Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Biochem Biophys Res Commun. 2012 Jun 8;422(3):476-81. doi: 10.1016/j.bbrc.2012.05.018. Epub 2012 May 10.
Under fasting conditions, triacylglycerol in adipose tissue undergoes lipolysis to supply fatty acids as energy substrates. Such lipolysis is regulated by hormones, which activate lipases via stimulation of specific signalling cascades. We previously showed that macrophage-derived soluble protein, AIM induces obesity-associated lipolysis, triggering chronic inflammation in fat tissue which causes insulin resistance. However, the mechanism of how AIM mediates lipolysis remains unknown. Here we show that AIM induces lipolysis in a manner distinct from that of hormone-dependent lipolysis, without activation or augmentation of lipases. In vivo and in vitro, AIM did not enhance phosphorylation of hormone-sensitive lipase (HSL) in adipocytes, a hallmark of hormone-dependent lipolysis activation. Similarly, adipose tissue from obese AIM-deficient and wild-type mice showed comparable HSL phosphorylation. Consistent with the suppressive effect of AIM on fatty acid synthase activity, the amount of saturated and unsaturated fatty acids was reduced in adipocytes treated with AIM. This response ablated transcriptional activity of peroxisome proliferator-activated receptor (PPARγ), leading to diminished gene expression of lipid-droplet coating proteins including fat-specific protein 27 (FSP27) and Perilipin, which are indispensable for triacylglycerol storage in adipocytes. Accordingly, the lipolytic effect of AIM was overcome by a PPARγ-agonist or forced expression of FSP27, while it was synergized by a PPARγ-antagonist. Overall, distinct modes of lipolysis appear to take place in different physiological situations; one is a supportive response against nutritional deprivation achieved by enhancing lipase activity, and the other is a pathological consequence of obesity, causing subclinical inflammation and metabolic disorders, mediated by abolishing droplet-coating proteins.
在禁食条件下，脂肪组织中的三酰甘油通过脂解作用供应脂肪酸作为能量底物。这种脂解作用受激素调节，激素通过刺激特定的信号级联反应来激活脂肪酶。我们之前曾表明，巨噬细胞衍生的可溶性蛋白 AIM 诱导肥胖相关的脂解作用，触发脂肪组织中的慢性炎症，导致胰岛素抵抗。然而，AIM 介导脂解作用的机制尚不清楚。在这里，我们表明 AIM 以一种与激素依赖性脂解作用不同的方式诱导脂解作用，而不激活或增强脂肪酶。在体内和体外，AIM 都不会增强脂肪细胞中激素敏感脂肪酶 (HSL) 的磷酸化，这是激素依赖性脂解作用激活的标志。同样，肥胖的 AIM 缺陷型和野生型小鼠的脂肪组织中 HSL 的磷酸化也没有差异。与 AIM 对脂肪酸合酶活性的抑制作用一致，用 AIM 处理的脂肪细胞中饱和和不饱和脂肪酸的量减少。这种反应抑制了过氧化物酶体增殖物激活受体 (PPARγ) 的转录活性，导致包括脂肪特异性蛋白 27 (FSP27) 和 perilipin 在内的脂质滴涂层蛋白的基因表达减少，这些蛋白对于脂肪细胞中三酰甘油的储存是必不可少的。因此，AIM 的脂解作用被 PPARγ 激动剂或 FSP27 的强制表达所克服，而被 PPARγ 拮抗剂协同增强。总的来说，不同的脂解作用模式似乎发生在不同的生理情况下；一种是通过增强脂肪酶活性来支持营养缺乏的反应，另一种是肥胖的病理后果，通过消除液滴涂层蛋白导致亚临床炎症和代谢紊乱。
