基于GH/IGF-1轴研究脂肪组织特异性敲除GHR基因对机体糖脂代谢的影响

Obesity, insulin resistance and metabolic syndromes are thought to be the result of a combination of genetic and environmental factors. Animal models which can show clinical features of these diseases are playing an important role in studying the development of pathogenesis. In addition to promoting the organism growth, growth hormone (GH) has effects on other important life process, including gene expression and protein synthesis in liver, lipid mobilization in metabolically active tissue and organs in response to insulin. GH/IGF-1 axis is widely involved in the glucose, lipid, protein and energy metabolism. However, the concrete regulation mechanisms of the fat tissue GH/IGF1 axis on organism glucose and lipid metabolism are still far from explicated. Using Cre/LoxP site-specific recombination enzyme system, we will construct a mouse model with the GH receptor specifically disrupted in fat tissue (Adipo-FAGHRKO) through crossing GHR-Flox mice with adiponectin-Cre transgenic mouse models. Adipo-FAGHRKO mice will be fed high-fat diet or stimulated by low temperature thereby to show the pathophysiologic process of metabolic syndrome such as obesity and diabetes. The aim of this project is not only to reveal the changes of GH/IGF1 axis signaling regulatory network on condition of the deletion of fat GHR gene together with environmental factors, but also reveal the possible mechanism of lipid metabolism, insulin response through cross-talk between GH and mTOR signal pathway. The results of our molecular, biochemical and genetic study will provide valuable theoretical basis for the developing of new drug therapy target and early diagnosis and treatment of obesity, fatty liver, diabetes and cancer caused by glucose and lipid metabolism disorder.

肥胖、胰岛素抵抗或代谢综合征的发生是遗传和环境因素共同作用的结果，构建较好展现这些疾病临床特征的动物模型是研究其发病机制的重要手段。生长激素不仅能促进机体生长，还调控蛋白质合成、代谢活跃组织中的脂肪动员及器官对胰岛素应答等重要生命过程。GH/IGF-1轴广泛参与机体糖、脂、蛋白和能量代谢过程，而其在脂肪组织中对糖脂代谢的具体调控机制还未完全明了。本研究基于Cre/LoxP组织特异性基因打靶技术，利用课题组前期构建的GHR-Flox小鼠与Adiponectin-Cre转基因小鼠杂交，产生脂肪特异性GHR基因敲除小鼠，利用该模型结合高脂饮食或低温刺激，全面展现肥胖、糖尿病等代谢疾病的病理过程，揭示脂肪GHR基因缺陷和环境因素共同作用时GH/IGF-1信号调控网络的变化，并通过研究GH与mTOR信号通路的相互影响揭示其可能的作用机制，为糖脂代谢紊乱相关疾病的新药物靶点开发和早期诊断提供新思路。

由脑垂体合成并分泌的生长激素（Growth Hormone，GH）通过与其受体（Growth hormone receptor，GHR）结合，在生长发育和代谢过程中发挥重要作用。已有研究者通过利用多种GHR基因全敲除或组织特异性敲除小鼠证明了GH/GHR功能紊乱不仅会导致生长发育缺陷，而且还可能与多种代谢紊乱相关疾病有关。本研究基于 Cre-LoxP技术，利用本实验室前期构建的 GHR-Flox小鼠和 Adipoq-Cre小鼠杂交，成功获得一种新型脂肪组织特异性敲除 GHR基因小鼠模型AdGHRKO，并研究了AdGHRKO小鼠在高脂饮食和寒冷环境刺激下的代谢适应性。我们的研究结果发现，脂肪GHR基因缺失可通过促进脂质合成和脂肪细胞分化而加速高脂饮食诱导的肥胖，但又可通过游离脂肪酸的捕获机制保护肝脏在高脂饮食条件下免受异位脂肪沉积的影响。此外我们还发现在脂肪组织特异性缺失GHR基因的情况下，低温诱导的棕色脂肪产热和白色脂肪棕色化过程受到抑制。我们的研究结果成功揭示了GH/IGF-1轴调控网络变化与机体糖脂代谢紊乱的关系及可能的作用机制，为糖脂代谢紊乱造成的肥胖、糖尿病、脂肪肝的早期诊断和治疗提供理论依据。