Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea.
Diabetes. 2010 Nov;59(11):2772-80. doi: 10.2337/db10-0145. Epub 2010 Aug 26.
The angiopoietin-like protein 4 (Angptl4)/fasting-induced adipose factor (Fiaf) is known as a regulator of peripheral lipid and glucose metabolism. In the present study, we investigated the physiological role of Angptl4 in central regulation of body weight homeostasis.
Hypothalamic Angptl4 expression levels were measured using immunoblot assay during feeding manipulation or after administration of leptin, insulin, and nutrients. The effects of Angptl4 on food intake, body weight, and energy expenditure were determined following intracerebroventricular (ICV) administration of Angptl4 in C57BL/6 mice. Food intake, energy metabolism, and feeding responses to leptin, insulin, and nutrients were compared between Angptl4-null mice and their wild littermates. Finally, the relationship of hypothalamic AMP-activated protein kinase (AMPK) and Angptl4 was studied.
Hypothalamic Angptl4 expression levels were increased upon food intake or administration of leptin, insulin, and nutrients. Furthermore, central administration of Angptl4 suppressed food intake and body weight gain but enhanced energy expenditure. These effects were mediated via suppression of hypothalamic AMPK activities. Consistently, Angptl4-null mice displayed increased body weight and hypothalamic AMPK activity but reduced energy expenditure. Food intake following a fast was significantly greater in Angptl4-null mice, which was normalized by centrally administered Angptl4. Moreover, anorectic responses to leptin, insulin, and glucose were diminished in Angptl4-null mice. In contrast, Angptl4-null mice were resistant to diet-induced obesity, indicating obesity-promoting effects of Angptl4 under the condition of fat-enriched diet.
We have demonstrated that hypothalamic Angptl4 is regulated by physiological appetite regulators and mediates their anorexigenic effects via inhibition of hypothalamic AMPK activity. Therefore, Angptl4 appears to have an important role in central regulation of energy metabolism.
血管生成素样蛋白 4（Angptl4）/禁食诱导脂肪因子（Fiaf）是一种外周脂质和葡萄糖代谢的调节剂。在本研究中，我们研究了 Angptl4 在体重稳态中枢调节中的生理作用。
在喂养操作期间或给予瘦素、胰岛素和营养素后，使用免疫印迹测定法测量下丘脑 Angptl4 的表达水平。在 C57BL/6 小鼠中经脑室内（ICV）给予 Angptl4 后，确定 Angptl4 对食物摄入、体重和能量消耗的影响。比较 Angptl4 缺失小鼠与其野生同窝仔鼠之间的食物摄入、能量代谢以及对瘦素、胰岛素和营养素的摄食反应。最后，研究了下丘脑 AMP 激活的蛋白激酶（AMPK）与 Angptl4 的关系。
摄食或给予瘦素、胰岛素和营养素后，下丘脑 Angptl4 的表达水平增加。此外，中枢给予 Angptl4 可抑制食物摄入和体重增加，但可增强能量消耗。这些作用是通过抑制下丘脑 AMPK 活性介导的。一致地，Angptl4 缺失小鼠表现出体重增加和下丘脑 AMPK 活性降低，但能量消耗减少。禁食后，Angptl4 缺失小鼠的食物摄入量显著增加，而经中枢给予 Angptl4 则可使其正常化。此外，Angptl4 缺失小鼠对瘦素、胰岛素和葡萄糖的厌食反应减弱。相反，Angptl4 缺失小鼠对饮食诱导的肥胖具有抗性，表明在富含脂肪的饮食条件下，Angptl4 具有促进肥胖的作用。
我们已经证明，下丘脑 Angptl4 受生理食欲调节剂的调节，并通过抑制下丘脑 AMPK 活性来介导其摄食抑制作用。因此，Angptl4 似乎在能量代谢的中枢调节中具有重要作用。
