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Thyroid hormone receptor β (THRB) is posttranslationally modified by small ubiquitin-like modifier (SUMO). We generated a mouse model with a mutation that disrupted sumoylation at lysine 146 (K146Q) and resulted in desumoylated THRB as the predominant form in tissues. The THRB K146Q mutant mice had normal serum thyroxine (T4), markedly elevated serum thyrotropin-stimulating hormone (TSH; 81-fold above control), and enlargement of both the pituitary and the thyroid gland. The marked elevation in TSH, despite a normal serum T4, indicated blunted feedback regulation of TSH. The THRB K146Q mutation altered the recruitment of transcription factors to the TSHβ gene promoter, compared with WT, in hyperthyroidism and hypothyroidism. Thyroid hormone content (T4, T3, and rT3) in the thyroid gland of the THRB K146Q mice was 10-fold lower (per gram tissue) than control, despite normal TSH bioactivity. The expression of thyroglobulin and dual oxidase 2 genes in the thyroid was reduced and associated with modifications of cAMP response element-binding protein DNA binding and cofactor interactions in the presence of the desumoylated THRB. Therefore, thyroid hormone production had both TSH-dependent and TSH-independent components. We conclude that THRB sumoylation at K146 was required for normal TSH feedback regulation and TH synthesis in the thyroid gland, by a TSH-independent pathway.

Background: Few studies have focused on the association between lifestyle and subclinical hypothyroidism (SCH). The purpose of this study was to investigate the association between lifestyle and thyroid function in SCH. Methods: This study was a part of a community-based and cross-sectional study, the Epidemiological Survey of Thyroid Diseases in Fujian Province, China. A total of 159 participants with SCH (81 males and 78 females) and 159 euthyroid (87 males and 72 females) participants without any missing data were included in the analysis. General information and lifestyle information including sleep, exercise, diet and smoking habits of the participants was collected by questionnaire and Pittsburgh sleep quality index scale (PSQI) was collected. Thyroid stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb), thyroid globulin antibody (TgAb) and urine iodine concentration (UIC) were tested. Thyroid homeostasis parameter thyroid' s secretory capacity (SPINA-GT), Jostel's TSH index (TSHI), thyrotroph T4 sensitivity index (TTSI) were calculated. Logistic regression and multiple linear regression were performed to assess associations. Results: Compared with euthyroid subjects, patients with SCH were more likely to have poor overall sleep quality (15.1 vs.25.8 %, P = 0.018) and l less likely to stay up late on weekdays (54.7 vs. 23.9 % P < 0.001). In SCH group, exercise was the influencing factor of TSH (β= -0.224, P = 0.004), thyroid secretory capacity (β = 0.244, P = 0.006) and thyrotropin resistance (β = 0.206, P = 0.009). Iodine excess was the influencing factor of thyroid secretory capacity (β = 0.209, P = 0.001) and pituitary thyroid stimulating function (β = 0.167, P = 0.034). Smoking was the influencing factor of pituitary thyroid stimulating function (β = 0.161, P = 0.040). Staying up late on weekends was the influencing factor of thyroid secretory capacity (β = 0.151, P = 0.047). After adjusting for possible confounders, logistic regression showed that those with poor overall sleep quality assessed by PSQI and iodine excess had an increased risk of SCH (OR 2.159, 95 %CI 1.186–3.928, P = 0.012 and OR 2.119, 95 %CI 1.008–4.456, P = 0.048, respectively). Conclusions: Lifestyle including sleep, smoking, diet and exercise was closely related to thyroid function especially thyroid homeostasis in SCH. [ABSTRACT FROM AUTHOR]