OBJECTIVE-Visceral obesity increases risk of insulin resistance and type 2 diabetes. This may partly be due to a regionspecific resistance to insulin's antilipolytic 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 nonobese subjects in whom 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 and 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 antilipolytic 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 and phosphodiesterase-3B and increased the expression of endothelin receptor-B (ET B R) in visceral but not in subcutaneous adipocytes. These effects were mediated via ET B R with signals through protein kinase C and calmodulin pathways. The effect of ET-1 could be mimicked by knockdown of IRS-1. A bdominal obesity contributes to the pathogenesis of insulin resistance and, thereby, type2 diabetes (1,2). Release of free fatty acids (FFAs) from fat cells during lipolysis may be involved in the negative consequences of excess adipose tissue (3-5). This process is inhibited by insulin, which activates a signaling pathway including insulin substrate (IRS)-1, phosphatidylinositol 3-kinase (PI3K), AKT, and, ultimately, the enzyme phosphodiesterase-3B (PDE3B), which breaks down cyclic AMP. There are important regional variations in the antilipolytic effect of insulin. Subcutaneous adipocytes are much more sensitive than visceral adipocytes because of a higher receptoraffinity and higher expression of IRS-1 (6 -8). Site variations in adipocyte lipolysis elevate release of FFAs from the visceral compared with the subcutaneous adipose tissue during hyperinsulinemia (e.g., postprandially). Only visceral fat is linked to the liver, and a high FFA mobilization to the liver results in hepatic insulin resistance, dyslipidemia, hyperglycemia, and hyperinsulinemia, all of which are features of type 2 diabetes (3-5). CONCLUSIONS-ET-The factors that determine the relative insulin sensitivity of various adipose tissue depots are not well understood, but local environment may contribute. Adipocytes are surrounded by stromal vascular cells, including endothelial cells, which secrete endothelin-1 (ET-1), a potent vasoconstrictor. Plasma levels of ET-1 are increased in obesity and type 2 diabetes (9 -13), although the major source of circulating ET-1 in these conditions is not ...

DHCC attenuates MCP-1 and adiponectin production in human adipocytes, thereby reducing the expression of both pro- and anti-inflammatory factors. These effects may explain the difficulties so far in determining the role of DHCC in insulin sensitivity and obesity in humans.

Objective: Levels of the vascular peptide endothelin-1 (ET-1) are significantly elevated in obesity. Adipose tissue-derived ET-1 attenuates insulin-mediated antilipolysis in human visceral adipocytes through the activation of the ET receptor B (ET B R), thereby linking ET-1 to insulin resistance. Whether ET-1 has direct effects on lipolysis in human adipocytes is not known. Research design and subjects: Endothelin-1 receptor (ETR) mRNA expression was determined by quatitative PCR in 130 nonobese and obese subjects. ET-1 mRNA in different adipose tissue regions was also assessed. ETR protein expression was analyzed by western blotting in 37 subjects. The effect of ET-1 on lipolysis was assessed in freshly isolated adipocytes and in vitro differentiated adipocytes from human donors. Results: Freshly isolated human adipocytes incubated with different concentrations of ET-1 showed no acute effect on lipolysis. In contrast, a 24 h incubation in primary cultures of human adipocytes resulted in a significant 50% increase in lipolysis. This effect was concentration dependent and could be mimicked by an agonist of the ET A receptor but not with a selective ET B R agonist. Adipocyte differentiation was not affected by any of the agonists. In subcutaneous (s.c.) adipose tissue from 19 nonobese and 18 obese subjects, the protein expression of ET A R was significantly higher in obese subjects whereas there was no difference in ET B R expression. Interestingly, the differences in protein expression were not observed at the mRNA level as ET A R expression was similar between lean and obese subjects. Conclusion: Long-term but not acute incubation of human adipocytes with ET-1 results in a significant increase in lipolysis. This appears to be mediated through the activation of ET A R, demonstrating a yet another receptor-specific effect of ET-1. In addition, the protein expression of ET A R is increased in s.c. adipose tissue in obesity, possibly through post-transcriptional mechanisms. An increased effect of ET-1 could be a mechanism that contributes to increased basal lipolysis in human obesity.