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Exp. Mol. Med., Mar 03 2025, | https://doi.org/10.1038/s12276-025-01411-6 The brown fat-specific overexpression of RBP4 improves thermoregulation and systemic metabolism by activating the canonical adrenergic signaling pathway

Jong Yoen Park ^1,8, Eun Sun Ha ^1,8, Jimin Lee ², Pierre-Jacques Brun ³, Yeri Kim ¹, Sung Soo Chung ⁴, Daehee Hwang ^2,5, Seung-Ah Lee^6,7,* and Kyong Soo Park ^1,6,*

¹Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
²School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
³Department of Medicine, Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁴Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
⁵Bioinformatics Institute, Bio-MAX, Seoul National University, Seoul, Republic of Korea.
⁶Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea.
⁷ProGen Co. Ltd., 07789 Seoul, Republic of Korea.
⁸These authors contributed equally: Jong Yoen Park, Eun Sun Ha.

^*Corresponding authors: correspondence to Seung-Ah Lee or Kyong Soo Park

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.

논문정보

형식Research article
게재일2025년 03월 (BRIC 등록일 2025-03-05)
연구진국내(교신)+국외 연구진
분야 의약학 > 분자세포의학

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