Introduction and Objective: Clinical evidence indicates that β1-blockers increase the risk of insulin resistance and metabolic disorders in obesity, yet the responsible cellular mechanisms remain unclear. This study aimed to identify the key effector cell type mediating β1-adrenergic regulation of obesity-induced metabolic dysfunction.Methods: Metabolic and immune phenotypes were assessed in high-fat diet (HFD)-fed mice with or without atenolol. CD4+ T cell-specific ADRB1 knockout mice underwent metabolic profiling, including glucose/insulin tolerance, serum lipids, hepatic enzymes, and histology. Hepatic and adipose Th subsets were analyzed by flow cytometry. ADRB1-overexpressing Th0 cells were adoptively transferred into Rag1-/- mice for functional validation. In vitro, Th1 differentiation and molecular analyses were performed to investigate ADRB1-mediated mechanisms.Results: CD4+ T cell-specific ADRB1 deletion in HFD-fed mice was sufficient to recapitulate atenolol-induced metabolic dysfunction, including worsened insulin resistance, glucose intolerance, and hepatic steatosis with inflammation, accompanied by hepatic Th1 expansion and increased IFN-γ. In vitro, ADRB1 activation suppressed, whereas its loss promoted, Th1 differentiation. Mechanistically, ADRB1 signaling intrinsically constrained Th1 lineage commitment through a cAMP-CREB-TOX-IL-12R axis. Adoptive transfer of ADRB1-overexpressing Th0 cells into Rag1-/- mice restored metabolic homeostasis, confirming a T cell-intrinsic causal role.Conclusion: β1-adrenergic signaling in CD4+ T cells restrained Th1-driven inflammation and maintained metabolic homeostasis. Genetic disruption of ADRB1 was necessary and sufficient to drive Th1-mediated hepatic inflammation and systemic insulin resistance, establishing T cell-intrinsic β1-adrenergic signaling as a central immune checkpoint linking obesity to metabolic dysfunction.
R. Qi: None. X. Lyu: None. L. Yao: None. L. You: None. J. Yan: None. C. Hu: None.
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