Lamp-2 deficiency prevents high-fat diet-induced obese diabetes via enhancing energy expenditure.
Lamp-2 deficiency prevents high-fat diet-induced obese diabetes via enhancing energy expenditure.
复制标题
DOI：
10.1016/j.bbrc.2015.08.010
复制
发表时间：
2015-09
影响因子：
3.1
通讯作者：
M. Yasuda‐Yamahara;S. Kume;K. Yamahara;Jun Nakazawa;Masami Chin‐Kanasaki;H. Araki;S. Araki;D. Koya
中科院分区：
文献类型：
--
作者：
M. Yasuda‐Yamahara;S. Kume;K. Yamahara;Jun Nakazawa;Masami Chin‐Kanasaki;H. Araki;S. Araki;D. Koya
自噬过程是维持细胞内环境稳定所必需的，包括自噬体形成和随后与溶酶体融合降解。虽然自噬体形成在糖尿病发病机制中的作用最近已被证明，但后一过程的作用仍不清楚。这项研究分析了高脂饮食（HFD）喂养的小鼠缺乏溶酶体相关膜蛋白-2（lamp-2），这是与溶酶体融合和随后自噬体降解所必需的。尽管lamp-2缺陷小鼠在正常饮食喂养下葡萄糖代谢几乎没有改变，但它们表现出对高脂饮食（HFD）诱导的肥胖、高胰岛素血症性高血糖和组织脂质蓄积的抵抗，伴随着更高的能量消耗。在HFD喂养的lamp-2缺陷小鼠中，棕色脂肪组织中产热基因的表达水平显著增加。在与能量消耗相关的一些血清因子中，HFD喂养的lamp-2缺陷小鼠的成纤维细胞生长因子（FGF）21的血清水平及其mRNA表达水平以ER应激依赖性方式而非PPARα依赖性方式显著升高。总之，自噬体的lamp-2依赖性融合和降解过程参与了肥胖糖尿病的发病机制，为自噬和糖尿病提供了新的见解。
Autophagy process is essential for maintaining intracellular homeostasis and consists of autophagosome formation and subsequent fusion with lysosome for degradation. Although the role of autophagosome formation in the pathogenesis of diabetes has been recently documented, the role of the latter process remains unclear. This study analyzed high-fat diet (HFD)-fed mice lacking lysosome-associated membrane protein-2 (lamp-2), which is essential for the fusion with lysosome and subsequent degradation of autophagosomes. Although lamp-2 deficient mice showed little alteration in glucose metabolism under normal diet feeding, they showed a resistance against high-fat diet (HFD)-induced obesity, hyperinsulinemic hyperglycemia and tissues lipid accumulation, accompanied with higher energy expenditure. The expression levels of thermogenic genes in brown adipose tissue were significantly increased in HFD-fed lamp-2-deficient mice. Of some serum factors related to energy expenditure, the serum level of fibroblast growth factor (FGF) 21 and its mRNA expression level in the liver were significantly higher in HFD-fed lamp-2-deficient mice in an ER stress-, but not PPARα-, dependent manner. In conclusion, a lamp-2-depenedent fusion and degradation process of autophagosomes is involved in the pathogenesis of obese diabetes, providing a novel insight into autophagy and diabetes.