PPA1 Regulates Systemic Insulin Sensitivity by Maintaining Adipocyte Mitochondria Function as a Novel PPARγ Target Gene

Abstract

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 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 demonstrate the importance of PPA1 in maintaining adipose tissue function and whole-body metabolic homeostasis.