The effects of endothelin-1 in human adipose tissue
Abstract: Obesity is a result of an imbalance between energy intake and energy expenditure ending in an excessive accumulation of body fat. Being overweight or obese increases the risk of death because of obesity related complications, e.g. insulin resistance, type 2 diabetes, cardiovascular diseases and some types of cancer. This multifactorial disease is influenced by both genetic and environmental factors and has already reached epidemic proportions. Adipose tissue serves as an energy reservoir and is very important in the regulation of energy homeostasis but it also acts as a secretory organ and as an active signaling tissue. The signaling molecules secreted by adipose tissue modulate metabolism and function of both adipose tissue and other organs in the body which can have a negative impact on health. Obesity and type 2 diabetes are also associated with increased levels of non-esterified fatty acids (NEFAs) in the circulation due to enhanced lipolysis (the enzymatic hydrolysis of triacylglycerides into NEFAs and glycerol). Growing evidence suggests that NEFAs are involved in mediating insulin resistance in these conditions, especially in abdominal obesity. Adipose tissue consists of several other cell types except adipocytes. It is a highly vascularised tissue and thus endothelial cells are present. They release the vascular peptide endothelin- 1 (ET-1), an extremely potent vasoconstrictor involved in the regulation of blood pressure but also a multifunctional peptide with cytokine-like activity that can affect several aspects of cell function with both positive and negative effects. A number of studies show that plasma levels of ET-1 are increased in insulin resistance, obesity and type 2 diabetes and that ET-1 might contribute to the development of several metabolic diseases. The majority of studies have concentrated on the role of ET-1 in glucose metabolism while studies assessing the role of ET-1 in lipid metabolism are lacking. The overall aim of this thesis was to study the effect of ET-1 in human adipose tissue. When the present project was started, there were no published studies regarding the role of ET-1 in affecting hormone-stimulated and/or basal lipolysis in human adipose tissue. We set out to study the effect of ET-1 in lipid metabolism in human adipocytes and to try to characterize the signaling pathway. In paper I, we investigated whether human adipose tissue releases the vascular peptide ET-1 and whether it could account for regional differences in the regulation of lipolysis. We confirm that ET-1 levels are increased in obese subjects and that subcutaneous (SC) adipose tissue contributes to an elevated release of ET-1 in vivo in the obese state. ET-1 also attenuates the antilipolytic effect of insulin in omental (OM) but not SC adipocytes after long-term treatment. Our study shows that ET-1 signals via the ETB-receptor (ETBR) and mediates its action by decreasing the protein expression and/or activity of several signaling proteins involved in the antilipolytic pathway of insulin. In paper II, we further investigated the regional expression and cellular origin of ET-1 and its receptors in adipose tissue and whether ET-1 has any effects on basal lipolysis. We observed that ET-1 expression was higher in SC compared to OM fat and that it is released from non-adipocytes within adipose tissue. ET-1 increases basal lipolysis in SC adipocytes after long-term treatment possibly through the ETA-receptor (ETAR) which was also shown to be increased at the protein levels in obese SC adipose tissue. In addition, the effect on basal lipolysis was positively correlated with BMI. In conclusion, ET-1 has a dual effect on lipolysis in adipocytes. In visceral adipocytes it promotes an insulin resistant state where insulin-mediated inhibition of hormone-stimulated lipolysis is attenuated via ETBR. Conversely, in SC cells, ET-1 increases basal lipolysis via ETAR. Both these effects result in an increased release of NEFAs from adipose tissue. It is quite possible that increased ET-1 release via these mechanisms could contribute to the development of insulin resistance and type 2 diabetes in obesity.
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