1 Montreal Heart Institute, Research Center, 12368 University of Montreal , Montreal, QC H1T 1C8, Canada.
2 Departments of Surgery and Pharmacology, Faculty of Medicine, 12368 University of Montreal , Montréal H3T 1J4, QC, Canada.
Exp Biol Med (Maywood). 2018 Jan;243(1):45-49. doi: 10.1177/1535370217745505. Epub 2017 Dec 1.
Angiopoietin-like 2 (ANGPTL2) is an inflammatory adipokine linking obesity to insulin resistance. Intermittent fasting, on the other hand, is a lifestyle intervention able to prevent obesity and diabetes but difficult to implement and maintain. Our objectives were to characterize a link between ANGPTL2 and intermittent fasting and to investigate whether the knockdown of ANGPTL2 reproduces the benefits of intermittent fasting on weight gain and insulin responsiveness in knockdown and wild-type littermates mice. Intermittent fasting, access to food ad libitum once every other day, was initiated at the age of three months and maintained for four months. Intermittent fasting decreased by 63% (p < 0.05) gene expression of angptl2 in adipose tissue of wild-type mice. As expected, intermittent fasting improved insulin sensitivity (p < 0.05) and limited weight gain (p < 0.05) in wild-type mice. Knockdown mice fed ad libitum, however, were comparable to wild-type mice following the intermittent fasting regimen: insulin sensitivity and weight gain were identical, while intermittent fasting had no additional impact on these parameters in knockdown mice. Energy intake was similar between both wild-type fed intermittent fasting and ANGPTL2 knockdown mice fed ad libitum, suggesting that intermittent fasting and knockdown of ANGPTL2 equally lower feeding efficiency. These results suggest that the reduction of ANGPTL2 could be a useful and promising strategy to prevent obesity and insulin resistance, although further investigation of the mechanisms linking ANGPTL2 and intermittent fasting is warranted. Impact statement Intermittent fasting is an efficient diet pattern to prevent weight gain and improve insulin sensitivity. It is, however, a difficult regimen to follow and compliance is expected to be very low. In this work, we demonstrate that knockdown of ANGPTL2 in mice fed ad libitum mimics the beneficial effects of intermittent fasting on weight gain and insulin sensitivity in wild-type mice. ANGPTL2 is a cytokine positively associated with fat mass in humans, which inactivation in mice improves resistance to a high-fat metabolic challenge. This study provides a novel pathway by which IF acts to limit obesity despite equivalent energy intake. The development of a pharmacological ANGPTL2 antagonist could provide an efficient tool to reduce the burden of obesity.
血管生成素样蛋白 2 (ANGPTL2) 是一种炎症脂肪因子，将肥胖与胰岛素抵抗联系起来。另一方面，间歇性禁食是一种能够预防肥胖和糖尿病的生活方式干预措施，但很难实施和维持。我们的目标是描述 ANGPTL2 与间歇性禁食之间的联系，并研究 ANGPTL2 的敲低是否能在敲低和野生型同窝仔鼠中重现间歇性禁食对体重增加和胰岛素反应性的益处。从三个月大开始，每隔一天自由进食一次，即开始间歇性禁食，并持续四个月。间歇性禁食使野生型小鼠脂肪组织中 angptl2 的基因表达降低了 63%（p<0.05）。正如预期的那样，间歇性禁食改善了野生型小鼠的胰岛素敏感性（p<0.05）并限制了体重增加（p<0.05）。然而，自由进食的敲低小鼠在接受间歇性禁食方案后与野生型小鼠相当：胰岛素敏感性和体重增加相同，而间歇性禁食对敲低小鼠的这些参数没有额外的影响。两种野生型间歇性禁食和 ANGPTL2 敲低的自由进食小鼠的能量摄入相似，这表明间歇性禁食和 ANGPTL2 的敲低同样降低了进食效率。这些结果表明，降低 ANGPTL2 可能是预防肥胖和胰岛素抵抗的一种有用且有前途的策略，尽管需要进一步研究 ANGPTL2 与间歇性禁食之间的联系机制。
间歇性禁食是一种预防体重增加和改善胰岛素敏感性的有效饮食模式。然而，这是一种难以遵循的方案，预计依从性非常低。在这项工作中，我们证明了在自由进食的小鼠中敲低 ANGPTL2 可以模拟间歇性禁食对野生型小鼠体重增加和胰岛素敏感性的有益影响。ANGPTL2 是一种与人类脂肪量呈正相关的细胞因子，其在小鼠中的失活可提高其对高脂肪代谢挑战的抵抗力。这项研究提供了一种新的途径，即 IF 尽管能量摄入相等，但仍能限制肥胖。开发一种药理学上的 ANGPTL2 拮抗剂可能提供一种有效的工具来减轻肥胖的负担。
