The Role of Autophagy in Adipocyte Browning of Combination With α-lipoic acid and Genistein in Ovariectomy-Induced Obesity in Rats

• Main Authors: TSAI, PEI-FANG, 蔡佩芳
• Other Authors: SHEN, HSIN-HSUEH
• Format: Others
• Language: zh-TW
• Published: 2019
• Online Access: http://ndltd.ncl.edu.tw/handle/jksbh9

碩士 === 國防醫學院 === 藥理學研究所 === 107 === Estrogen deficiency caused by menopause increases the incidence of obesity, leading to insulin resistance, type 2 diabetes, and metabolic syndromes. Obesity is characterized by increased white adipose tissue mass and has been associated with chronic low-grade inflammatory responses. WAT can not only store fat, but secrete many adipokinses, such as leptin and adiponectin. The main function of leptin is to regulate appetite and food intake by hypothalamus, which is positively correlated with obesity. In obese condition, WAT secretes leptin to reduce energy intake, and finally leads to excessive leptin secretion and leptin resistance. Moreover, the main function of adiponectin is to regulate glucose balance and fatty acid decomposition. In recent years, it has been found that development of beige adipocytes (browning of WAT) can increase energy expenditure and be used for obesity management. In the process of WAT browning, it is regulated by many regulatory factors, such as uncoupling protein-1 (UCP-1), PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16), peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and cell death-inducing DNA fragmentation factor A (DFFA)-like effector α (CIDEA). It is reported that inhibition of autophagy promotes beige adipocytes formation. There are a number of regulatory factors that are involved in the regulation of autophagy, such as the mammalian target of rapamycin (mTOR), Beclin1, microtubule-associated protein 1 light chain 3 (LC3) and p62/sequestosome-1 (SQSTM1). α-lipoic acid (ALA) is a disulfide derivative of octanoic acid which serves as an antioxidant and exerts anti-obesity properties. Studies have shown that ALA can improve obesity and its associated diseases, such as fatty liver, insulin resistance and type 2 diabetes, by increasing WAT browning to promote the heat production of adipose tissue. Phytoestrogen genistein (GEN) is structural and functional mimic to estrogen and exerts both ER agonistic or antagonistic activity. GEN also possesses anti-obesity capacity during estrogen deficiency. Previous study in our laboratory has demonstrated that chronic treatment of ALA 200 mg/kg or GEN 30 mg/kg showed improvement of estrogen deficiency-induced obesity, respectively. The aim of this study is to investigate whether combination of ALA and GEN (AG) with half dose (ALA 100mg/kg and GEN 15mg/kg) produces additional effect on estrogen deficiency-induced obesity and further explored its underlying mechanism. Results showed administration of AG reduced OVX-induced body weight gain and adiposity as well as improved glucose intolerance. AG decreased plasma levels of leptin and increased plasma levels of adiponectin. AG prevented adipocyte hypertrophy and enhanced IRS1, p-AKT and Glut4 protein expression in retroperitoneal WAT. In 3T3-L1 adipocytes, AG reduced lipid accumulation and enhanced p-IRS1 and Glut4 protein expression. In addition, AG induced WAT browning by elevating UCP-1, PRDM16, PGC-1α and CIDEA protein expression in inguinal WAT and 3T3-L1 adipocytes. This browning effect of WAT by AG may result from inhibition of autophagy, evidenced by down-regulation Beclin1 and LC3 and increased p-mTOR and p62/SQSTM1 in vivo and in vitro. Thus, combination of AG may reduce adverse effects and provide a promising approach to prevent estrogen deficiency-induced obesity.