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 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.