TSHR调节胰岛素受体通路活性介导TSH参与肝脏胰岛素信号转导的机制

Epidemiological evidence indicates that thyroid stimulating hormone (TSH) is positively correlated with insulin resistance. High level of serum TSH led to abnormal glucose level. These phenomena suggested that TSH could independently regulate glucose metabolism, whereas the mechanisms were unclear yet. We previously reported that TSH existed in liver tissue, which could regulate lipid and cholesterol metabolism. However, as the most important glucose metabolism organ, the exact roles of TSH regulating glucose pathway were still not clear in liver. We previously reported that abnormal glucose level decreased in TSHR-knockout mice, whereas no study was carried out to demonstrate the mechanism of TSH regulating insulin pathway. As a member of G protein coupled receptor family, it was reported that TSHR can physiologically cooperate with RTKs in many tissues. In this study, the function of TSHR regulated insulin receptor in liver insulin pathway was discussed. The influences of TSHR to insulin pathway and glucose metabolism were evaluated. The molecules participating in the relationship between TSHR and insulin receptor were identified, and the influences of these molecules to insulin pathway and glucose metabolism were discussed. This research may provide theoretical basis for the relationship between subclinical hypothyroidism (SCH) and insulin resistance, and new therapeutic strategies to improve insulin sensitivity in SCH patients.

流行病学资料显示亚临床甲状腺功能减退与胰岛素抵抗有相关性。血清TSH升高导致糖代谢紊乱，提示TSH可能独立参与血糖调节，但具体机制并不明确。本课题组前期证实肝脏存在功能性TSHR，在肝脏脂肪、胆固醇代谢中起调节作用。然而，肝脏作为最重要的糖代谢器官，其TSHR对糖代谢的调控机制鲜有报道。本课题组前期研究发现，TSHR缺失小鼠肝脏糖代谢紊乱，血糖水平降低。但TSHR对肝脏胰岛素信号通路的调节机制未见报道。TSHR作为G蛋白偶联受体家族成员，其与酪氨酸激酶受体有生理功能和分子水平的相互作用，但在肝脏中并无明确报道。本课题拟在动物模型以及细胞水平上，开展TSHR调节Insulin R参与肝脏胰岛素信号通路的机制研究。评估TSHR对胰岛素代谢的影响。鉴定肝脏中介导TSHR调节胰岛素受体活性的信号分子种类，探讨其对胰岛素通路的影响。为降低亚甲减患者的胰岛素抵抗患病风险提供理论依据和可能的治疗思路。

亚临床甲状腺功能减退症（Subclinical hypothyroidism, SCH）表现为促甲状腺激素（Thyroid Stimulating Hormone, TSH）升高，甲状腺激素（Thyroid Hormone, TH）在正常范围。流行病学资料显示亚临床甲状腺功能减退与胰岛素抵抗（Insulin Resistance, IR）有相关性。血清TSH升高导致糖脂代谢紊乱，提示TSH可能独立参与糖脂代谢调节。本课题组首先在临床流行病调查数据中发现，胰岛素水平与肝脏脂代谢异常、非酒精性脂肪肝（NAFLD）患病率成正相关，提示胰岛素可能是NAFLD的独立危险因素。具体分子机制未知。. 本课题组通过高脂饮食（High Fat Diet, HFD）喂养组学筛选以及分子生物学验证，鉴定到了一个关键蛋白WDR6，发现其能够参与肝脏糖脂代谢。进一步研究发现，TSH、胰岛素都可以调节WDR6的水平。目前针对WDR6的了解较少，在代谢领域罕有报道。本研究对WDR6进行初步了解，并对其在肝脏中参与糖脂代谢的分子机制进行了探索，发现WDR6主要分布于细胞质中，能够影响细胞能量感应器AMPK 磷酸化水平，进而影响肝脏甘油三酯合成途径相关分子，并能通过影响内质网应激关键分子BIP的蛋白水平，调节内质网应激，参与肝脏脂质沉积。TSH能够调节WDR6的水平，TSHR敲除小鼠肝脏WDR6明显降低，WDR6敲减的HepG2细胞对TSH的响应能力下降。另外，在IR状态下，胰岛素调节糖代谢能力降低，但是仍能依赖于WDR6，调节脂代谢。. 本项目明确了一个新的参与肝脏脂代谢的关键调节分子WDR6。WDR6能够响应TSH、Insulin的调节，并且在胰岛素抵抗条件下，介导胰岛素调节肝脏脂代谢。我们的研究目前明确了TSH和胰岛素能够共同作用于WDR6，从而参与胰岛素抵抗条件下的肝脏糖脂代谢。