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-β/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.

中文翻译：

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Gdf11基因转移可防止高脂饮食诱导的肥胖症，并改善肥胖和STZ诱导的糖尿病小鼠的代谢稳态。

背景技术显示出生长分化因子11（GDF11）可逆转心肌细胞上与年龄有关的肥大，并被认为是抗衰老的年轻化因子。GDF11在调节代谢稳态中的作用尚不清楚。在这项研究中，我们调查了GDF11在调节代谢稳态和能量平衡中的功能。方法采用流体动力学注射方法，将带有小鼠Gdf11基因的质粒递送至小鼠体内，并在肝脏中产生持续的Gdf11表达，并在血液中产生其蛋白水平。高脂饮食（HFD）诱导的肥胖症被用来研究Gdf11基因转移对HFD诱导的肥胖，高血糖，胰岛素抵抗和肝脂质蓄积的影响。使用HFD诱导的肥胖和STZ诱导的糖尿病模型检查了GDF11对肥胖和糖尿病小鼠代谢稳态的影响。结果Gdf11基因转移可缓解HFD诱导的肥胖症，高血糖症，胰岛素抵抗和脂肪肝的发展。在肥胖和STZ诱导的糖尿病小鼠中，Gdf11基因转移可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体温调节的基因的表达，下调了白色脂肪组织以及涉及肝脂质和葡萄糖代谢的炎症基因的表达。GDF11的过表达还激活了白色脂肪组织中的TGF-β/ Smad2，PI3K / AKT / FoxO1和AMPK信号通路。