BAT Transcriptomics in DIO Vehicle or Cotadutide Mice

Early drivers of Type 2 diabetes mellitus (T2D) include ectopic fat accumulation, especially in the liver, that significantly impairs insulin sensitivity. In a T2D setting, GLP-1R/GCGR dual agonists have been shown to reduce glycaemia, body weight and hepatic steatosis. We utilized cotadutide, a well characterized GLP-1R/GCGR dual-agonist, to demonstrate improved insulin sensitivity during hyperinsulinemic euglycemic clamp following sub-chronic dosing in male, diet-induced obese mice. Cotadutide or GCGR monoagonist treatment resulted in specific increased brown adipose tissue (BAT) insulin-stimulated glucose uptake, while GLP-1R monoagonist only showed a weak effect. BAT from cotadutide treated mice had induction of UCP-1 protein, increased mitochondrial area and a transcriptomic profile of increased fat oxidation and mitochondrial activity. Thus, GLP-1R/GCGR dual agonism provides multimodal efficacy to decrease hepatic steatosis and consequently improve insulin sensitivity, in concert with recovery of endogenous ß-cell function and reduced insulin demand. This substantiates GLP-1R/GCGR dual-agonism as a novel and effective T2D treatment. Overall design: To investiagate the mechanistic impact of cotadutide treatment on brown adipose tissue (BAT), we condcuted RNA-sequencing on BAT from diet-induced obese (DIO) mice treated with vehicle or cotadutide (n=4-5 mice per group) to determine differentially expressed genes.

2型糖尿病（Type 2 diabetes mellitus, T2D）的早期致病因素包括异位脂肪堆积，尤以肝脏异位脂肪堆积最为显著，可显著损伤胰岛素敏感性。在T2D模型中，胰高血糖素样肽-1受体/胰高血糖素受体双重激动剂（GLP-1R/GCGR dual agonists）已被证实可降低血糖、减轻体重并改善肝脂肪变性。本研究使用表征充分的科他鲁肽（cotadutide）——一种胰高血糖素样肽-1受体/胰高血糖素受体双重激动剂，证实了在雄性饮食诱导肥胖小鼠中，经亚慢性给药后，高胰岛素正糖钳夹试验（hyperinsulinemic euglycemic clamp）中胰岛素敏感性得到改善。科他鲁肽或胰高血糖素受体单激动剂（GCGR monoagonist）处理可特异性增强棕色脂肪组织（BAT）的胰岛素刺激葡萄糖摄取，而胰高血糖素样肽-1受体单激动剂（GLP-1R monoagonist）仅表现出微弱效果。经科他鲁肽处理的小鼠的棕色脂肪组织中，解偶联蛋白1（UCP-1）蛋白表达上调，线粒体面积增加，且呈现脂肪氧化增强与线粒体活性提升的转录组特征（transcriptomic profile）。综上，胰高血糖素样肽-1受体/胰高血糖素受体双重激动可通过多模态作用机制改善肝脂肪变性，进而提升胰岛素敏感性，同时伴随内源性β细胞功能恢复与胰岛素需求降低。这证实胰高血糖素样肽-1受体/胰高血糖素受体双重激动是一种全新且有效的T2D治疗手段。总体实验设计：为探究科他鲁肽处理对棕色脂肪组织（BAT）的机制性影响，我们对溶剂对照组或科他鲁肽处理组的饮食诱导肥胖（DIO）小鼠的棕色脂肪组织进行RNA测序（RNA-sequencing），每组各4-5只小鼠，以鉴定差异表达基因（differentially expressed genes）。