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

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.