Loss of mitochondrial protease ClpP protects mice from diet-induced obesity and insulin resistance
Loss of mitochondrial protease ClpP protects mice from diet-induced obesity and insulin resistance
复制标题
DOI：
10.15252/embr.201745009
复制
发表时间：
2018-03-01
期刊：
影响因子：
7.7
通讯作者：
Deepa, Sathyaseelan S.
中科院分区：
文献类型：
--
作者：
Bhaskaran, Shylesh;Pharaoh, Gavin;Deepa, Sathyaseelan S.
酪蛋白溶解肽酶P （ClpP）是一种哺乳动物质量控制蛋白酶，被认为在线粒体未折叠蛋白反应（UPRmt）的启动中发挥重要作用，这是一种有助于维持线粒体蛋白稳态的逆行信号反应。线粒体功能障碍与代谢紊乱的发生有关，为了了解upmt缺陷对代谢的影响，我们对ClpP敲除（ClpP(-/-)）小鼠进行了分析。给ClpP（-/-）小鼠喂食adlium减少了肥胖，并矛盾地改善了胰岛素敏感性。ClpP缺失增加了ClpP小鼠的全身能量消耗，线粒体生物发生标志物在ClpP（-/-）小鼠的白色脂肪组织（WAT）中选择性上调。当受到代谢应激（如高脂肪饮食）的挑战时，尽管热量摄入相似，ClpP（-/-）小鼠可免受饮食引起的肥胖、葡萄糖耐受不良、胰岛素抵抗和肝脂肪变性的影响。我们的研究结果表明，ClpP的缺失会触发小鼠的代偿反应，并表明ClpP可能在哺乳动物的UPRmt启动中是不必要的。因此，我们意外地发现，小鼠缺乏ClpP在代谢方面是有益的。
Caseinolytic peptidase P (ClpP) is a mammalian quality control protease that is proposed to play an important role in the initiation of the mitochondrial unfolded protein response (UPRmt), a retrograde signaling response that helps to maintain mitochondrial protein homeostasis. Mitochondrial dysfunction is associated with the development of metabolic disorders, and to understand the effect of a defective UPRmt on metabolism, ClpP knockout (ClpP(-/-)) mice were analyzed. ClpP(-/-) mice fed adlibitum have reduced adiposity and paradoxically improved insulin sensitivity. Absence of ClpP increased whole-body energy expenditure and markers of mitochondrial biogenesis are selectively up-regulated in the white adipose tissue (WAT) of ClpP(-/-) mice. When challenged with a metabolic stress such as high-fat diet, despite similar caloric intake, ClpP(-/-) mice are protected from diet-induced obesity, glucose intolerance, insulin resistance, and hepatic steatosis. Our results show that absence of ClpP triggers compensatory responses in mice and suggest that ClpP might be dispensable for mammalian UPRmt initiation. Thus, we made an unexpected finding that deficiency of ClpP in mice is metabolically beneficial.