AIMS/HYPOTHESIS Mitochondrial oxidative phosphorylation (OxPhos) is essential for energy production and survival. However, the tissue-specific and systemic metabolic effects of OxPhos function in adipocytes remain incompletely understood. METHODS We used adipocyte-specific Crif1 (also known as Gadd45gip1) knockout (AdKO) mice with decreased adipocyte OxPhos function. AdKO mice fed a normal chow or high-fat diet were evaluated for glucose homeostasis, weight gain and energy expenditure (EE). RNA sequencing of adipose tissues was used to identify the key mitokines affected in AdKO mice, which included fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). For in vitro analysis, doxycycline was used to pharmacologically decrease OxPhos in 3T3L1 adipocytes. To identify the effects of GDF15 and FGF21 on the metabolic phenotype of AdKO mice, we generated AdKO mice with global Gdf15 knockout (AdGKO) or global Fgf21 knockout (AdFKO). RESULTS Under high-fat diet conditions, AdKO mice were resistant to weight gain and exhibited higher EE and improved glucose tolerance. In vitro pharmacological and in vivo genetic inhibition of OxPhos in adipocytes significantly upregulated mitochondrial unfolded protein response-related genes and secretion of mitokines such as GDF15 and FGF21. We evaluated the metabolic phenotypes of AdGKO and AdFKO mice, revealing that GDF15 and FGF21 differentially regulated energy homeostasis in AdKO mice. Both mitokines had beneficial effects on obesity and insulin resistance in the context of decreased adipocyte OxPhos, but only GDF15 regulated EE in AdKO mice. CONCLUSIONS/INTERPRETATION The present study demonstrated that the adipose tissue adaptive mitochondrial stress response affected systemic energy homeostasis via cell-autonomous and non-cell-autonomous pathways. We identified novel roles for adipose OxPhos and adipo-mitokines in the regulation of systemic glucose homeostasis and EE, which facilitated adaptation of an organism to local mitochondrial stress.

中文翻译：

---

氧化磷酸化中的脂肪细胞特异性缺陷增加了全身能量消耗，并防止了小鼠模型中饮食引起的肥胖。

目的/假设线粒体氧化磷酸化（OxPhos）对于能量产生和生存至关重要。然而，OxPhos功能在脂肪细胞中的组织特异性和全身代谢作用仍未完全了解。方法我们使用脂肪细胞特异性的Crif1（也称为Gadd45gip1）基因敲除（AdKO）小鼠，其脂肪细胞OxPhos功能降低。饲喂正常饮食或高脂饮食的AdKO小鼠的葡萄糖体内稳态，体重增加和能量消耗（EE）。脂肪组织的RNA测序用于鉴定在AdKO小鼠中受影响的关键丝裂霉素，其中包括成纤维细胞生长因子21（FGF21）和生长分化因子15（GDF15）。为了进行体外分析，使用强力霉素在药理学上降低了3T3L1脂肪细胞中的OxPhos。为了确定GDF15和FGF21对AdKO小鼠代谢表型的影响，我们生成了具有整体Gdf15基因敲除（AdGKO）或整体Fgf21基因敲除（AdFKO）的AdKO小鼠。结果在高脂饮食条件下，AdKO小鼠对体重增加有抵抗力，并表现出较高的EE和改善的糖耐量。脂肪细胞中OxPhos的体外药理和体内遗传抑制作用显着上调了线粒体未折叠的蛋白质反应相关基因以及GDF15和FGF21等线粒体的分泌。我们评估了AdGKO和AdFKO小鼠的代谢表型，揭示了GDF15和FGF21差异调节AdKO小鼠的能量稳态。在脂肪细胞OxPhos降低的情况下，这两种丝氨酸因子均对肥胖和胰岛素抵抗具有有益作用，但AdKO小鼠中只有GDF15调节了EE。结论/解释本研究表明，脂肪组织适应性线粒体应激反应通​​过细胞自主和非细胞自主途径影响全身能量稳态。我们确定了脂肪OxPhos和脂肪-mitokines在调节全身性葡萄糖稳态和EE中的新作用，这有助于使生物适应局部线粒体应激。