Gdf11 gene transfer prevents high fat diet-induced obesity and improves metabolic homeostasis in obese and STZ-induced diabetic mice
Gdf11 gene transfer prevents high fat diet-induced obesity and improves metabolic homeostasis in obese and STZ-induced diabetic mice
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Gdf11 基因转移可预防高脂饮食诱导的肥胖并改善肥胖和 STZ 诱导的糖尿病小鼠的代谢稳态
DOI：
10.1186/s12967-019-02166-1
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发表时间：
2019-12-17
影响因子：
7.4
通讯作者：
Zhang, Chunbo
中科院分区：
文献类型：
--
作者：
Lu, Bingxin;Zhong, Jianing;Zhang, Chunbo
背景：生长分化因子11(GDF11)具有逆转心肌细胞增龄性肥大的作用，被认为是一种延缓衰老的年轻化因子。GDF11在调节代谢动态平衡中的作用尚不清楚。在本研究中，我们研究了GDF11在调节代谢动态平衡和能量平衡中的作用。方法采用流体动力注射的方法，将携带小鼠Gdf11基因的载体导入小鼠体内，在小鼠肝脏中持续表达Gdf11，并在血液中表达Gdf11蛋白。采用高脂饮食(HFD)诱导的肥胖模型，观察Gdf11基因转移对HFD诱导的肥胖、高血糖、胰岛素抵抗和肝脂沉积的影响。采用高脂饮食诱导的肥胖和链脲佐菌素诱导的糖尿病模型，观察GDF11对肥胖和糖尿病小鼠代谢稳态的影响。结果Gdf11基因转移可减轻HFD诱导的肥胖、高血糖、胰岛素抵抗和脂肪肝的发生。在肥胖和STZ诱导的糖尿病小鼠中，Gdf11基因转移可以恢复葡萄糖代谢并改善胰岛素抵抗。机制研究表明，Gdf11基因转移增加了小鼠的能量消耗，上调了棕色脂肪组织中负责温度调节的基因的表达，下调了白色脂肪组织中炎症基因和参与肝脏脂肪和糖代谢的基因的表达。GDF11的过表达还激活了白色脂肪组织中的转化生长因子-β/Smad2、PI3K/AKT/FoxO1和AMPK信号通路。结论GDF11在调节代谢稳态和能量平衡方面具有重要作用，可作为药物干预治疗代谢性疾病的靶点。
Background The growth differentiation factor 11 (GDF11) was shown to reverse age-related hypertrophy on cardiomyocytes and considered as anti-aging rejuvenation factor. The role of GDF11 in regulating metabolic homeostasis is unclear. In this study, we investigated the functions of GDF11 in regulating metabolic homeostasis and energy balance. Methods Using a hydrodynamic injection approach, plasmids carrying a mouse Gdf11 gene were delivered into mice and generated the sustained Gdf11 expression in the liver and its protein level in the blood. High fat diet (HFD)-induced obesity was employed to examine the impacts of Gdf11 gene transfer on HFD-induced adiposity, hyperglycemia, insulin resistance, and hepatic lipid accumulation. The impacts of GDF11 on metabolic homeostasis of obese and diabetic mice were examined using HFD-induced obese and STZ-induced diabetic models. Results Gdf11 gene transfer alleviates HFD-induced obesity, hyperglycemia, insulin resistance, and fatty liver development. In obese and STZ-induced diabetic mice, Gdf11 gene transfer restores glucose metabolism and improves insulin resistance. Mechanism study reveals that Gdf11 gene transfer increases the energy expenditure of mice, upregulates the expression of genes responsible for thermoregulation in brown adipose tissue, downregulates the expression of inflammatory genes in white adipose tissue and those involved in hepatic lipid and glucose metabolism. Overexpression of GDF11 also activates TGF-beta/Smad2, PI3K/AKT/FoxO1, and AMPK signaling pathways in white adipose tissue. Conclusions These results demonstrate that GDF11 plays an important role in regulating metabolic homeostasis and energy balance and could be a target for pharmacological intervention to treat metabolic disease.