A mouse model of human mitofusin-2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion.
A mouse model of human mitofusin-2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion.
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DOI：
10.7554/elife.82283
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发表时间：
2023-02-01
期刊：
影响因子：
7.7
通讯作者：
Savage DB
中科院分区：
文献类型：
--
作者：
Mann JP;Duan X;Patel S;Tábara LC;Scurria F;Alvarez-Guaita A;Haider A;Luijten I;Page M;Protasoni M;Lim K;Virtue S;O'Rahilly S;Armstrong M;Prudent J;Semple RK;Savage DB
线粒体功能障碍在肥胖和胰岛素抵抗中已有报道，但原发性遗传线粒体功能障碍通常与这些无关，反对直接的因果关系。最近在人类中发现的一个罕见的例外是由编码线粒体融合蛋白2的MFN 2中的p.Arg707Trp突变引起的下半身脂肪损失、瘦素缺乏的严重上半身脂肪过度生长和胰岛素抵抗的综合征。线粒体功能障碍的选择性形式如何导致组织和脂肪库特异性生长异常和全身生化紊乱尚不清楚。为了解决这个问题，产生Mfn 2 R707 W/R707 W敲入小鼠，并对食物和高脂肪饮食进行表型分析。电子显微镜显示脂肪特异性线粒体形态异常。在分离的线粒体中测得的氧化磷酸化是不受干扰的，但在脂肪组织中细胞的整合应激反应被激活。脂肪质量和分布，体重，全身葡萄糖和脂质代谢没有变化，但血清瘦素和脂联素浓度，并从脂肪外植体分泌减少。在野生型脂肪细胞的综合应激反应的药理学诱导也减少了瘦素和脂联素的分泌，这表明在体内的研究结果的解释。这些数据表明，p.Arg707Trp MFN 2突变选择性地扰乱线粒体形态，激活脂肪组织中的综合应激反应。在小鼠中，这不会破坏大多数脂肪细胞功能或全身代谢，而在人类中，它与病理性脂肪重塑和代谢疾病有关。在这两个物种中，瘦素分泌的不成比例的影响可能与细胞自主诱导的综合应激反应。
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 MFN2, 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, Mfn2R707W/R707W 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.