The regulatory effect of endothelin-1 on adipogenesis and lipolysis

• Main Authors: Chih-Chan Lien, 連之嬋
• Other Authors: Chi-Chang Juan
• Format: Others
• Language: zh-TW
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/77589471164276871070

博士 === 國立陽明大學 === 生理學研究所 === 104 === Obesity, a state of pathological hyperplasia or/and hypertrophy of adipose tissue, may be caused by enhanced proliferation or/and differentiation abilities of preadipocytes or/and triglyceride accumulation in adipocytes. Through adipogenesis, the excessive energy can be stored in adipocytes, which is efficient to reduce blood glucose and lipids. But excessive lipid accumulation leads to adipocyte hypertrophy, which may subsequently induce adipose tissue inflammation and affect adipocytokine expression and secretion. On the other hand, lipolysis can provide energy to the body, but exaggerated lipolysis will increase plasma free fatty acid (FFA). Previous studies showed that adipose tissue inflammation and increased plasma FFA would increase the risks of cardiovascular disease, insulin resistance and diabetes. Therefore, understating the regulatory mechanisms of adipogenesis and lipolysis may provide a new concept of preventing and treating these diseases. Endothelin-1 (ET-1) is a potent vasoconstrictive peptide produced and secreted mainly by endothelial cells. Studies have demonstrated that in adipocytes, ET-1 possesses regulatory effects on glucose and free fatty acid uptake and it also affects leptin, resistin and adiponectin secretion and expression. These observations suggest that ET-1 may have the ability to regulate adipocyte physiology. In addition, ET-1 could inhibit adipocyte differentiation and induce lipolysis, but the underlying mechanisms are still unclear. Hence, in this study, we investigated the effects of ET-1 on adipogenesis and lipolysis. First, 3T3-L1 preadipocytes and Sprague-Dawley rats were used to explore the effect of ET-1 on adipogenesis and the underlying mechanisms. Results showed that ET-1 increased cell proliferation under preadipocyte and mitotic clonal expansion stages through PKC pathway. During differentiation, ET-1 inhibited the expressions of proadipogenic transcription factors (C/EBPα and PPARγ) and adipocyte marker (ALBP) and increased preadipocyte marker (Pref-1) expression partially through ERK signaling pathway. Results of in vivo study demonstrated that chronic ET-1 infusion did not affect fat pad weight but increased adipocyte number and decreased adipocyte size. Second, 3T3-L1 preadipocytes were used to explore the effects of ET-1 on lipolysis and the underlying mechanisms. Results showed that ET-1, via endothelin A receptor (ETAR), induced an increase in intracellular calcium through cGMP pathway, which subsequently activated ERK pathway and induced hormone sensitive lipase (HSL) phosphorylation and lipolysis. In vivo study also demonstrated that ET-1 treatment increased plasma FFA and glycerol. These findings suggested that elevated circulating ET-1 levels and nutrition overload might enhance adipogenesis, resulting in the development of obesity. Furthermore, high level of plasma ET-1 increased plasma FFA, which enhanced the risks of cardiovascular disease, insulin resistance and diabetes. The results of the present study provide evidence to support the hypothesis that the cardiovascular system manipulates adipose tissue development and lipid metabolism via vasoactive factors, such as ET-1.