TGR5在长期热量限制小鼠棕色脂肪T3转换下降和体重反弹中的作用

Caloric restriction is an important way for treatment of metabolic diseases and weight loss. However, most patients may manifested with reduced triiodothyronine (T3), weight loss plateau, or even weight regain during long-term calorie restriction. The underlying mechanism of this phenomenon is unknown. Studies show that calorie restriction induced downregulation of type 2 deiodinase (D2) and inhibition of T4 conversion to T3 are the main reasons for T3 decrease. G protein-coupled receptor for bile acids (TGR5) has been proved to be involved in energy metabolism regulation. Recent studies suggest that TGR5 induced the expression of D2 in brown adipose tissue. Our previous studies also found that the expression of TGR5 in brown adipose tissue decreased significantly in mice under long-term caloric restriction. However, whether the decrease of TGR5 is a key factor for T3 reduction and whether it has an impact on weight regain under long-term calorie restriction, are need further exploration. Here we will use in vivo transfection of TGR5 gene, high bile acid diet to intervene long-term caloric restriction mice, observe the expression of TGR5, D2 and intracellular T3 in brown adipose tissue, detect thyroid function, the content and activity of brown adipose tissue during different period of calorie restriction. The results will explore the role of TGR5 in calorie restriction, and may provide the potential target for prevention of weight regain during long-term calorie restriction.

热量限制是减重和治疗代谢性疾病的重要途径。然而，长期热量限制患者常出现T3水平降低、减重进入平台期，甚至体重反弹的现象，其机制不明。研究表明，热量限制所致脱碘酶D2表达下调、抑制T4向T3转换，是T3水平下降的主要原因。胆汁酸受体TGR5因具能量代谢调控功能，是目前研究的热点。新近研究提示，TGR5可诱导棕色脂肪D2表达。课题组前期研究发现，长期热量限制小鼠棕色脂肪TGR5表达明显下降，但其是否系长期热量限制所致T3降低的关键因素，是否对体重反弹产生影响，则需进一步探索。我们拟分别采用活体转染TGR5受体基因、高胆汁酸饮食等方式干预长期热量限制的肥胖小鼠，观察热量限制不同时期，小鼠棕色脂肪TGR5、D2和胞内T3的表达，甲状腺功能改变，以及棕色脂肪含量及活性的变化。从而明确TGR5在热量限制中所起的作用，为长期热量限制所致T3减低、体重反弹提供干预靶点。

热量限制是减重和治疗代谢性疾病的重要途经。然而，热量限制调节体重和能量代谢的机制，尤其是长期热量限制与体重调节的关系，尚未完全阐明。本项目采用高脂喂养的C57BL/6J小鼠造成肥胖模型，给予肥胖小鼠75%热量限制（限食）3月，观察限食对小鼠生长体重、糖脂代谢、代谢率的影响，分析其对能量调节相关因素甲状腺功能、棕色脂肪活性和分布、脂肪细胞D2和TRβ表达的影响。进一步通过体内动物实验和体外细胞实验，初步分析胆汁酸-TGR5通路在限食调节体重和能量代谢变化中的作用。结果显示，高脂饮食诱导小鼠体重增加，糖脂代谢紊乱，基础代谢率下降；限食可降低肥胖小鼠的体重，提高基础代谢率，纠正高脂诱导的肥胖小鼠代谢紊乱状态，其代谢改善效应可能与胆汁酸-TGR5表达增加，上调棕色脂肪、腹部皮下及附睾白色脂肪Dio2、UCP1等的表达，促进机体产热有关。研究证实，胆汁酸干预可模拟限食干预的减重及代谢改善效应。本课题研究结果为明确限食的代谢改善效应及其机制提供了重要的理论基础，为限食后体重动态变化（减重-平台-反弹）提供了宝贵的前期基础，对肥胖等代谢性疾病人群的健康防治具有重要意义。