TSH受体在脂毒性诱发甲状腺TSH抵抗中的作用及机制

Elevated serum TSH levels are often found in metabolic syndrome or obesity patients. We also noticed a decreased TSH level among those who underwent a weight-loss surgery with declined postoperative serum triglyceride levels. In those patients, TSH resistance may also exist except for insulin resistance, causing a compensatory increase in serum TSH levels. Notably, no studies have been reported to date regarding the relationship between lipotoxicity and TSH resistance. A large-scale epidemiological survey conducted by us found that hypertriglyceridemia can increase the risk of hypothyroidism. We also found that in the rat fed with high-fat (lard) diet, the triglycerides and free fatty acid (FFA) deposited in the thyroid, serum thyroid hormone (TT4) levels were significantly reduced, and free fatty acid levels were negatively correlated with TT4, which suggested that high-fat diet can induce the occurrence of hypothyroidism. Based on our previous study, we mainly focuse on the effect of lipotoxicity induced by high triglyceride on the occurrence of hypothyroidism here, using in vitro (FFA treated thyroid cells and interference, blocking or activate the expression of key molecules, etc.) and in vivo (high-fat diet, conditional knockout of thyroid gene, drug intervention and other animal models) experiments, we will demonstrate the effect of TSHR functional deficiency in TSH resistance induced by lipotoxicity, elucidate the regulatory pathways and key molecular, clarify the patho-physiological changes that lipotoxicity induced hypothyroidism, which will reveal the pathogenesis of hypothyroidism and further provide newly evidence for its prevention and treatment strategies.

代谢综合征或肥胖症患者常伴有血清TSH水平升高，减重手术后血清甘油三酯水平下降，TSH水平也随之下降。就像存在胰岛素抵抗一样，这类患者也可能存在TSH抵抗，引起TSH水平代偿性升高。脂毒性是否诱发TSH抵抗国内外未见报道。本课题组大规模流行病学调查发现，血甘油三酯与TSH水平显著正相关；基础研究证实，高脂（猪油）喂养的大鼠甲状腺内甘油三酯、游离脂肪酸沉积，血TSH水平升高，TSH生物学效应降低，提示脂毒性与TSH抵抗密切关联。本项目在此基础上将以甲状腺TSH受体为切入点，在分子、细胞和整体三个水平，采用体外（游离脂肪酸处理甲状腺细胞及阻断或激活关键分子表达等）和体内（高脂饮食、条件性甲状腺基因敲除、药物干预等动物模型）相结合的策略，阐明脂毒性调控TSH受体表达的途径和关键分子，初步探讨TSH受体缺陷在脂毒性诱发TSH抵抗中的作用，为揭示亚甲减的发病机制及制订防治策略提供新的依据和思路。

代谢综合征或肥胖症患者常伴有血清TSH水平升高，而减重手术后血清甘油三酯水平下降，TSH水平也随之下降。就像存在胰岛素抵抗一样，这类患者也可能存在TSH抵抗，引起TSH水平代偿性升高。脂毒性诱发胰岛素抵抗在糖尿病的发生发展中具有重要作用，但脂毒性是否诱发TSH抵抗国内外未见报道。本课题组大规模流行病学调查发现，脂毒性增加亚甲减（TSH水平升高）的患病风险；基础研究证实，高脂（猪油）喂养的大鼠甲状腺内甘油三酯、游离脂肪酸沉积，血TSH水平升高，TSH生物学效应降低，提示脂毒性与TSH抵抗密切关联。该项目进一步研究证实：1.高脂饮食通过诱导内质网应激导致Tg下降和甲状腺功能减退;缓解内质网应激可改善高脂导致的Tg水平下降和甲状腺功能减退。2.高脂饮食导致甲状腺组织脂质谱的改变。3.应用MMI饮水喂养C57BL/6可以创立一种新型非侵入性、简单易行的SCH小鼠模型。4.伴着亚甲减的历程进展,经常会伴有脂代谢紊乱。在这个过程中,ER stress很可能发挥了重要的作用。5.纠正亚临床甲减的ER stress后,脂代谢紊乱得到明显改善。该项目共发表SCI论文15篇，获得国家发明专利2项，已转化。研究成果为揭示亚甲减的发病机制及制订防治策略提供新的依据和思路。