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

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

Abbreviations: ERK, extracellular signal–related kinase; ET-1, endothelin-1; ET_AR, endothelin receptor-A; ET_BR, 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

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_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 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_BR signaling pathways, which affect multiple steps in insulin signaling.

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