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

Suzhen Chen, Yanping Wang, Qian Zhou, Qiqi Qian, Quanxin Jiang, Chuchu Liu, Yan Liu, Peihui Zhou, Jie Xiong, Yao Zhang, Ning Wang, Yang Emma Li, Limin Yin, Hongyuan Yang and Junli Liu ()
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Suzhen Chen: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yanping Wang: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Qian Zhou: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Qiqi Qian: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Quanxin Jiang: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Chuchu Liu: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yan Liu: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Peihui Zhou: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Jie Xiong: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yao Zhang: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Ning Wang: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yang Emma Li: University of New South Wales
Limin Yin: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Hongyuan Yang: University of New South Wales
Junli Liu: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56026-2

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