Faculty, Staff and Student Publications

Language

English

Publication Date

1-14-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-56026-2

PMID

39809799

PMCID

PMC11733280

PubMedCentral® Posted Date

6-14-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Middle-aged obesity, characterized by excessive fat accumulation and systemic energy imbalance, often precedes various health complications. Recent research has unveiled a surprising link between DNA damage response and energy metabolism. Here, we explore the role of Eepd1, a DNA repair enzyme, in regulating adipose tissue function and obesity onset. Eepd1 is primarily expressed in adipose tissue, where its downregulation or deletion accelerates obesity development. We show that Eepd1 ablation hinders PKA activation, thereby inhibiting lipolysis and thermogenesis in adipose tissue. Notably, cold exposure enhances Eepd1's myristoylation, facilitating its anchorage to adipocyte membranes and subsequent activation of PKA, while a mutation at the myristoylation site of Eepd1 disrupts this process. Moreover, individuals with obesity exhibit reduced Eepd1 expression. Pharmacological restoration of Eepd1 with Retigabine dihydrochloride effectively mitigates obesity. This study reveals Eepd1's unexpected role in promoting adipose lipolysis and thermogenesis, underscoring its potential as a promising therapeutic target to combat obesity.

Keywords

Lipolysis, Thermogenesis, Cyclic AMP-Dependent Protein Kinases, Obesity, Animals, Humans, Mice, Male, Adipose Tissue, Mice, Inbred C57BL, Mice, Knockout, Adipocytes, Female

Published Open-Access

yes

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