Synthetic small molecule analogues of the immunomodulatory Acanthocheilonema viteae product ES-62 promote metabolic homeostasis during obesity in a mouse model
Synthetic small molecule analogues of the immunomodulatory Acanthocheilonema viteae product ES-62 promote metabolic homeostasis during obesity in a mouse model
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DOI：
10.1016/j.molbiopara.2019.111232
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发表时间：
2019-12-01
影响因子：
1.5
通讯作者：
Harnett, William
中科院分区：
文献类型：
--
作者：
Lumb, Felicity E.;Crowe, Jenny;Harnett, William
肥胖是人类公共卫生问题中增长最快的问题之一，其后遗症与2型糖尿病一样，代表着不断恶化的终生疾病。在过去的15年里，数据开始来自人类，更频繁地是来自老鼠的研究，支持寄生虫感染可以预防这种情况的想法。因此，我们研究了抗炎刺五加线虫ES-62产物的两个合成小分子类似物(SMA)在高热量饮食诱导的肥胖C57BL/6J小鼠模型中预防代谢功能障碍的潜力。我们发现，在持续暴露于高卡路里饮食(HCD)前一周开始，每周皮下注射SMA(各1微克)，可降低空腹血糖水平，并逆转在暴露于HCD后约7周和13周时观察到的雄性小鼠葡萄糖清除受损的情况。当在HCD开始13周后给予SMA治疗时，喂食HCD约38周的雄性小鼠的空腹血糖水平也降低了，这表明SMA治疗潜力。在大多数情况下，在雌性小鼠身上没有观察到保护作用。SMA治疗对回肠绒毛长度缩短和肝纤维化均有保护作用，但对雌性小鼠的保护作用更明显。先前对小鼠的研究表明，对代谢功能障碍的保护通常与免疫系统朝着2型/抗炎方向的两极分化有关，但我们试图将改善的代谢参数与这种变化联系起来的尝试失败了。因此，需要进一步分析，以确定行动机制。然而，总体而言，我们的数据清楚地表明，类药物SMA作为预防或治疗与肥胖相关的代谢紊乱的潜力。
One of the most rapidly increasing human public health problems is obesity, whose sequelae like type-2 diabetes, represent continuously worsening, life-long conditions. Over the last 15 years, data have begun to emerge from human and more frequently, mouse studies, that support the idea that parasitic worm infection can protect against this condition. We have therefore investigated the potential of two synthetic small molecule analogues (SMAs) of the anti-inflammatory Acanthocheilonema viteae product ES-62, to protect against metabolic dysfunction in a C57BL/6 J mouse model of high calorie diet-induced obesity. We found weekly subcutaneous administration of the SMAs in combination (1 mu g of each), starting one week before continuous exposure to high calorie diet (HCD), decreased fasting glucose levels and reversed the impaired glucose clearance observed in male mice, when measured at approximately 7 and 13 weeks after exposure to HCD. Fasting glucose levels were also-reduced in male mice fed a HCD for some 38 weeks when given SMA-treatment 13 weeks after the start of HCD, indicating an SMA-therapeutic potential. For the most part, protective effects were not observed in female mice. SMA treatment also conferred protection against each of reduced ileum villus length and liver fibrosis, but more prominently in female mice. Previous studies in mice indicate that protection against metabolic dysfunction is usually associated with polarisation of the immune system towards a type-2/anti-inflammatory direction but our attempts to correlate improved metabolic parameters with such changes were unsuccessful. Further analysis will therefore be required to define mechanism of action. Nevertheless, overall our data clearly show the potential of the drug-like SMAs as a preventative or treatment for metabolic dysregulation associated with obesity.