Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands.
Department of Bariatric Surgery, Rijnstate Hospital/Vitalys Clinic, Arnhem, the Netherlands; Nutrition and Disease Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands.
Mol Metab. 2020 Oct;40:101033. doi: 10.1016/j.molmet.2020.101033. Epub 2020 Jun 3.
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.
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.
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.
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.
在小鼠研究中表明，禁食时脂肪组织中脂蛋白脂肪酶（LPL）活性的降低是通过诱导抑制剂 ANGPTL4 介导的。在此，我们通过确定延长禁食对人皮下脂肪组织中 ANGPTL4 和 LPL 基因和蛋白表达的影响来验证这一概念。
23 名志愿者在 18:00 时吃标准餐，并于次日 20:00 开始禁食。在进餐后 2 小时和 26 小时采血并采集脐周脂肪组织活检。
与之前的小鼠数据一致，人脂肪组织中的 LPL 活性在禁食时显著降低（-60%），同时 ANGPTL4 mRNA 增加（+90%），ANGPTL8 mRNA 减少（-94%）。脂肪组织中的 ANGPTL4 蛋白水平也因禁食而显著增加（+46%），而 LPL mRNA 和蛋白水平保持不变。与脂肪组织数据一致，血浆 ANGPTL4 水平在禁食时升高（+100%），而血浆 ANGPTL8 降低（-79%）。胰岛素水平在禁食时显著降低，下调了原代人脂肪细胞中的 ANGPTL4 mRNA 和蛋白。相比之下，皮质醇水平在禁食时显著升高，上调了原代人脂肪细胞中的 ANGPTL4 mRNA 和蛋白，脂肪酸也是如此。
人脂肪组织中的 ANGPTL4 水平通过增加血浆皮质醇和游离脂肪酸以及降低血浆胰岛素而升高，导致 LPL 活性降低。本临床试验注册号为 NCT03757767。
