达乌尔黄鼠“健康肥胖”的血糖稳态及调控机理

Obesity increases the risk of type 2 diabetes and other metabolic disease. However, the development of diabetes in the obese is not inevitable. A population of the obese which we called ‘healthy obese individuals’ appears able to remain healthy and avoid most of the negative implications that obesity normally entails. Understanding why some people are able to avoid developing diabetes may provide valuable insights into both diseases and in particular provide novel routes for treatment. Progress however is hindered by the availability of a good animal model for this phenomenon. Previous study have shown that most rodents have an annual cycle of body weight change that reflects enormous changes in their levels of adiposity. For example, hibernating rodents (such as Daurian ground squirrels) accumulate adipose tissue in the Autumn. This state can be induced by endogenous annual rhythm independent of the diet or photoperiod. Using this animal it is therefore possible to produce obese or lean animals independent of feeding on high fat diets. We suggest that through millions of years of evolution it is likely that hibernation rodents have evolved mechanisms to cope with the negative sequalae of the obese state. Moreover the ability to independently manipulate obesity and diet provides a powerful tool for separating the effects of these factors on insulin resistance, hypertension and hepatic steatosis. In this study, we use Daurian ground squirrels as our obejects. These animals might be a valuable tool to explore ‘healthy obesity’. This application then is basically a proof of concept project to explore the ‘natural obesity’ in one species and to follow what the consequences of this obesity are for insulin resistance, glucose homeostasis and other features of the metabolic syndrome in the context of the lipotoxicity hypothesis. From which we can also deeply understand how ground squirrels can survive in a seasonal world.

肥胖增加了罹患糖尿病等代谢疾病的风险，但仍有部分“健康肥胖”个体能免受代谢疾病的威胁。冬眠动物经常表现出“自然肥胖”，很多冬眠动物在秋季的育肥期迅速积累脂肪。但是冬眠动物“自然肥胖”的发生过程具有明显的周期性，翌年春季动物体重可自发回复至正常状态。我们对黄鼠体重年周期变化过程中的血糖稳态及调控模式所知甚少。年周期性“自然肥胖”经过长期进化，是冬眠动物为适应季节性气候变化而产生的正常生理响应，或许是能免受相关代谢疾病影响的一个“健康肥胖”模型。本研究以达乌尔黄鼠为研究对象，通过内源性年节律的影响，可以诱导其发生“自然肥胖”。通过检测血糖耐受能力和胰岛素敏感性，可以确定“自然肥胖”是否为“健康肥胖”。确定“健康肥胖”表型后，研究黄鼠不同组织的脂质含量和分子表达，验证“脂毒性假说”，并且明确“健康肥胖”黄鼠维持血糖稳态的分子调控机制。从而阐明黄鼠适应严酷生境的生理策略，也为代谢疾病提供治疗手段。

项目背景：肥胖相关代谢疾病成为威胁人类健康的主要慢性疾病之一。肥胖人群中仍有少数“健康肥胖”人群并未表现出代谢综合征。很多野生哺乳动物经常表现出“自然肥胖”，达乌尔黄鼠就是一种典型贮脂类冬眠动物，在夏秋季大量积累白色脂肪组织。达乌尔黄鼠“自然肥胖”可能为人类“健康肥胖”的机理揭示提供重要的参考。.主要研究内容：1）为判断达乌尔黄鼠的“自然肥胖”是否为“健康肥胖”，我们在野外捕获达乌尔黄鼠，并将其在实验室中饲养，同时检测了不同育肥阶段动物的体重、身体成分、葡萄糖耐受性与胰岛素敏感性、主要代谢器官中粗脂肪含量及甘油三酯、胆固醇含量。2）为检测达乌尔黄鼠“自然肥胖”与高脂食物诱导肥胖之间的区别，我们选取快速育肥期的黄鼠，并分别用高脂食物和对照食物进行饲喂。在饲喂期间对体重、能量收支和血糖稳态进行测定。3）为深入研究育肥期黄鼠保持血糖稳态的具体机制，我们通过进一步实验比较了起始育肥期与完成育肥期黄鼠肝脏和肌肉中的代谢组及肠道中的微生物组。.重要结果：1）雌性达乌尔黄鼠体重和体脂在育肥期明显增加。在育肥过程中，黄鼠的葡萄糖耐受性和胰岛素敏感性未发生明显变化，其肝脏和肌肉的粗脂肪含量及甘油三酯、胆固醇含量均在育肥完成后恢复至与起始育肥期相同的水平。2）通过增加消化率和可代谢能效率，高脂食物饲喂的育肥期黄鼠能进一步增加体重。高脂食物饲喂后动物呼吸商降低，血糖耐受性降低，胰岛素敏感性不变。3）育肥完成后肝脏中的几种脂肪酸代谢产物有显著下调。血清中甘油和脂肪酸等则有显著上升。与育肥前期相比，育肥完成后共有33个属的微生物出现差异表达，表明育肥过程黄鼠肠道微生物群落发生了明显变化。.关键数据：血糖耐受性及胰岛素敏感性分析数据，代谢组学及微生物组学数据。.科学意义：“自然肥胖”的达乌尔黄鼠表现出“健康肥胖”的表型，对其机理的进一步揭示可能为人类代谢疾病的治疗提供重要参考。