PDF(Pubmed)
Abstract：
Semaglutide is an anti-diabetes and weight loss drug that decreases food intake, slows gastric emptying, and increases insulin secretion. Patients begin treatment with low-dose semaglutide and increase dosage over time as efficacy plateaus. With increasing dosage, there is also greater incidence of gastrointestinal side effects. One reason for the plateau in semaglutide efficacy despite continued low food intake is due to compensatory actions whereby the body becomes more metabolically efficient to defend against further weight loss. Mitochondrial uncoupler drugs decrease metabolic efficiency, therefore we sought to investigate the combination therapy of semaglutide with the mitochondrial uncoupler BAM15 in diet-induced obese mice. Mice were fed high-fat western diet (WD) and stratified into six treatment groups including WD control, BAM15, low-dose semaglutide without or with BAM15, and high-dose semaglutide without or with BAM15. Combining BAM15 with either semaglutide dose decreased body fat and liver triglycerides, which was not achieved by any monotherapy, while high-dose semaglutide with BAM15 had the greatest effect on glucose homeostasis. This study demonstrates a novel approach to improve weight loss without loss of lean mass and improve glucose control by simultaneously targeting energy intake and energy efficiency. Such a combination may decrease the need for semaglutide dose escalation and hence minimize potential gastrointestinal side effects.
摘要：
塞马鲁肽是一种抗糖尿病和减肥药，可减少食物摄入，减缓胃排空，并增加胰岛素分泌。患者开始使用低剂量司马鲁肽治疗，并随着疗效稳定而随时间增加剂量。随着剂量的增加，胃肠道副作用的发生率也更高。尽管持续的低食物摄入，司马鲁肽功效仍处于平稳状态的一个原因是由于代偿作用，从而使身体在代谢上变得更有效，以防御进一步的体重减轻。线粒体解偶联剂药物降低代谢效率，因此,我们试图在饮食诱导的肥胖小鼠中研究司马鲁肽与线粒体解偶联剂BAM15的联合治疗.小鼠饲喂高脂肪西方饮食（WD），并分为6个治疗组，包括WD对照组，BAM15，不含或含BAM15的低剂量司马鲁肽，不含或含BAM15的高剂量司马鲁肽。BAM15与司马鲁肽剂量联合使用可降低体脂和肝脏甘油三酯，这不是通过任何单一疗法实现的，而高剂量司马鲁肽和BAM15对葡萄糖稳态的影响最大。这项研究证明了一种新颖的方法，可以通过同时针对能量摄入和能量效率来改善体重减轻而不损失瘦体重并改善葡萄糖控制。这样的组合可以减少对司马鲁肽剂量递增的需要,并因此使潜在的胃肠道副作用最小化。
