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

Area of Science:

• Endocrinology
• Immunology
• Metabolic Disorders

Background:

• The role of thyroid-stimulating hormone receptor (TSHR) in macrophages concerning adipose tissue metabolic disorders is not fully understood.
• Subclinical hypothyroidism (SCH) is linked to metabolic complications, but the underlying mechanisms involving macrophage TSHR are unclear.

Purpose of the Study:

• To investigate the function of macrophage TSHR in the development of metabolic and inflammatory disorders during SCH.
• To elucidate the molecular mechanisms by which TSHR signaling in macrophages impacts adipose tissue homeostasis.

Main Methods:

• Generated macrophage-specific TSHR knockout mice (LysM-Cre Tshr^fl/fl) and induced SCH using methimazole.
• Assessed metabolic and inflammatory phenotypes using glucose/insulin tolerance tests, histology, and molecular analyses.
• Examined mitochondrial function and macrophage polarization in vitro and in vivo, focusing on TSH stimulation and Cyclophilin D (CypD) inhibition.

Main Results:

• Macrophage TSHR deletion attenuated SCH-induced insulin resistance, inflammation, and adipocyte hypertrophy.
• TSH promoted proinflammatory macrophage polarization via TSHR-dependent mitochondrial dysfunction, including mPTP overactivation and oxidative stress.
• CypD mediated TSH-induced mitochondrial dysfunction, and its inhibition with cyclosporine A (CsA) reversed these effects both in vitro and in vivo.

Conclusions:

• TSHR signaling in macrophages exacerbates adipose tissue dysfunction in SCH by disrupting mitochondrial homeostasis and promoting pro-inflammatory polarization.
• The TSHR-CypD axis represents a potential therapeutic target for managing metabolic disorders associated with SCH.