Down-Regulation of Hepatic PPA1 Protects Against Obesity by Elevating FGF21 Production via eIF2α Phosphorylation

Chronic overnutrition promotes excessive hepatic triglyceride accumulation, subsequently leading to insulin resistance and systemic metabolic dysfunction. Inorganic pyrophosphatase 1 (PPA1), an enzyme that hydrolyzes inorganic pyrophosphate, plays a key role in driving synthetic biochemical reactions. Here, we identified PPA1 as a novel regulator of systemic energy expenditure that functions by controlling hepatic production of fibroblast growth factor 21 (FGF21). FGF21 is a hormone predominantly secreted by the liver that protects against obesity by enhancing whole-body energy expenditure. Although nutritional states and various transcription factors are known to regulate hepatic FGF21 expression, the underlying mechanisms remain elusive. In this study, we demonstrate that hepatic-specific deletion of PPA1 effectively attenuates high-fat diet–induced obesity, reduces hepatic lipid deposition, and improves systemic insulin sensitivity in vivo. PPA1 ablation in the liver significantly elevates circulating FGF21 levels and increases whole-body energy expenditure by promoting adipose tissue browning and thermogenesis. Knockdown of hepatic FGF21 expression partially counteracts the protective effect conferred by PPA1 deficiency. Mechanistically, hepatic PPA1 deficiency elevates FGF21 through the GCN2/eIF2α/ATF4 pathway, a process that is dependent on the loss of its enzymatic activity. Our findings not only establish PPA1 as a critical regulator of systemic energy metabolism but also identify it as a novel modulator of FGF21, highlighting its potential as a therapeutic target for obesity and related metabolic disorders. ARTICLE HIGHLIGHTS Pyrophosphatase 1 (PPA1) is upregulated in livers of high-fat diet–induced obese mice and metabolic dysfunction–associated steatotic liver disease patients. Hepatic PPA1 deletion protects mice against high-fat diet–induced obesity and related metabolic disorders by promoting whole-body energy expenditure. Deficiency of hepatic PPA1 expression facilitates fibroblast growth factor 21 production by activating the GCN2/eIF2α/ATF4 signaling pathway.