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Review
. 2020 Dec;21(12):e13086.
doi: 10.1111/obr.13086. Epub 2020 Jul 6.

Endothelin-1 in the pathophysiology of obesity and insulin resistance

Haley N Jenkins  1 , Osvaldo Rivera-Gonzalez  1 , Yann Gibert  2 , Joshua S Speed  1
Affiliations
Review

Endothelin-1 in the pathophysiology of obesity and insulin resistance

Haley N Jenkins et al. Obes Rev. 2020 Dec.

Abstract

The association between plasma endothelin-1 (ET-1) and obesity has been documented for decades, yet the contribution of ET-1 to risk factors associated with obesity is not fully understood. In 1994, one of first papers to document this association also noted a positive correlation between plasma insulin and ET-1, suggesting a potential contribution of ET-1 to the development of insulin resistance. Both endogenous receptors for ET-1, ETA and ETB are present in all insulin-sensitive tissues including adipose, liver and muscle, and ET-1 actions within these tissues suggest that ET-1 may be playing a role in the pathogenesis of insulin resistance. Further, antagonists for ET-1 receptors are clinically approved making these sites attractive therapeutic targets. This review focuses on known mechanisms through which ET-1 affects plasma lipid profiles and insulin signalling in these metabolically important tissues and also identifies gaps in our understanding of ET-1 in obesity-related pathophysiology.

Keywords: ET-1; insulin resistance; obesity.

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Figures

Figure 1:
Figure 1:
Mechanisms by which obesity promotes insulin resistance. Excess adipose in obesity reduces circulating adiponectin. Lower adiponectin, an insulin sensitizing adipokine, reduces the effect of insulin to inhibit glycogenolysis and gluconeogenesis by the liver and muscle. Insulin resistance also causes loss if insulin mediated glucose uptake by muscle via Glucose Transporter 4 (GLUT4) leading to elevated plasma glucose. In adipocytes, loss of insulin signaling pathways causes increased lipolysis by increasing lipoprotein lipase (LPL) activity and decreasing hormone sensitive lipase (HSL), thereby promoting hyperlipidemia.
Figure 2:
Figure 2:
Classical signaling pathways associated with endothelin receptor binding.
Figure 3:
Figure 3:
Hypothetical scheme by which ET-1 promotes insulin resistance in the obese state.
Figure 4:
Figure 4:
Diseases for which endothelin receptor antagonists were tested. Lists were generated by searching the drug names listed within ClinicalTrials.gov. Green font indicates a disease in which endothelin antagonists have been approved for treatment.
See this image and copyright information in PMC

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