JNK2 in myeloid cells impairs insulin's vasodilator effects in muscle during early obesity development through perivascular adipose tissue dysfunction

Rick I. Meijer, Femke P. M. Hoevenaars, Erik H. Serné, John S. Yudkin, Tom J. A. Kokhuis, Ester M. Weijers, Victor W. M. van Hinsbergh, Yvo M. Smulders, Etto C. Eringa

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Reduced vasodilator properties of insulin in obesity are caused by changes in perivascular adipose tissue and contribute to microvascular dysfunction in skeletal muscle. The causes of this dysfunction are unknown. The effects of a short-term Western diet on JNK2-expressing cells in perivascular adipose tissue (PVAT) on insulin-induced vasodilation and perfusion of skeletal muscle were assessed. In vivo, 2 wk of Western diet (WD) reduced whole body insulin sensitivity and insulin-stimulated muscle perfusion, determined using contrast ultrasonography during the hyperinsulinemic clamp. Ex vivo, WD triggered accumulation of PVAT in skeletal muscle and blunted its ability to facilitate insulin-induced vasodilation. Labeling of myeloid cells with green fluorescent protein identified bone marrow as a source of PVAT in muscle. To study whether JNK2-expressing inflammatory cells from bone marrow were involved, we transplanted JNK2 / bone marrow to WT mice. Deletion of JNK2 in bone marrow rescued the vasodilator phenotype of PVAT during WD exposure. JNK2 deletion in myeloid cells prevented the WD-induced increase in F4/80 expression. Even though WD and JNK2 deletion resulted in specific changes in gene expression of PVAT; epididymal and subcutaneous adipose tissue; expression of tumor necrosis factor-α, interleukin-1β, interleukin-6, or protein inhibitor of STAT1 was not affected. In conclusion, short-term Western diet triggers infiltration of JNK2-positive myeloid cells into PVAT, resulting in PVAT dysfunction, nonclassical inflammation, and loss of insulin-induced vasodilatation in vivo and ex vivo.

Original languageEnglish
Pages (from-to)H364-H374
JournalAmerican Journal of Physiology. Heart and Circulatory Physiology
Volume317
Issue number2
DOIs
Publication statusPublished - 1 Aug 2019

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