Meijer, Rick I2; Bakker, Wineke3; Alta, Caro-Lynn A F3; Sipkema, Pieter3; Yudkin, John S4; Viollet, Benoit5; Richter, Erik6; Smulders, Yvo M2; van Hinsbergh, Victor W M3; Serné, Erik H2; Eringa, Etto C3
1 Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, Københavns Universitet2 Department of Internal Medicine, VU University Medical Center, Amsterdam3 Laboratory for Physiology, VU University Medical Center, Amsterdam4 Department of Medicine, University College London5 INSERM, U1016, Cochin Institute / Centre National de la Recherche Scientifique, UMR8104 / Paris Descartes University, Paris6 Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, Københavns Universitet
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 AMPKa2(+/+) and AMPKa2(-/-) were studied. In AMPKa2(-/-) resistance arteries, insulin caused vasoconstriction in the presence of PVAT, and AMPKa2(+/+) 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 AMPKa2 signaling. PVAT from obese mice inhibits insulin-induced vasodilation, which can be restored by inhibition of JNK.