Genetic variance and lipolysis regulation: implications for obesity.
Catecholamines are the major lipolytic hormones in human fat cells, and lipolytic catecholamine resistance is described in obesity. Studies on twins and in rare genetic disorders suggest a strong heredity component of catecholamine-induced lipolysis. Polymorphisms in catecholamine receptor signalling pathways have been described, several of which associate with obesity. Many polymorphisms in adrenoceptor genes are functional in transfected cell lines. The importance of polymorphisms in catecholamine signalling pathways for lipolysis regulation is discussed. A Trp64Arg polymorphism in the beta3-receptor, which associates with obesity, is accompanied by changes in lipolytic sensitivity of the receptor in human fat cells. Similarly, a Gln16Glu and an Arg164Ile variation in the beta2-adrenoceptor cause marked variations in the lipolytic sensitivity of this receptor in human adipocytes. Furthermore, beta2-adrenoceptor gene polymorphisms associate with obesity. A dinucleotide (CA) intron repeat in hormone-sensitive lipase gene is linked to obesity and markedly decreases the ability of catecholamines to activate the lipase and thereby lipolysis in human fat cells. However, an Arg389Gly polymorphism in the beta1-adrenoceptor, which alters receptor function in transfected cell lines, has no effect on lipolysis in human fat cells and is not associated with obesity. Thus, polymorphism in human genes that are involved in catecholamine signal transduction have effects on fat cell lipolysis and also relate to obesity. The lipolysis effects of these polymorphisms cannot always be predicted from gene transfer experiments on artificial cell lines. It is possible that genetic variance in catecholamine signalling pathways, through alterations in adipocyte lipolysis, may promote obesity.
Arner
P
P
Department of Medicine, Karolinska Institute at Huddinge University Hospital, Stockholm, Sweden. peter.arner@medhs.ki.se
D017667:Adipocytes / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics; D008049:Lipase / Q000235:genetics; D008066:Lipolysis / Q000235:genetics*; D009765:Obesity / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011943:Receptors, Adrenergic, beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
D002395:Catecholamines; D007328:Insulin; D011943:Receptors, Adrenergic, beta; D008049:Lipase