Mechanistic insights into TSH-mediated macrophage mitochondrial dysfunction via TSHR signaling in metabolic disorders

作者：Yuhan Zhang, Hanyu Wang, Mengfei Fu, Liu Yang, Xiao Dong Chen, Zixuan Wang, Jiaqi Liu, Hui Sun · 发表于：Free Radical Biology and Medicine · 年份：2025 · DOI：10.1016/j.freeradbiomed.2025.07.028 · 被引用次数：5 · 研究领域：Cancer, Hypoxia, and Metabolism、Diet and metabolism studies

The role of thyroid-stimulating hormone receptor (TSHR) in macrophages on adipose tissue metabolic disorders remains unclear. We generated macrophage-specific TSHR knockout mice (LysM-Cre Tshr fl/fl ) using the Cre/LoxP system and induced subclinical hypothyroidism (SCH) via methimazole treatment. Metabolic/inflammatory phenotypes were assessed via glucose/insulin tolerance tests, histology, and molecular analyses. Mitochondrial function and proinflammatory polarization were examined in primary peritoneal macrophages and RAW264.7 cells under TSH stimulation. The results showed macrophage TSHR deletion attenuated SCH-induced insulin resistance, inflammatory infiltration, and adipocyte hypertrophy. TSH triggered proinflammatory polarization via TSHR-dependent mitochondrial permeability transition pore (mPTP) overactivation, oxidative stress, and impaired electron transport chain function. Cyclophilin D (CypD), a key mPTP regulator, mediated TSH-induced mitochondrial dysfunction. Pharmacological CypD inhibition with cyclosporine A(CsA) reversed TSH-driven inflammation and metabolic deficits in vitro and in vivo . We conclude that TSH promotes adipose tissue dysfunction via macrophage TSHR signaling by enhancing CypD acetylation to disrupt mitochondrial homeostasis and drive pro-inflammatory polarization, unveiling the TSHR-CypD axis as a therapeutic target for SCH-related metabolic disorders. • Macrophage TSHR plays a key role in the metabolic disorders of adipose tissue in SCH ...