Vascular Peptide Endothelin-1 Links Fat Accumulation With Alterations of Visceral Adipocyte Lipolysis

• Published in: Diabetes (New York, N.Y.) Vol. 57; no. 2; pp. 378 - 386
• Main Authors: VAN HARMELEN, Vanessa, ERIKSSON, Anna, ARNER, Peter, ASTRÖM, Gaby, WAHLEN, Kerstin, NÄSLUND, Erik, KARPE, Fredrik, FRAYN, Keith, OLSSON, Tommy, ANDERSSON, Jonas, RYDEN, Mikel
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.02.2008
• Subjects: Abdomen; Adaptor Proteins, Signal Transducing - genetics; Adipocytes; Adipocytes - physiology; Adipose tissue; Adipose tissues; Adult; Aged; Biological and medical sciences; Body fat; Body Mass Index; Diabetes; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endothelin; Endothelin-1 - secretion; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Gene Expression Regulation; Glycerol; Humans; Insulin Receptor Substrate Proteins; Insulin Resistance; Kinases; Lipolysis; Male; Medical sciences; Medicin och hälsovetenskap; Middle Aged; Obesity; Obesity - blood; Obesity - physiopathology; Peptides; Physiological aspects; Protein expression; Proteins; Reference Values; Research design; Risk factors; RNA Interference; Surgery; Tumor necrosis factor-TNF; Endocrinopathy; Adipocyte; Peptides; Diabetes mellitus; Endothelin 1; Accumulation; Lipolysis
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db07-0893

Vascular Peptide Endothelin-1 Links Fat Accumulation With Alterations of Visceral Adipocyte Lipolysis Vanessa van Harmelen 1 , Anna Eriksson 1 , Gaby Åström 1 , Kerstin Wåhlén 1 , Erik Näslund 2 , Fredrik Karpe 3 , Keith Frayn 3 , Tommy Olsson 4 , Jonas Andersson 4 , Mikel Rydén 1 and Peter Arner 1 1 Department of Medicine, Karolinska Institutet at the Karolinska University Hospital, Stockholm, Sweden 2 Department of Clinical Sciences, Danderyds Hospital, Karolinska Institutet, Stockholm, Sweden 3 Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital Oxford, U.K 4 Department of Medicine, Umeå University Hospital, Umeå, Sweden Address correspondence and reprint requests to Peter Arner, MD, PhD, Karolinska Institutet, Department of Medicine, M63, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. E-mail: peter.arner{at}ki.se Abstract OBJECTIVE— Visceral obesity increases risk of insulin resistance and type 2 diabetes. This may partly be due to a region-specific 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. 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 B R signaling pathways, which affect multiple steps in insulin signaling. ERK, extracellular signal–related kinase ET-1, endothelin-1 ETAR, endothelin receptor-A ETBR, endothelin receptor-B FFA, free fatty acid GPDH, glycerol-3-phosphate dehydrogenase IRS, insulin receptor substrate MEK, mitogen-activated protein kinase kinase OM, omental PI3K, phosphatidylinositol 3-kinase PKC, protein kinase C SC, subcutaneous TNF, tumor necrosis factor Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 19 November 2007. DOI: 10.2337/db07-0893. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted November 13, 2007. Received July 2, 2007. DIABETES