Lipoatrophy and metabolic disturbance in mice with adipose-specific deletion of kindlin-2
Lipoatrophy and metabolic disturbance in mice with adipose-specific deletion of kindlin-2
复制标题
kindlin-2 脂肪特异性缺失小鼠的脂肪萎缩和代谢紊乱
DOI：
10.1172/jci.insight.128405
复制
发表时间：
2019-07-11
期刊：
影响因子：
8
通讯作者：
Xiao, Guozhi
中科院分区：
文献类型：
--
作者：
Gao, Huanqing;Guo, Yuxi;Xiao, Guozhi
Kindlin-2调节整合素介导的细胞对细胞外基质的粘附和迁移。我们最近的研究证实了kindin -2在调节间充质干细胞分化和骨骼发育中的重要作用。在本研究中，我们利用Adipoq-Cre bac转基因小鼠，在小鼠体内产生了脂肪组织特异性条件敲除kindlin-2。结果表明，在小鼠脂肪细胞中删除kindlin-2的表达会导致严重的脂肪营养不良，脂肪组织质量急剧减少。Kindlin-2消融升高了血液中非酯化脂肪酸和甘油三酯的水平，导致高脂肪饮食（HFD）喂养的突变小鼠出现大量脂肪肝。此外，hfd喂养的突变小鼠表现出II型糖尿病样表型，包括空腹血糖水平升高、葡萄糖耐受不良和外周胰岛素抵抗。Kindlin-2缺失显著降低PPAR γ、mTOR、AKT、β -catenin蛋白等多种关键因子的表达水平，抑制脂肪细胞基因表达和分化。最后，kindin -2的损失大大减少了瘦素的产生，导致高骨量表型。总之，这些研究确立了kindin -2在控制脂肪生成、脂质代谢以及骨稳态中的关键作用。
Kindlin-2 regulates integrin-mediated cell adhesion to and migration on the extracellular matrix. Our recent studies demonstrate important roles of kindlin-2 in regulation of mesenchymal stem cell differentiation and skeletal development. In this study, we generated adipose tissue-specific conditional knockout of kindlin-2 in mice by using Adipoq-Cre BAC-transgenic mice. The results showed that deleting kindlin-2 expression in adipocytes in mice caused a severe lipodystrophy with drastically reduced adipose tissue mass. Kindlin-2 ablation elevated the blood levels of nonesterified fatty acids and triglycerides, resulting in massive fatty livers in the mutant mice fed with high-fat diet (HFD). Furthermore, HFD-fed mutant mice displayed type II diabetes-like phenotypes, including elevated levels of fasting blood glucose, glucose intolerance, and peripheral insulin resistance. Kindlin-2 loss dramatically reduced the expression levels of multiple key factors, including PPAR gamma, mTOR, AKT, and beta-catenin proteins, and suppressed adipocyte gene expression and differentiation. Finally, kindlin-2 loss drastically reduced leptin production and caused a high bone mass phenotype. Collectively, these studies establish a critical role of kindlin-2 in control of adipogenesis and lipid metabolism as well as bone homeostasis.