Kulkarni Sameer S, Joffraud Magali, Boutant Marie, Ratajczak Joanna, Gao Arwen W, Maclachlan Catherine, Hernandez-Alvarez Maria Isabel, Raymond Frédéric, Metairon Sylviane, Descombes Patrick, Houtkooper Riekelt H, Zorzano Antonio, Cantó Carles
Nestlé Institute of Health Sciences, Lausanne, Switzerland.
École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Diabetes. 2016 Dec;65(12):3552-3560. doi: 10.2337/db15-1725. Epub 2016 Sep 9.
Mitochondrial function can be influenced by mitochondrial shape and connectivity with other cellular organelles through fusion and fission processes. Disturbances in mitochondrial architecture and mitochondrial fusion-related genes are observed in situations of type 2 diabetes and obesity, leading to a highly fissioned mitochondrial network. To directly test the effect of reduced mitochondrial fusion on hepatic metabolism, we generated mice with a liver-specific deletion of the Mfn1 gene (Mfn1LKO) and monitored their energy homeostasis, mitochondrial function, and susceptibility to diet-induced insulin resistance. Livers from Mfn1LKO mice displayed a highly fragmented mitochondrial network. This was coupled to an enhanced mitochondrial respiration capacity and a preference for the use of lipids as the main energy source. Although Mfn1LKO mice are similar to control mice fed a low-fat diet, they are protected against insulin resistance induced by a high-fat diet. Importantly, Mfn1 deficiency increased complex I abundance and sensitized animals to the hypoglycemic effect of metformin. Our results suggest that targeting Mfn1 could provide novel avenues to ameliorate glucose homeostasis in obese patients and improve the effectiveness of metformin.
线粒体功能可通过融合和裂变过程受到线粒体形态以及与其他细胞器连接性的影响。在2型糖尿病和肥胖情况下，会观察到线粒体结构及线粒体融合相关基因的紊乱，导致线粒体网络高度碎片化。为了直接测试线粒体融合减少对肝脏代谢的影响，我们构建了肝脏特异性缺失Mfn1基因的小鼠（Mfn1LKO），并监测它们的能量稳态、线粒体功能以及对饮食诱导的胰岛素抵抗的易感性。Mfn1LKO小鼠的肝脏显示出线粒体网络高度碎片化。这与增强的线粒体呼吸能力以及偏好使用脂质作为主要能量来源有关。尽管Mfn1LKO小鼠与喂食低脂饮食的对照小鼠相似，但它们对高脂饮食诱导的胰岛素抵抗具有抗性。重要的是，Mfn1缺乏增加了复合体I的丰度，并使动物对二甲双胍的降血糖作用敏感。我们的结果表明，靶向Mfn1可为改善肥胖患者的葡萄糖稳态以及提高二甲双胍的有效性提供新途径。
