甲状腺激素通过调控棕色脂肪GDF15影响机体能量代谢的作用及机制探讨

甲状腺激素是维持基础代谢率的重要激素，生长分化因子15（GDF15）是调控代谢的重要分泌蛋白，两者均与能量代谢密切相关。近年来，随着对代谢调控网络认识的不断深入，发现甲状腺激素可通过分泌蛋白间接参与代谢的调控。我们前期研究发现，甲亢患者血清GDF15水平显著升高，治疗后明显下降；进一步在甲亢小鼠模型发现血清GDF15水平升高，棕色脂肪组织GDF15表达明显升高；体外实验结果表明，GDF15能增加棕色脂肪前体细胞增殖相关基因的表达、促进分化，并能提高成熟棕色脂肪细胞产热相关基因的表达。我们推测：甲状腺激素很可能通过调控棕色脂肪组织中的GDF15，促进棕色脂肪前体细胞的增殖、分化和棕色脂肪产热，进而影响全身的糖脂及能量代谢。本项目将综合运用人群队列，临床标本，模式动物，结合多种分子生物学手段，阐明棕色脂肪中GDF15在甲状腺激素主导的代谢调控网络中的重要作用，并为寻找肥胖防治的新靶点提供思路。

Thyroid hormone is a major regulator of basic metabolic rate, while growth differentiation factor (GDF15) is a secreted protein involved in metabolism, both of which are closely related to energy metabolism. In the past few years, with more understanding about the regulatory network of metabolism, it is increasingly recognized that thyroid hormone could indirectly get involved in metabolic control by influencing the production of certain secreted proteins. Our recent studies revealed elevated serum GDF15 levels in hyperthyroid patients, which lowered after normalization of thyroid status. This phenomenon was replicated in a hyperthyroid mouse model and dramatically elevated GDF15 transcription was observed in the brown adipose tissues. Ex vivo studies further indicated that GDF15 overexpression by lenti-virus transfection promoted the proliferation and differentiation of brown adipose progenitor cells, as well as the thermogenesis of differentiated brown adipocytes. We hypothesize that thyroid hormone might influence the whole body glycolipid and energy metabolism via regulating the production of GDF15 in brown adipocytes, promoting its progenitor proliferation, differentiation and thermogenesis. In this project, cohort study, clinical specimen, transgenic mouse models, and multiple molecular biological techniques will be utilized to delineate the role of GDF15 in a thyroid hormone-dominated regulatory network of metabolism, and also to identify novel targets for treating obesity.