PPA1 Regulates Systemic Insulin Sensitivity by Maintaining Adipocyte Mitochondria Function as a Novel PPARγ Target Gene
figureposted on 2021-03-15, 20:42 authored by Ye Yin, Yangyang Wu, Xu Zhang, Yeting Zhu, Yue Sun, Jiani Yu, Yufei Gong, Peng Sun, Haiyan Lin, Xiao Han
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 catalyzes the hydrolysis of PPi to Pi, and is required for anabolism to take place in cells. Although alternation of PPA1 has been related to some diseases, the importance of PPA1 in metabolic syndromes has never been discussed before. In this study, we found that global PPA1 knockout mice (PPA1+/-) showed impaired glucose tolerance and severe insulin resistance under HFD feeding. In addition, impaired adipose tissue development and ectopic lipid accumulation were also observed. Conversely, overexpression of PPA1 in adipose tissue by AAV 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 PPARγ 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 demonstrated the importance of PPA1 in maintaining adipose tissue function and whole body metabolic homeostasis.