Perivascular Adipose Tissue Control of Insulin-Induced Vasoreactivity in Muscle Is Impaired in db/db Mice
- Rick I. Meijer1,2,
- Wineke Bakker2,
- Caro-Lynn A.F. Alta2,
- Pieter Sipkema2,
- John S. Yudkin1,3,
- Benoit Viollet4,5,6,
- Erik A. Richter7,
- Yvo M. Smulders1,
- Victor W.M. van Hinsbergh2,
- Erik H. Serné1 and
- Etto C. Eringa2⇓
- 1Department of Internal Medicine, VU University Medical Center, Amsterdam, the Netherlands
- 2Laboratory for Physiology, VU University Medical Center, Amsterdam, the Netherlands
- 3Department of Medicine, University College London, London, U.K.
- 4INSERM, U1016, Cochin Institute, Paris, France
- 5Centre National de la Recherche Scientifique, UMR8104, Paris, France
- 6Paris Descartes University, Paris, France
- 7Department of Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark
- Corresponding author: Etto C. Eringa, .
R.I.M. and W.B. contributed equally to this study.
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 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.
- Received November 16, 2011.
- Accepted August 1, 2012.
- © 2013 by the American Diabetes Association.
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