Objective

Studies in mice have shown that the decrease in lipoprotein lipase (LPL) activity in adipose tissue upon fasting is mediated by induction of the inhibitor ANGPTL4. Here, we aimed to validate this concept in humans by determining the effect of a prolonged fast on ANGPTL4 and LPL gene and protein expression in human subcutaneous adipose tissue.

Methods

Twenty-three volunteers ate a standardized meal at 18.00 h and fasted until 20.00 h the next day. Blood was drawn and periumbilical adipose tissue biopsies were collected 2 h and 26 h after the meal.

Results

Consistent with previous mouse data, LPL activity in human adipose tissue was significantly decreased by fasting (−60%), concurrent with increased ANGPTL4 mRNA (+90%) and decreased ANGPTL8 mRNA (−94%). ANGPTL4 protein levels in adipose tissue were also significantly increased by fasting (+46%), whereas LPL mRNA and protein levels remained unchanged. In agreement with the adipose tissue data, plasma ANGPTL4 levels increased upon fasting (+100%), whereas plasma ANGPTL8 decreased (−79%). Insulin, levels of which significantly decreased upon fasting, downregulated ANGPTL4 mRNA and protein in primary human adipocytes. By contrast, cortisol, levels of which significantly increased upon fasting, upregulated ANGPTL4 mRNA and protein in primary human adipocytes as did fatty acids.

Conclusion

ANGPTL4 levels in human adipose tissue are increased by fasting, likely via increased plasma cortisol and free fatty acids and decreased plasma insulin, resulting in decreased LPL activity.

This clinical trial was registered with identifier NCT03757767.

中文翻译：

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空腹诱导人脂肪组织中的ANGPTL4并降低LPL活性。

目的

小鼠研究表明，禁食后脂肪组织中脂蛋白脂肪酶（LPL）活性的降低是由抑制剂ANGPTL4的诱导介导的。在这里，我们旨在通过确定长期禁食对人皮下脂肪组织中ANGPTL4和LPL基因和蛋白质表达的影响，在人中验证这一概念。

方法

23名志愿者在18.00小时吃了一顿标准餐，第二天禁食至20.00小时。饭后2小时和26小时抽血并收集脐周脂肪组织活检。

结果

与先前的小鼠数据一致，禁食可显着降低人脂肪组织中的LPL活性（-60％），同时增加ANGPTL4 mRNA（+ 90％）和降低ANGPTL8 mRNA（-94％）。禁食也可显着增加脂肪组织中ANGPTL4的蛋白水平（+ 46％），而LPL mRNA和蛋白的水平则保持不变。与脂肪组织数据一致，禁食后血浆ANGPTL4水平升高（+ 100％），而血浆ANGPTL8降低（-79％）。胰岛素，禁食后其水平显着降低，下调了人类原代脂肪细胞中的ANGPTL4 mRNA和蛋白。相比之下，禁食后皮质醇的水平显着增加，与脂肪酸一样，初级人类脂肪细胞中的ANGPTL4 mRNA和蛋白上调。

结论

禁食可增加人脂肪组织中ANGPTL4的水平，这可能是通过血浆皮质醇和游离脂肪酸的增加以及血浆胰岛素的减少，从而导致LPL活性降低。

该临床试验注册了标识符NCT03757767。