The brown fat-specific overexpression of RBP4 improves thermoregulation and systemic metabolism by activating the canonical adrenergic signaling pathway
Abstract Retinol-binding protein 4 (RBP4), the sole specific carrier for retinol (vitamin A) in circulation, is highly expressed in liver and adipose tissues. Previous studies have demonstrated that RBP4 plays a role in cold-mediated adipose tissue browning and thermogenesis. However, the role of RB...
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Nature Publishing Group
2025-03-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-025-01411-6 |
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| author | Jong Yoen Park Eun Sun Ha Jimin Lee Pierre-Jacques Brun Yeri Kim Sung Soo Chung Daehee Hwang Seung-Ah Lee Kyong Soo Park |
| author_facet | Jong Yoen Park Eun Sun Ha Jimin Lee Pierre-Jacques Brun Yeri Kim Sung Soo Chung Daehee Hwang Seung-Ah Lee Kyong Soo Park |
| author_sort | Jong Yoen Park |
| collection | DOAJ |
| description | Abstract Retinol-binding protein 4 (RBP4), the sole specific carrier for retinol (vitamin A) in circulation, is highly expressed in liver and adipose tissues. Previous studies have demonstrated that RBP4 plays a role in cold-mediated adipose tissue browning and thermogenesis. However, the role of RBP4 in brown adipose tissue and its metabolic significance remain unclear. Here we generated and studied transgenic mice that express human RBP4 (hRBP4), specifically in brown adipocytes (UCP1-RBP4 mice), to better understand these uncertainties. When fed a chow diet, these mice presented significantly lower body weights and fat mass than their littermate controls. The UCP1-RBP4 mice also showed significant improvements in glucose clearance, enhanced energy expenditure and increased thermogenesis in response to a cold challenge. This was associated with increased lipolysis and fatty acid oxidation in brown adipose tissue, which was attributed to the activation of canonical adrenergic signaling pathways. In addition, high-performance liquid chromatography analysis revealed that plasma RBP4 and retinol levels were elevated in the UCP1-RBP4 mice, whereas their hepatic retinol levels decreased in parallel with a chow diet. Steady-state brown fat levels of total retinol were significantly elevated in the UCP1-RBP4 mice, suggesting that their retinol uptake was increased in RBP4-expressing brown adipocytes when fed a chow diet. These findings reveal a critical role for RBP4 in canonical adrenergic signaling that promotes lipid mobilization and oxidation in brown adipocytes, where the harnessed energy is dissipated as heat by adaptive thermogenesis. |
| format | Article |
| id | doaj-art-e355fe15447041c6987f17db5ca005b6 |
| institution | DOAJ |
| issn | 2092-6413 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj-art-e355fe15447041c6987f17db5ca005b62025-08-20T03:04:59ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132025-03-0157355456610.1038/s12276-025-01411-6The brown fat-specific overexpression of RBP4 improves thermoregulation and systemic metabolism by activating the canonical adrenergic signaling pathwayJong Yoen Park0Eun Sun Ha1Jimin Lee2Pierre-Jacques Brun3Yeri Kim4Sung Soo Chung5Daehee Hwang6Seung-Ah Lee7Kyong Soo Park8Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National UniversityDepartment of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National UniversitySchool of Biological Sciences, Seoul National UniversityDepartment of Medicine, Institute of Human Nutrition, College of Physicians and Surgeons, Columbia UniversityDepartment of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National UniversityBiomedical Research Institute, Seoul National University HospitalSchool of Biological Sciences, Seoul National UniversityGenomic Medicine Institute, Medical Research Center, Seoul National UniversityDepartment of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National UniversityAbstract Retinol-binding protein 4 (RBP4), the sole specific carrier for retinol (vitamin A) in circulation, is highly expressed in liver and adipose tissues. Previous studies have demonstrated that RBP4 plays a role in cold-mediated adipose tissue browning and thermogenesis. However, the role of RBP4 in brown adipose tissue and its metabolic significance remain unclear. Here we generated and studied transgenic mice that express human RBP4 (hRBP4), specifically in brown adipocytes (UCP1-RBP4 mice), to better understand these uncertainties. When fed a chow diet, these mice presented significantly lower body weights and fat mass than their littermate controls. The UCP1-RBP4 mice also showed significant improvements in glucose clearance, enhanced energy expenditure and increased thermogenesis in response to a cold challenge. This was associated with increased lipolysis and fatty acid oxidation in brown adipose tissue, which was attributed to the activation of canonical adrenergic signaling pathways. In addition, high-performance liquid chromatography analysis revealed that plasma RBP4 and retinol levels were elevated in the UCP1-RBP4 mice, whereas their hepatic retinol levels decreased in parallel with a chow diet. Steady-state brown fat levels of total retinol were significantly elevated in the UCP1-RBP4 mice, suggesting that their retinol uptake was increased in RBP4-expressing brown adipocytes when fed a chow diet. These findings reveal a critical role for RBP4 in canonical adrenergic signaling that promotes lipid mobilization and oxidation in brown adipocytes, where the harnessed energy is dissipated as heat by adaptive thermogenesis.https://doi.org/10.1038/s12276-025-01411-6 |
| spellingShingle | Jong Yoen Park Eun Sun Ha Jimin Lee Pierre-Jacques Brun Yeri Kim Sung Soo Chung Daehee Hwang Seung-Ah Lee Kyong Soo Park The brown fat-specific overexpression of RBP4 improves thermoregulation and systemic metabolism by activating the canonical adrenergic signaling pathway Experimental and Molecular Medicine |
| title | The brown fat-specific overexpression of RBP4 improves thermoregulation and systemic metabolism by activating the canonical adrenergic signaling pathway |
| title_full | The brown fat-specific overexpression of RBP4 improves thermoregulation and systemic metabolism by activating the canonical adrenergic signaling pathway |
| title_fullStr | The brown fat-specific overexpression of RBP4 improves thermoregulation and systemic metabolism by activating the canonical adrenergic signaling pathway |
| title_full_unstemmed | The brown fat-specific overexpression of RBP4 improves thermoregulation and systemic metabolism by activating the canonical adrenergic signaling pathway |
| title_short | The brown fat-specific overexpression of RBP4 improves thermoregulation and systemic metabolism by activating the canonical adrenergic signaling pathway |
| title_sort | brown fat specific overexpression of rbp4 improves thermoregulation and systemic metabolism by activating the canonical adrenergic signaling pathway |
| url | https://doi.org/10.1038/s12276-025-01411-6 |
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