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

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

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 histo

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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