB - 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 NH2-terminal kinase (JNK) in db/db PVAT restored insulin-induced vasodilation in an adiponectindependent 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.

U2 - 10.2337/db11-1603

DO - 10.2337/db11-1603

M3 - Journal article

C2 - 23048187

SN - 0012-1797

VL - 62

SP - 590

EP - 598

JO - Diabetes

JF - Diabetes

IS - 2

ER -