Obesity-associated type 2 diabetes mellitus (T2DM) entails insulin resistance and loss of β-cell mass. Adipose tissue mitochondrial dysfunction is emerging as a key component in the etiology of T2DM. Identifying approaches to preserve mitochondrial function, adipose tissue integrity, and β-cell mass during obesity is a major challenge. Mitochondrial ferritin (FtMT) is a mitochondrial matrix protein that chelates iron. We sought to determine whether perturbation of adipocyte mitochondria influences energy metabolism during obesity. We used an adipocyte-specific doxycycline-inducible mouse model of FtMT overexpression (FtMT-Adip mice). During a dietary challenge, FtMT-Adip mice are leaner but exhibit glucose intolerance, low adiponectin levels, increased reactive oxygen species damage, and elevated GDF15 and FGF21 levels, indicating metabolically dysfunctional fat. Paradoxically, despite harboring highly dysfunctional fat, transgenic mice display massive β-cell hyperplasia, reflecting a beneficial mitochondria-induced fat-to-pancreas interorgan signaling axis. This identifies the unique and critical impact that adipocyte mitochondrial dysfunction has on increasing β-cell mass during obesity-related insulin resistance.

中文翻译：

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糖尿病并发症的新模型：脂肪细胞线粒体功能障碍引发大量 β 细胞增生

肥胖相关的 2 型糖尿病 (T2DM) 会导致胰岛素抵抗和 β 细胞量减少。脂肪组织线粒体功能障碍正在成为 T2DM 病因学的一个关键组成部分。确定在肥胖期间保持线粒体功能、脂肪组织完整性和 β 细胞质量的方法是一项重大挑战。线粒体铁蛋白 (FtMT) 是一种螯合铁的线粒体基质蛋白。我们试图确定脂肪细胞线粒体的扰动是否会影响肥胖期间的能量代谢。我们使用了脂肪细胞特异性多西环素诱导的 FtMT 过表达小鼠模型（FtMT-Adip 小鼠）。在饮食挑战期间，FtMT-Adip 小鼠更瘦，但表现出葡萄糖耐受不良、脂联素水平低、活性氧损伤增加以及 GDF15 和 FGF21 水平升高，表明代谢功能失调的脂肪。矛盾的是，尽管含有高度功能失调的脂肪，转基因小鼠显示出大量的 β 细胞增生，反映了有益的线粒体诱导的脂肪-胰腺器官间信号轴。这确定了脂肪细胞线粒体功能障碍对肥胖相关胰岛素抵抗期间 β 细胞质量增加的独特而关键的影响。