Association between thyroid hormone resistance and obesity: a cross‐sectional study and mouse stimulation test

Abstract Objective Thyroid hormone influences key metabolic pathways, and reduced sensitivity to thyroid hormone is considered a new risk factor for adverse metabolic outcomes. However, the association between thyroid hormone resistance and obesity in euthyroid individuals is still unknown. Methods We enrolled 8021 euthyroid individuals, calculated thyroid hormone resistance indices, and analyzed the association between thyroid hormone resistance and obesity by regression analysis. Furthermore, we conducted the thyrotropin‐releasing hormone stimulation test in both control and obese mice ( n = 5) to demonstrate the association. Results The euthyroid adults with overweight and obesity had increased thyroid hormone resistance indices (all p < 0.05). BMI and prevalence of overweight and obesity increased (odds ratio of thyroid feedback quantile‐based index [OR TFQI ] = 1.164, p = 0.036; OR of free triiodothyronine/free thyroxine [OR FT3/FT4 ] = 1.508, p < 0.001) following the elevation of thyroid hormone resistance indices. Mediation analysis indicated a complete mediation effect (beta coefficient of indirect effect [β Ind ]= 6.838, p < 0.001) of metabolic disorders in the relationship. Furthermore, in the mice with obesity, the thyrotropin response to thyrotropin‐releasing hormone stimulation (68.33–90.89 pg/mL) was comparatively blunted ( p = 0.029). Conclusions Euthyroid individuals with obesity exhibit both central and peripheral thyroid hormone resistance, a phenomenon that is more pronounced in individuals with metabolic abnormalities. Thyroid hormone resistance is associated with an increased prevalence of overweight and obesity mediated by metabolic disorders.