Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Department of Endocrinology and Nutrition, Hospital Clínic. School of Medicine, University of Barcelona, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain.
Cell. 2013 Sep 26;155(1):172-87. doi: 10.1016/j.cell.2013.09.003.
Mitofusin 2 (MFN2) plays critical roles in both mitochondrial fusion and the establishment of mitochondria-endoplasmic reticulum (ER) interactions. Hypothalamic ER stress has emerged as a causative factor for the development of leptin resistance, but the underlying mechanisms are largely unknown. Here, we show that mitochondria-ER contacts in anorexigenic pro-opiomelanocortin (POMC) neurons in the hypothalamus are decreased in diet-induced obesity. POMC-specific ablation of Mfn2 resulted in loss of mitochondria-ER contacts, defective POMC processing, ER stress-induced leptin resistance, hyperphagia, reduced energy expenditure, and obesity. Pharmacological relieve of hypothalamic ER stress reversed these metabolic alterations. Our data establish MFN2 in POMC neurons as an essential regulator of systemic energy balance by fine-tuning the mitochondrial-ER axis homeostasis and function. This previously unrecognized role for MFN2 argues for a crucial involvement in mediating ER stress-induced leptin resistance.
线粒体融合蛋白 2（MFN2）在线粒体融合和建立线粒体-内质网（ER）相互作用中发挥着关键作用。下丘脑 ER 应激已成为瘦素抵抗发展的一个致病因素，但潜在机制在很大程度上尚不清楚。在这里，我们表明，在饮食诱导肥胖的情况下，下丘脑厌食性 pro-opiomelanocortin（POMC）神经元中的线粒体-ER 接触减少。POMC 特异性敲除 Mfn2 导致线粒体-ER 接触丧失、POMC 加工缺陷、ER 应激诱导的瘦素抵抗、暴食、能量消耗减少和肥胖。下丘脑 ER 应激的药理学缓解逆转了这些代谢变化。我们的数据表明，POMC 神经元中的 MFN2 通过精细调节线粒体-ER 轴的平衡和功能，成为调节全身能量平衡的重要调节因子。MFN2 的这一先前未被认识到的作用表明其在介导 ER 应激诱导的瘦素抵抗中具有关键作用。
