Bone Marrow-Derived JNK2-Positive Cells in Perivascular Adipose Tissue Blunt Microvascular Insulin-Induced Vasodilation Early During Nutrient Excess

Rationale Obesity is associated with impaired delivery of insulin and glucose by the microcirculation in skeletal muscle. Perivascular adipose tissue (PVAT) has anticontractile properties that are lost in obesity, thereby blunting insulin-induced vasodilation. We hypothesized that microvascular dysfunction develops during a two-week Western Diet (WD) and that PVAT is involved in this development, both inand ex-vivo. We further hypothesized that c-Jun N-terminal kinase 2 (JNK2) expressing cells from the bone marrow in PVAT are causative for the change in PVAT function. Methods and Results In C57Bl/6 mice after two weeks of WD, PVAT weight around the gracilis arteries increased compared to chowfed controls. Mice on WD had reduced insulin-induced microvascular recruitment, along with insulin resistance, as shown by Contrast Enhanced Ultrasound (CEU) during a hyperinsulinemic euglycemic clamp. To study whether perfusion defects were caused by altered effects of PVAT on muscle resistance arteries (RA), insulin responses of RA from chow or WD mice were studied by pressure myography, in the absence, or presence of PVAT. Chow RA showed insulin-induced vasodilation after incubation with chow PVAT, but not when incubated alone or with WD PVAT. Moreover, insulin induced vasoconstriction in WD RA with WD PVAT, but not chow PVAT. Transplantation with JNK2-/bone marrow restored the insulin-induced vasodilation by WD-PVAT. Conclusions Impaired insulin-induced muscle perfusion is an early phenomenon during exposure to nutrient excess and is caused by endothelial as well as PVAT dysfunction. The latter is caused by infiltration of JNK2 positive cells from bone marrow in PVAT.