The vascular peptide endothelin-1 links fat accumulation with alterations of visceral adipocyte lipolysis

Abstract

Objective: Visceral obesity increases the risk of insulin resistance and type-2 diabetes. This may partly be due to a region specific resistance to insulin's anti-lipolytic effect in visceral adipocytes. We investigated whether adipose tissue releases the vascular peptide endothelin-1 (ET-1) and whether ET-1 could account for regional differences in lipolysis.

Research Design and Methods: One group consisted of eleven obese and eleven non-obese subjects, in which ET-1 levels were compared between abdominal subcutaneous and arterialized blood samples. A second group included subjects undergoing anti-obesity surgery. Abdominal subcutaneous and visceral adipose tissues were obtained to study the effect of ET-1 on differentiated adipocytes regarding lipolysis, gene and protein expression.

Results: Adipose tissue had a marked net release of ET-1 in vivo, which was 2.5 fold increased in obesity. In adipocytes treated with ET-1, the anti-lipolytic effect of insulin was attenuated in visceral but not in subcutaneous adipocytes, which could not be explained by effects of ET-1 on adipocyte differentiation. ET-1 decreased the expression of insulin receptor, insulin receptor substrate-1 (IRS-1) and phosphodiesterase-3B and increased the expression of endothelin-receptor-B (ET_BR) in visceral but not in subcutaneous adipocytes. These effects were mediated via ET_BR with signals through protein kinase C and calmodulin-pathways. The effect of ET-1 could be mimicked by knock-down of IRS-1.

Conclusions: ET-1 is released from human adipose tissue and links fat accumulation to insulin resistance. It selectively counteracts insulin inhibition of visceral adipocyte lipolysis via ET_BR signaling pathways which affect multiple steps in insulin-signaling.