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Beta3-Adrenergic receptor downregulation leads to adipocyte catecholamine resistance in obesity

ABSTRACT: This project investigates mechanisms underlying catecholamine resistance in obesity. We found that adipocyte Beta3-adrenergic receptor (Adrb3), the dominant isoform mediating lipolysis, undergoes transcriptional downregulation after ligand exposure or inflammatory stimulation, representing homologous and heterologous desensitization, respectively. Both processes are mediated by the EPAC-RAP2A-PI-PLC-TRIB1 signaling axis, which promotes degradation of the transcription factor C/EBP-alpha and suppresses Adrb3 expression. Pharmacologic inhibition of EPAC/RAP restored Beta3-adrenergic responsiveness, enhanced lipolysis, and improved energy expenditure in obese mice. These findings reveal a molecular pathway contributing to catecholamine resistance and impaired energy mobilization in obesity.

PROVIDER: GSE315788 | GEO | 2026/01/07

REPOSITORIES: GEO

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