An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models
An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models
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DOI：
10.1007/s00125-019-05082-7
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发表时间：
2020-04-01
期刊：
影响因子：
8.2
通讯作者：
Shong, Minho
中科院分区：
文献类型：
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作者：
Choi, Min Jeong;Jung, Saet-Byel;Shong, Minho
目的/假设线粒体氧化磷酸化（OxPhos）对能量产生和生存至关重要。然而，脂肪细胞中OxPhos功能的组织特异性和全身代谢作用仍不完全清楚。方法我们使用脂肪细胞特异性Crif1（也称为Gadd45gip1）敲除（AdKO）小鼠，脂肪细胞OxPhos功能下降。分别饲喂正常食物和高脂肪食物的AdKO小鼠进行葡萄糖稳态、体重增加和能量消耗（EE）的评估。利用脂肪组织RNA测序鉴定AdKO小鼠受影响的关键分裂因子，包括成纤维细胞生长因子21 （FGF21）和生长分化因子15 （GDF15）。体外分析，多西环素可降低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，我们产生了GDF15全基因敲除（AdGKO）或FGF21全基因敲除（AdFKO）的AdKO小鼠。结果在高脂肪饮食条件下，AdKO小鼠对体重增加有抵抗性，表现出更高的EE和改善的葡萄糖耐量。在体外药理学和体内遗传抑制脂肪细胞中，OxPhos显著上调线粒体未折叠蛋白反应相关基因和线粒体分裂因子如GDF15和FGF21的分泌。我们对AdGKO和AdFKO小鼠的代谢表型进行了评估，发现GDF15和FGF21对AdKO小鼠的能量稳态调节存在差异。在脂肪细胞OxPhos降低的情况下，这两种分裂因子对肥胖和胰岛素抵抗都有有益的影响，但只有GDF15调节AdKO小鼠的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。我们发现了脂肪OxPhos和脂肪丝裂因子在调节全身葡萄糖稳态和EE中的新作用，这促进了生物体对局部线粒体应激的适应。
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.