Myristoylated Eepd1 Enhances Lipolysis and Thermogenesis through PKA Activation to Combat Obesity
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 enz...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56026-2 |
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| author | 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 Junli Liu |
| author_facet | 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 Junli Liu |
| author_sort | Suzhen Chen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-f447b4dfcebd4102922b1fe44856b182 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-f447b4dfcebd4102922b1fe44856b1822025-01-19T12:31:17ZengNature PortfolioNature Communications2041-17232025-01-0116112110.1038/s41467-025-56026-2Myristoylated Eepd1 Enhances Lipolysis and Thermogenesis through PKA Activation to Combat ObesitySuzhen Chen0Yanping Wang1Qian Zhou2Qiqi Qian3Quanxin Jiang4Chuchu Liu5Yan Liu6Peihui Zhou7Jie Xiong8Yao Zhang9Ning Wang10Yang Emma Li11Limin Yin12Hongyuan Yang13Junli Liu14Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineSchool of Biotechnology and Biomolecular Sciences, University of New South WalesShanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineSchool of Biotechnology and Biomolecular Sciences, University of New South WalesShanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineAbstract 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.https://doi.org/10.1038/s41467-025-56026-2 |
| spellingShingle | 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 Junli Liu Myristoylated Eepd1 Enhances Lipolysis and Thermogenesis through PKA Activation to Combat Obesity Nature Communications |
| title | Myristoylated Eepd1 Enhances Lipolysis and Thermogenesis through PKA Activation to Combat Obesity |
| title_full | Myristoylated Eepd1 Enhances Lipolysis and Thermogenesis through PKA Activation to Combat Obesity |
| title_fullStr | Myristoylated Eepd1 Enhances Lipolysis and Thermogenesis through PKA Activation to Combat Obesity |
| title_full_unstemmed | Myristoylated Eepd1 Enhances Lipolysis and Thermogenesis through PKA Activation to Combat Obesity |
| title_short | Myristoylated Eepd1 Enhances Lipolysis and Thermogenesis through PKA Activation to Combat Obesity |
| title_sort | myristoylated eepd1 enhances lipolysis and thermogenesis through pka activation to combat obesity |
| url | https://doi.org/10.1038/s41467-025-56026-2 |
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