School of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia.
School of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia.
Mol Metab. 2024 Aug;86:101983. doi: 10.1016/j.molmet.2024.101983. Epub 2024 Jul 1.
Mitochondria facilitate thousands of biochemical reactions, covering a broad spectrum of anabolic and catabolic processes. Here we demonstrate that the adipocyte mitochondrial proteome is markedly altered across multiple models of insulin resistance and reveal a consistent decrease in the level of the mitochondrial processing peptidase miPEP.
To determine the role of miPEP in insulin resistance.
To experimentally test this observation, we generated adipocyte-specific miPEP knockout mice to interrogate its role in the aetiology of insulin resistance.
We observed a strong phenotype characterised by enhanced insulin sensitivity and reduced adiposity, despite normal food intake and physical activity. Strikingly, these phenotypes vanished when mice were housed at thermoneutrality, suggesting that metabolic protection conferred by miPEP deletion hinges upon a thermoregulatory process. Tissue specific analysis of miPEP deficient mice revealed an increment in muscle metabolism, and upregulation of the protein FBP2 that is involved in ATP hydrolysis in the gluconeogenic pathway.
These findings suggest that miPEP deletion initiates a compensatory increase in skeletal muscle metabolism acting as a protective mechanism against diet-induced obesity and insulin resistance.
线粒体促进数千种生化反应,涵盖广泛的合成代谢和分解代谢过程。在这里,我们证明了脂肪细胞线粒体蛋白质组在多种胰岛素抵抗模型中明显改变,并揭示了线粒体加工肽酶 miPEP 的水平持续下降。
确定 miPEP 在胰岛素抵抗中的作用。
为了实验验证这一观察结果,我们生成了脂肪细胞特异性 miPEP 敲除小鼠,以研究其在胰岛素抵抗发病机制中的作用。
我们观察到一种强烈的表型,其特征是胰岛素敏感性增强和脂肪量减少,尽管食物摄入和体力活动正常。令人惊讶的是,当小鼠被安置在热中性环境中时,这些表型消失了,这表明 miPEP 缺失赋予的代谢保护取决于体温调节过程。miPEP 缺失小鼠的组织特异性分析显示肌肉代谢增加,以及参与糖异生途径中 ATP 水解的 FBP2 蛋白上调。
这些发现表明,miPEP 缺失会引发骨骼肌代谢的代偿性增加,作为一种针对饮食诱导肥胖和胰岛素抵抗的保护机制。