Adenylosuccinate Synthase 1 Deficiency Improves Energy Metabolism by Promoting Adipose Tissue Re‐esterification via Glycerol Kinase Upregulation

Purine metabolism enzymes have a well‐established role in maintaining the nucleotide pool, thereby sustaining cellular energy homeostasis. Although reduced purine nucleotide concentrations have been reported can influence uncoupling protein 1 (UCP1)activity in thermogenic adipocytes, our study identifies adenylosuccinate synthase 1 (Adss1), an enzyme in de novo purine biosynthesis, as a critical regulator of metabolic remodeling in inguinal white adipose tissue (iWAT) through a mechanism distinct from UCP1 activity. Adipose‐specific Adss1 knockout mice showed increased energy expenditure and resistance to diet‐induced obesity with improved metabolic dysfunction. Loss of Adss1 upregulates glycerol kinase (Gk) expression, thereby stimulating glycerol‐dependent fatty acid re‐esterification in iWAT. This adaptation prevents lipotoxic accumulation of free fatty acids and drives lipid synthesis–oxidation cycling, activating thermogenic programs. The Adss1 deficiency‐driven iWAT browning and re‐esterification are abolished in adipose‐specific Adss1 and Gk double‐knockout mice, confirming the functional dependence on Gk. Mechanistically, Adss1 interacts with histone deacetylase 3 (HDAC3) in the cytosol of beige adipocytes, altering its nucleo‐cytoplasmic distribution. Adss1 deficiency reduced nuclear HDAC3 and increased cytosolic pools, which suppresses HDAC activity and enhances histone H3 lysine 27 acetylation at the Gk promoter, elevating Gk expression. Collectively, our findings reveal an unrecognized role of Adss1 in adipose physiology, highlighting its potential as a regulator of adipose energy metabolism.