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。