2. Academic Validation
  3. Overproduction of endothelin-1 impairs glucose tolerance but does not promote visceral adipose tissue inflammation or limit metabolic adaptations to exercise

Overproduction of endothelin-1 impairs glucose tolerance but does not promote visceral adipose tissue inflammation or limit metabolic adaptations to exercise

  • Am J Physiol Endocrinol Metab. 2019 Sep 1;317(3):E548-E558. doi: 10.1152/ajpendo.00178.2019.
Thomas J Jurrissen 1 2,  Zachary I Grunewald 1 2,  Makenzie L Woodford 1 2,  Nathan C Winn 1 3,  James R Ball 1,  Thomas N Smith 1,  Andrew A Wheeler 4,  Arthur L Rawlings 4,  Kevin F Staveley-O'Carroll 4,  Yan Ji 5,  William P Fay 5 6 7,  Pierre Paradis 8,  Ernesto L Schiffrin 8 9,  Victoria J Vieira-Potter 1,  Paul J Fadel 10,  Luis A Martinez-Lemus 2 5,  Jaume Padilla 1 2
Affiliations

Affiliations

  • 1 Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri.
  • 2 Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri.
  • 3 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee.
  • 4 Department of Surgery, University of Missouri, Columbia, Missouri.
  • 5 Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, University of Missouri, Columbia, Missouri.
  • 6 Department of Medicine, University of Missouri, Columbia, Missouri.
  • 7 Research Service, Harry S. Truman Memorial Veterans Hospital, University of Missouri, Columbia, Missouri.
  • 8 Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada.
  • 9 Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada.
  • 10 Department of Kinesiology, University of Texas at Arlington, Arlington, Texas.
PMID: 31310581 DOI: 10.1152/ajpendo.00178.2019
Abstract

Endothelin-1 (ET-1) is a potent vasoconstrictor and proinflammatory peptide that is upregulated in obesity. Herein, we tested the hypothesis that ET-1 signaling promotes visceral adipose tissue (AT) inflammation and disrupts glucose homeostasis. We also tested if reduced ET-1 is a required mechanism by which exercise ameliorates AT inflammation and improves glycemic control in obesity. We found that 1) diet-induced obesity, AT inflammation, and glycemic dysregulation were not accompanied by significantly increased levels of ET-1 in AT or circulation in wild-type mice and that endothelial overexpression of ET-1 and consequently increased ET-1 levels did not cause AT inflammation yet impaired glucose tolerance; 2) reduced AT inflammation and improved glucose tolerance with voluntary wheel running was not associated with decreased levels of ET-1 in AT or circulation in obese mice nor did endothelial overexpression of ET-1 impede such exercise-induced metabolic adaptations; 3) chronic pharmacological blockade of ET-1 receptors did not suppress AT inflammation in obese mice but improved glucose tolerance; and 4) in a cohort of human subjects with a wide range of body mass indexes, ET-1 levels in AT, or circulation were not correlated with markers of inflammation in AT. In aggregate, we conclude that ET-1 signaling is not implicated in the development of visceral AT inflammation but promotes glucose intolerance, thus representing an important therapeutic target for glycemic dysregulation in conditions characterized by hyperendothelinemia. Furthermore, we show that the salutary effects of exercise on AT and systemic metabolic function are not contingent on the suppression of ET-1 signaling.

Keywords

adipose tissue; endothelin-1; exercise; glucose control; inflammation.

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