Centre de Recherche des Cordeliers, INSERM U872, Paris, France.
Autophagy. 2010 Aug;6(6):754-63. doi: 10.4161/auto.6.6.12574. Epub 2010 Aug 3.
Adipose tissue lipoatrophy caused by caveolin gene deletion in mice is not linked to defective adipocyte differentiation. We show that adipose tissue development cannot be rescued by endothelial specific caveolin-1 re-expression, indicating primordial role of caveolin in mature adipocytes. Partial or total caveolin deficiency in adipocytes induced broad protein expression defects, including but not limited to previously described downregulation of insulin receptor. Global alterations in protein turnover, and accelerated degradation of long-lived proteins were found in caveolin-deficient adipocytes. Lipidation of endogenous LC3 autophagy marker and distribution of GFP-LC3 into aggregates demonstrated activated autophagy in the absence of caveolin-1 in adipocytes. Furthermore, electron microscopy revealed autophagic vacuoles in caveolin-1 deficient but not control adipocytes. Surprisingly, significant levels of lipidated LC3-II were found around lipid droplets of normal adipocytes, maintained in nutrient-rich conditions or isolated from fed mice, which do not display autophagy. Altogether, these data indicate that caveolin deficiency induce autophagy in adipocytes, a feature that is not a physiological response to fasting in normal fat cells. This likely resulted from defective insulin and lipolytic responses that converge in chronic nutrient shortage in adipocytes lacking caveolin-1. This is the first report of a pathological situation with autophagy as an adaptative response to adipocyte failure.
脂肪组织中的脂解导致的脂肪营养不良小鼠的小窝蛋白基因缺失与脂肪细胞分化缺陷无关。我们表明，内皮细胞特异性小窝蛋白-1的重新表达不能挽救脂肪组织的发育，这表明小窝蛋白在成熟脂肪细胞中起着原始作用。脂肪细胞中部分或完全缺乏小窝蛋白会引起广泛的蛋白质表达缺陷，包括但不限于胰岛素受体的下调。在缺乏小窝蛋白的脂肪细胞中发现了蛋白质周转率的全局改变和长寿蛋白的降解加速。内源性 LC3 自噬标记的脂化和 GFP-LC3 分布到聚集体表明，在没有小窝蛋白-1 的情况下，脂肪细胞中自噬被激活。此外，电子显微镜显示，小窝蛋白-1 缺乏的脂肪细胞中存在自噬空泡，但在对照脂肪细胞中则没有。令人惊讶的是，在正常脂肪细胞中，即使在营养丰富的条件下或从进食的小鼠中分离出来，也能发现脂质化的 LC3-II 围绕在脂肪滴周围，而且这些细胞不显示自噬。总的来说，这些数据表明，小窝蛋白缺乏会诱导脂肪细胞发生自噬，这一特征不是正常脂肪细胞对禁食的生理反应。这很可能是由于胰岛素和脂解反应的缺陷导致的，这些缺陷在缺乏小窝蛋白-1的脂肪细胞中导致慢性营养缺乏。这是自噬作为脂肪细胞衰竭的适应性反应的病理情况的首次报道。
