PPA1 Facilitates Thermogenesis in Brown and Beige Fat by Regulating the Mitochondrial Localization of FUS

Abstract

Objective

Brown and beige adipocytes dissipate energy through thermogenesis, and the impaired thermogenic function of these adipocytes is a key driver of obesity and related metabolic disorders. However, the molecular mechanisms governing adipocyte thermogenesis are not fully understood. This study investigated the role of inorganic pyrophosphatase 1 (PPA1) in regulating adipocyte thermogenesis and assessed its potential as a therapeutic target for obesity and metabolic disorders.

Methods

To investigate the function of PPA1 in adipose tissue thermogenesis, we generated adipose-specific heterozygous PPA1 knockout mice via the Cre-loxP system and established cold exposure models. PPA1 deletion effects were assessed by hematoxylin and eosin (H&E) staining, immunofluorescence, quantitative polymerase chain reaction (qPCR), and immunoblotting. Mitochondrial changes during browning were further characterized via transmission electron microscopy (TEM), mitochondrial DNA (mtDNA) quantification, qPCR, and Western blotting. The molecular mechanisms involved were subsequently dissected via mass spectrometry, coimmunoprecipitation (Co-IP), and immunofluorescence colocalization.

Results

Adi-PPA1^fl/+ mice presented impaired adipose tissue thermogenesis upon cold exposure. Mechanistically, PPA1 deficiency impaired adipose browning in an enzyme activity-independent manner. PPA1 knockdown promoted the aberrant translocation and accumulation of fused in sarcoma (FUS) to mitochondria, which triggered mitochondrial dysfunction and suppressed browning. Crucially, silencing FUS effectively rescued the mitochondrial defects caused by PPA1 depletion.

Conclusion

PPA1 functions as a nonenzymatic positive regulator of adipocyte thermogenesis by interacting with FUS to prevent its mitochondrial mislocalization, thereby maintaining mitochondrial function and promoting adipose browning. These findings highlight PPA1 as a potential therapeutic avenue for obesity and metabolic disorders.

Keywords

PPA1 / Adipose browning / Thermogenesis / Mitochondria / FUS / Obesity

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Funding

National Natural Science Foundation of China(82270874)

Capital Medical University(PYZ24119)

RIGHTS & PERMISSIONS

The Author(s), under exclusive licence to the Huazhong University of Science and Technology