TY - JOUR
T1 - Intricacies of the endothelin system in human obesity: Role in the development of complications and potential as a therapeutic target
AU - Schinzari, Francesca
AU - Cardillo, Carmine
PY - 2020
Y1 - 2020
N2 - Activation of the vascular endothelin-1 (ET-1) system is a key abnormality in vascular dysfunction of human obesity, especially in patients developing complications, such as the metabolic syndrome, diabetes, and atherosclerosis. Vascular insulin resistance, an increased insulin-stimulated endothelial production of ET-1 combined with impaired nitric oxide availability, is the hallmark of obesity-related vasculopathy, but dysregulated adipokine release from obese adipose tissue may contribute to the predominance of ET-1-dependent vasoconstriction. ET-1, in turn, might determine unhealthy obese adipose tissue expansion, with visceral and perivascular adipose tissue changes driving the release of inflammatory cytokines and atherogenic chemo-kines. In addition, ET-1 might also play a role in the development of the metabolic complications of obesity. Studies have shown inhibition of lipoprotein lipase activity by ET-1, with consequent hypertriglyceridemia. Also, ET-1 in pancreatic islets seems to contribute to beta cell dysfunction, hence affecting insulin production and development of diabetes. Moreover, ET-1 may play a role in nonalcoholic steatohepatitis. Recent clinical trials using innovative design have demonstrated that antagonism of ET-type A receptors protects against some complications of obesity and diabetes, such as nephropathy. These findings encourage further investigation to evaluate whether targeting the ET-1 system could afford better protection against other consequences of the obesity epidemic.
AB - Activation of the vascular endothelin-1 (ET-1) system is a key abnormality in vascular dysfunction of human obesity, especially in patients developing complications, such as the metabolic syndrome, diabetes, and atherosclerosis. Vascular insulin resistance, an increased insulin-stimulated endothelial production of ET-1 combined with impaired nitric oxide availability, is the hallmark of obesity-related vasculopathy, but dysregulated adipokine release from obese adipose tissue may contribute to the predominance of ET-1-dependent vasoconstriction. ET-1, in turn, might determine unhealthy obese adipose tissue expansion, with visceral and perivascular adipose tissue changes driving the release of inflammatory cytokines and atherogenic chemo-kines. In addition, ET-1 might also play a role in the development of the metabolic complications of obesity. Studies have shown inhibition of lipoprotein lipase activity by ET-1, with consequent hypertriglyceridemia. Also, ET-1 in pancreatic islets seems to contribute to beta cell dysfunction, hence affecting insulin production and development of diabetes. Moreover, ET-1 may play a role in nonalcoholic steatohepatitis. Recent clinical trials using innovative design have demonstrated that antagonism of ET-type A receptors protects against some complications of obesity and diabetes, such as nephropathy. These findings encourage further investigation to evaluate whether targeting the ET-1 system could afford better protection against other consequences of the obesity epidemic.
KW - Adipokines
KW - Adipose Tissue
KW - Adipose tissue
KW - Cytokines
KW - Diabetes Mellitus, Type 2
KW - Diabetic Nephropathies
KW - Dyslipidemia
KW - Endothelin
KW - Endothelin Receptor Antagonists
KW - Endothelin-1
KW - Endothelium, Vascular
KW - Humans
KW - Insulin
KW - Insulin Resistance
KW - Insulin-Secreting Cells
KW - NASH
KW - Non-alcoholic Fatty Liver Disease
KW - Obesity
KW - Prediabetes
KW - Receptor, Endothelin A
KW - Vasoconstriction
KW - Adipokines
KW - Adipose Tissue
KW - Adipose tissue
KW - Cytokines
KW - Diabetes Mellitus, Type 2
KW - Diabetic Nephropathies
KW - Dyslipidemia
KW - Endothelin
KW - Endothelin Receptor Antagonists
KW - Endothelin-1
KW - Endothelium, Vascular
KW - Humans
KW - Insulin
KW - Insulin Resistance
KW - Insulin-Secreting Cells
KW - NASH
KW - Non-alcoholic Fatty Liver Disease
KW - Obesity
KW - Prediabetes
KW - Receptor, Endothelin A
KW - Vasoconstriction
UR - http://hdl.handle.net/10807/202359
U2 - 10.1139/cjpp-2019-0651
DO - 10.1139/cjpp-2019-0651
M3 - Article
SN - 0008-4212
VL - 98
SP - 563
EP - 569
JO - Canadian Journal of Physiology and Pharmacology
JF - Canadian Journal of Physiology and Pharmacology
ER -