Vascular peptide endothelin-1 links fat accumulation with alterations of visceral adipocyte lipolysis.
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.


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.
van Harmelen
Vanessa
V
Karolinska Institutet, Department of Medicine, M63, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden.
Eriksson
Anna
A
Aström
Gaby
G
Wåhlén
Kerstin
K
Näslund
Erik
E
Karpe
Fredrik
F
Frayn
Keith
K
Olsson
Tommy
T
Andersson
Jonas
J
Rydén
Mikel
M
Arner
Peter
P
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D017667:Adipocytes / Q000502:physiology*; D000328:Adult; D000368:Aged; D015992:Body Mass Index; D019332:Endothelin-1 / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008066:Lipolysis; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000503:physiopathology*; D034622:RNA Interference; D012016:Reference Values
D048868:Adaptor Proteins, Signal Transducing; D019332:Endothelin-1; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins