Tong Dan, Xiang Jie, Liu Wei, Sun Fang, Wang Lijuan, Mou Aidi, Cao Tingbing, Zhou Qing, You Mei, Liao Yingying, Gao Peng, Liu Daoyan, Lu Zongshi, Zhu Zhiming
Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing, China.
Diabetol Metab Syndr. 2024 Feb 1;16(1):33. doi: 10.1186/s13098-024-01270-7.
Roux-en-Y gastric bypass (RYGB) surgery is an effective metabolic surgery against diabetes and obesity. Clinical evidence indicates that patients with severe obesity have a poor curative effect in losing weight if they suffer from leptin or its receptor deficiency, but the underlying mechanism remains elusive. Here, we investigated the effect of leptin receptor deficiency on metabolic dysfunction in db/db mice treated by RYGB surgery.
The db/db mice and their heterozygote control db/m mice were subjected to RYGB or sham surgery. Body weight, blood glucose, food intake and glucose tolerance were evaluated. Micro-PET/CT and histological analysis were performed to examine the glucose uptake of tissues and the fat changes in mice. The key factors in glucose and fatty acid metabolism were detected by western blot analysis.
Compared with the sham group, the db/db mice in the RYGB group showed more significant weight regain after surgical recovery and improvement in hyperinsulinemia and glucose tolerance. However, the total body fat and multiple organ lipid deposition of RYGB-treated db/db mice was increased. The underlying mechanism studies suggested that the activation of AMPK regulated GLUT4 to increase glucose uptake, but AMPK could not promote fatty acid oxidation through the JAK2/STAT3 pathway under leptin receptor deficiency in db/db mice.
We conclude that leptin receptor deficiency impedes the AMPK activation-mediated fat catabolism but does not affect AMPK-related glucose utilization after metabolic surgery in db/db mice. This result helps select surgical indications for patients with obesity and diabetes.
Roux-en-Y胃旁路术（RYGB）是一种治疗糖尿病和肥胖症的有效代谢手术。临床证据表明，重度肥胖患者若患有瘦素或其受体缺乏症，减肥疗效较差，但其潜在机制仍不清楚。在此，我们研究了瘦素受体缺乏对接受RYGB手术的db/db小鼠代谢功能障碍的影响。
对db/db小鼠及其杂合子对照db/m小鼠进行RYGB手术或假手术。评估体重、血糖、食物摄入量和葡萄糖耐量。进行Micro-PET/CT和组织学分析，以检测小鼠组织的葡萄糖摄取和脂肪变化。通过蛋白质免疫印迹分析检测葡萄糖和脂肪酸代谢的关键因子。
与假手术组相比，RYGB组的db/db小鼠术后恢复后体重反弹更显著，高胰岛素血症和葡萄糖耐量得到改善。然而，接受RYGB治疗的db/db小鼠的全身脂肪和多器官脂质沉积增加。潜在机制研究表明，AMPK的激活调节GLUT4以增加葡萄糖摄取，但在db/db小鼠瘦素受体缺乏的情况下，AMPK不能通过JAK2/STAT3途径促进脂肪酸氧化。
我们得出结论，瘦素受体缺乏会阻碍AMPK激活介导的脂肪分解代谢，但不影响db/db小鼠代谢手术后AMPK相关的葡萄糖利用。这一结果有助于为肥胖和糖尿病患者选择手术适应症。
