Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom.
Elife. 2023 Feb 1;12:e82283. doi: 10.7554/eLife.82283.
Mitochondrial dysfunction has been reported in obesity and insulin resistance, but primary genetic mitochondrial dysfunction is generally not associated with these, arguing against a straightforward causal relationship. A rare exception, recently identified in humans, is a syndrome of lower body adipose loss, leptin-deficient severe upper body adipose overgrowth, and insulin resistance caused by the p.Arg707Trp mutation in , encoding mitofusin 2. How the resulting selective form of mitochondrial dysfunction leads to tissue- and adipose depot-specific growth abnormalities and systemic biochemical perturbation is unknown. To address this, knock-in mice were generated and phenotyped on chow and high fat diets. Electron microscopy revealed adipose-specific mitochondrial morphological abnormalities. Oxidative phosphorylation measured in isolated mitochondria was unperturbed, but the cellular integrated stress response was activated in adipose tissue. Fat mass and distribution, body weight, and systemic glucose and lipid metabolism were unchanged, however serum leptin and adiponectin concentrations, and their secretion from adipose explants were reduced. Pharmacological induction of the integrated stress response in wild-type adipocytes also reduced secretion of leptin and adiponectin, suggesting an explanation for the in vivo findings. These data suggest that the p.Arg707Trp MFN2 mutation selectively perturbs mitochondrial morphology and activates the integrated stress response in adipose tissue. In mice, this does not disrupt most adipocyte functions or systemic metabolism, whereas in humans it is associated with pathological adipose remodelling and metabolic disease. In both species, disproportionate effects on leptin secretion may relate to cell autonomous induction of the integrated stress response.
线粒体功能障碍已在肥胖和胰岛素抵抗中被报道，但原发性遗传线粒体功能障碍通常与这些疾病无关，这表明它们之间不存在直接的因果关系。一个最近在人类中发现的罕见例外是一种综合征，其特征为下半身脂肪减少、瘦素缺乏导致的上半身脂肪过度生长、胰岛素抵抗，这些是由编码线粒体融合蛋白 2 的 p.Arg707Trp 突变引起的。导致这种选择性线粒体功能障碍的原因尚不清楚，它如何导致组织和脂肪库特异性生长异常以及全身生化紊乱。为了解决这个问题，我们生成了 敲入小鼠，并在标准饮食和高脂肪饮食下对其进行表型分析。电子显微镜显示脂肪组织特异性的线粒体形态异常。分离的线粒体中氧化磷酸化未受影响，但脂肪组织中细胞整体应激反应被激活。脂肪量和分布、体重以及全身葡萄糖和脂质代谢没有变化，然而血清瘦素和脂联素浓度及其从脂肪外植体的分泌减少。野生型脂肪细胞中整体应激反应的药物诱导也减少了瘦素和脂联素的分泌，这表明这可以解释体内发现的现象。这些数据表明，p.Arg707Trp MFN2 突变选择性地扰乱了脂肪组织中线粒体的形态和整体应激反应的激活。在小鼠中，这不会破坏大多数脂肪细胞的功能或全身代谢，而在人类中，它与病理性脂肪重塑和代谢疾病有关。在这两种物种中，对瘦素分泌的不成比例影响可能与细胞自主诱导的整体应激反应有关。
