Mitochondrial dysfunction promotes metabolic stress responses in a cell-autonomous as well as organismal manner. The wasting hormone growth differentiation factor 15 (GDF15) is recognized as a biomarker of mitochondrial disorders, but its pathophysiological function remains elusive. To test the hypothesis that GDF15 is fundamental to the metabolic stress response during mitochondrial dysfunction, we investigated transgenic mice (Ucp1-TG) with compromised muscle-specific mitochondrial OXPHOS capacity via respiratory uncoupling. Ucp1-TG mice show a skeletal muscle-specific induction and diurnal variation of GDF15 as a myokine. Remarkably, genetic loss of GDF15 in Ucp1-TG mice does not affect muscle wasting or transcriptional cell-autonomous stress response but promotes a progressive increase in body fat mass. Furthermore, muscle mitochondrial stress-induced systemic metabolic flexibility, insulin sensitivity, and white adipose tissue browning are fully abolished in the absence of GDF15. Mechanistically, we uncovered a GDF15-dependent daytime-restricted anorexia, whereas GDF15 is unable to suppress food intake at night. Altogether, our evidence suggests a novel diurnal action and key pathophysiological role of mitochondrial stress-induced GDF15 in the regulation of systemic energy metabolism.

中文翻译：

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肌肉来源的 GDF15 在线粒体应激期间驱动昼夜厌食和全身代谢重塑。

线粒体功能障碍以细胞自主和有机方式促进代谢应激反应。消耗激素生长分化因子 15 (GDF15) 被认为是线粒体疾病的生物标志物，但其病理生理功能仍然难以捉摸。为了验证 GDF15 是线粒体功能障碍期间代谢应激反应基础的假设，我们通过呼吸解偶联研究了肌肉特异性线粒体 OXPHOS 能力受损的转基因小鼠 (Ucp1-TG)。Ucp1-TG 小鼠表现出骨骼肌特异性诱导和 GDF15 作为肌因子的昼夜变化。值得注意的是，Ucp1-TG 小鼠中 GDF15 的遗传缺失不会影响肌肉萎缩或转录细胞自主应激反应，但会促进体脂肪量的逐渐增加。此外，在没有 GDF15 的情况下，肌肉线粒体应激诱导的全身代谢灵活性、胰岛素敏感性和白色脂肪组织褐变完全消失。从机制上讲，我们发现了依赖 GDF15 的白天限制性厌食症，而 GDF15 无法抑制夜间的食物摄入。总之，我们的证据表明线粒体应激诱导的 GDF15 在调节全身能量代谢中具有新的昼夜作用和关键的病理生理学作用。