PPA1 Regulates Systemic Insulin Sensitivity by Maintaining Adipocyte Mitochondria Function as a Novel PPARγ Target Gene
PPA1 Regulates Systemic Insulin Sensitivity by Maintaining Adipocyte Mitochondria Function as a Novel PPARγ Target Gene
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PPA1 作为新型 PPARγ 靶基因通过维持脂肪细胞线粒体功能来调节全身胰岛素敏感性
DOI：
10.2337/db20-0622
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发表时间：
2021-06-01
期刊：
影响因子：
7.7
通讯作者：
Han, Xiao
中科院分区：
文献类型：
--
作者：
Yin, Ye;Wu, Yangyang;Han, Xiao
脂肪组织中线粒体功能的下调被认为是肥胖相关代谢紊乱发展的一个重要驱动因素。无机焦磷酸酶1（PPA 1）是一种催化无机焦磷酸盐水解为无机磷酸盐的酶，是细胞内发生凋亡所必需的。虽然PPA 1的改变与一些疾病有关，但PPA 1在代谢综合征中的重要性尚未被讨论。在本研究中，我们发现PPA 1基因敲除小鼠（PPA 1（+/-））在高脂饮食喂养下表现出糖耐量受损和严重的胰岛素抵抗。此外，还观察到脂肪组织发育受损和异位脂质蓄积。相反，通过腺相关病毒注射在脂肪组织中过表达PPA 1可以部分逆转PPA 1（+/-）小鼠中的代谢紊乱，这表明受损的脂肪组织功能是在PPA 1（+/-）小鼠中观察到的代谢紊乱的原因。机制研究表明，PPA 1作为一个过氧化物酶体增殖物激活受体γ靶基因，以维持脂肪细胞线粒体功能。果蝇脂肪体中PPA 1的特异性敲低导致线粒体形态受损，脂质储存减少，使果蝇对饥饿更加敏感。总之，我们的研究结果第一次证明了PPA 1在维持脂肪组织功能和全身代谢稳态中的重要性。
Downregulation of mitochondrial function in adipose tissue is considered as one important driver for the development of obesity-associated metabolic disorders. Inorganic pyrophosphatase 1 (PPA1) is an enzyme that catalyzes the hydrolysis of inorganic pyrophosphate to inorganic phosphate and is required for anabolism to take place in cells. Although alteration of PPA1 has been related to some diseases, the importance of PPA1 in metabolic syndromes has never been discussed. In this study, we found that global PPA1 knockout mice (PPA1(+/-)) showed impaired glucose tolerance and severe insulin resistance under high-fat-diet feeding. In addition, impaired adipose tissue development and ectopic lipid accumulation were observed. Conversely, overexpression of PPA1 in adipose tissue by adeno-associated virus injection can partly reverse the metabolic disorders in PPA1(+/-) mice, suggesting that impaired adipose tissue function is responsible for the metabolic disorders observed in PPA1(+/-) mice. Mechanistic studies revealed that PPA1 acted as a PPAR gamma target gene to maintain mitochondrial function in adipocytes. Furthermore, specific knockdown of PPA1 in fat body of Drosophila led to impaired mitochondria morphology, decreased lipid storage, and made Drosophila more sensitive to starvation. In conclusion, for the first time, our findings demonstrate the importance of PPA1 in maintaining adipose tissue function and whole-body metabolic homeostasis.