Abstract
Background: Recent studies suggest connection between the thyroid stimulating hormone (TSH) and insulin resistance (IR). Adipose tissue is one of insulin's target tissues. However, currently the regulatory mechanism of TSH on the adipose tissue is not fully investigated yet. Methods: We constructed a subclinical hypothyroidism (SCH) mouse model induced by methimazole with elevated TSH levels and then observed its metabolic profile, adipose tissue IR, and the adipose tissue macrophages (ATMs) phenotype. In vitro, we treated RAW264.7 cells and bone marrow-derived macrophages (BMDM) to assess the effect of TSH on macrophage polarization and explore the specific underlying mechanisms. Results: SCH mice exhibited a poorer metabolic profile and an advanced adipose tissue IR. Meanwhile, the number of M1 ATMs was increased in SCH mice adipose tissue. In vitro, TSH induced endoplasmic reticulum stress in macrophages, which activated the GRP78-ATF6-CHOP signaling pathway, and further promoted M1 macrophage polarization. 4-phenylbutyric acid (4-PBA), an endoplasmic reticulum stress inhibitor, corrected the polarization imbalance of ATMs in SCH mice adipose tissue and improved adipose tissue dysfunction and IR. Conclusion: TSH activated endoplasmic reticulum stress in macrophages, which induced the polarization of ATMs toward a pro-inflammatory M1 phenotype and promotes adipose tissue IR. Our findings highlight the possible relationship of TSH with immunity and metabolism.