Myristoylated Eepd1 Enhances Lipolysis and Thermogenesis through PKA Activation to Combat Obesity.

Summary

This mechanistic study identifies Eepd1 as an adipose-enriched, myristoylation-dependent activator of PKA signaling that drives lipolysis and thermogenesis. Loss of Eepd1 impairs cold-induced energy expenditure, while pharmacologic restoration (retigabine dihydrochloride) mitigates obesity, highlighting Eepd1 as a therapeutic target.

Key Findings

• Eepd1 is highly expressed in adipose tissue; its downregulation/deletion accelerates obesity.
• Eepd1 ablation impairs PKA activation, reducing lipolysis and thermogenesis; cold exposure enhances Eepd1 myristoylation and membrane anchoring.
• A myristoylation-site mutation disrupts PKA activation; obese individuals have reduced Eepd1 expression.
• Retigabine dihydrochloride pharmacologically restores Eepd1 function and mitigates obesity.

Clinical Implications

While preclinical, targeting Eepd1 myristoylation/PKA activation could inspire novel anti-obesity therapies that enhance thermogenesis; Eepd1 expression may serve as a biomarker.

Limitations

• Predominantly animal and cellular models; human causality and efficacy remain unproven
• Retigabine’s safety/repurposing feasibility for obesity requires rigorous clinical evaluation

Future Directions

Define upstream regulators of Eepd1 myristoylation, evaluate Eepd1 agonists or membrane-targeting strategies, and conduct translational studies in humans to assess biomarker utility and therapeutic efficacy.