Sun Shuoshuo, Zhang Ruixiang, Chen Yu, Xu Yijiao, Li Xingjia, Liu Chao, Chen Guofang, Wei Xiao
Department of Endocrinology, Affiliated Hospital of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People's Republic of China.
Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, People's Republic of China.
Nutr Metab (Lond). 2024 May 27;21(1):30. doi: 10.1186/s12986-024-00803-1.
Weight regain after weight loss is a challenge in obesity management. The metabolic changes and underlying mechanisms in obese people with weight fluctuation remain to be elucidated. In the present study, we aimed to profile the features and clinical significance of liver transcriptome in obese mice with weight regain after weight loss.
The male C57BL/6J mice were fed with standard chow diet or high-fat diet (HFD). After 9 weeks, the HFD-induced obese mice were randomly divided into weight gain (WG), weight loss (WL) and weight regain (WR) group. After 10 weeks of dietary intervention, body weight, fasting blood glucose (FBG), intraperitoneal glucose tolerance, triglycerides (TG), total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C) were measured. Morphological structure and lipid droplet accumulation in the liver were observed by H&E staining and oil red O staining, respectively. The liver transcriptome was detected by RNA sequencing. Protein expressions of liver cytochrome P450 3a11 (Cyp3a11) and E4 promoter-binding protein 4 (E4bp4) were determined by Western blot.
After 10 weeks of dietary intervention, the body weight, FBG, glucose area under the curve, T-CHO and LDL-C in WL group were significantly lower than those in WG group (P < 0.05). At 4 weeks of HFD re-feeding, the mice in WR group presented body weight and T-CHO significantly lower than those in WG group, whereas higher than those in WL group (P < 0.05). Hepatic vacuolar degeneration and lipid droplet accumulation in the liver were significantly alleviated in WL group and WR group, compared to those in WG group. The liver transcriptome associated with lipid metabolism was significantly altered during weight fluctuation in obese mice. Compared with those in WG group, Cyp3a11 in the liver was significantly upregulated, and E4bp4 was significantly downregulated in WL and WR groups.
Obese mice experience weight regain after weight loss by HFD re-feeding, but their glucose and lipid metabolism disorders are milder than those induced by the persistence of obesity. Downregulated E4bp4 and upregulated Cyp3a11 are detected in obese mice after weight loss, suggesting that the E4bp4-Cyp3a11 axis may involved in metabolic mechanisms underlying weight regulation.
体重减轻后的体重反弹是肥胖管理中的一项挑战。体重波动的肥胖人群的代谢变化及潜在机制仍有待阐明。在本研究中，我们旨在剖析体重减轻后体重反弹的肥胖小鼠肝脏转录组的特征及临床意义。
将雄性C57BL/6J小鼠分为标准饲料组和高脂饮食（HFD）组。9周后，将高脂饮食诱导的肥胖小鼠随机分为体重增加（WG）组、体重减轻（WL）组和体重反弹（WR）组。经过10周的饮食干预后，测量体重、空腹血糖（FBG）、腹腔葡萄糖耐量、甘油三酯（TG）、总胆固醇（T-CHO）和低密度脂蛋白胆固醇（LDL-C）。分别通过苏木精-伊红（H&E）染色和油红O染色观察肝脏的形态结构和脂滴积累情况。通过RNA测序检测肝脏转录组。通过蛋白质免疫印迹法测定肝脏细胞色素P450 3a11（Cyp3a11）和E4启动子结合蛋白4（E4bp4）的蛋白表达。
经过10周的饮食干预后，WL组的体重、FBG、葡萄糖曲线下面积、T-CHO和LDL-C均显著低于WG组（P < 0.05）。在重新给予高脂饮食4周时，WR组小鼠的体重和T-CHO显著低于WG组，但高于WL组（P < 0.05）。与WG组相比，WL组和WR组肝脏中的肝空泡变性和脂滴积累明显减轻。肥胖小鼠体重波动期间，与脂质代谢相关的肝脏转录组发生了显著变化。与WG组相比，WL组和WR组肝脏中的Cyp3a11显著上调，E4bp4显著下调。
高脂饮食重新喂养后，肥胖小鼠体重减轻后会出现体重反弹，但其糖脂代谢紊乱程度比持续肥胖引起的要轻。体重减轻后的肥胖小鼠中检测到E4bp4下调和Cyp3a11上调，提示E4bp4-Cyp3a11轴可能参与体重调节的代谢机制。
