Thyrotropin aggravates insulin resistance by promoting macrophage inflammation in subclinical hypothyroidism.
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ABSTRACT:
PROVIDER: PRJNA1149067 | ENA |
REPOSITORIES: ENA
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Project description:In subclinical hypothyroidism (SH), serum thyroid-stimulating hormone (TSH) correlated positively with insulin resistance; however, the precise mechanism is now unclear. Except for thyroid follicular epithelial cells, macrophages exhibit the highest level of TSHR expression. Thus, we wondered if TSH leads to insulin resistance by macrophages. We established thyroid-stimulating hormone receptor (Tshr) myeloid-specific knockout (TshrMKO) C57BL6 mice, and observed that TshrMKO mice showed improvement on high-fat diet (HFD) induced obesity and insulin resistance, compared to WT mice. TshrMKO animals showed decreased macrophages infiltration and M1 polarization in liver, adipose, and skeletal muscles. Co-culture experiments proved that Tshr deficient macrophages decreased gluconeogenesis in primary hepatocytes but increased glucose uptake in 3T3L1 adipocytes and L6 skeletal muscle cells through improving insulin signaling, versus WT. TSH promoted the release of Il6, Il1a and Il1b cytokines, which upregulated Egr1, Lcn2 and Socs3, reversed by the inhibitors Il6st and Il1ra. Lastly, EGR1 transcriptionally activated LCN2 and SOCS3. In conclusion, TSH promotes the secretion of IL6, IL1A, and IL1B via activating macrophage M1 polarization, which leads to that the upregulation of EGR1, transcriptionally activating LCN2 and SOCS3 and inducing insulin resistance in liver, adipose, and skeletal muscle in SH.
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Project description:No recent study has focused on clinical features of subclinical hypothyroidism (SCH), especially in older patients. TSH measurement has remarkably evolved these last 20 years and thus reconsideration is needed. In our prospective multicenter study (2012-2014) including 807 subjects aged <60 years (<60y) and 531 subjects ≥60 years (≥60y), we have monitored 11 hypothyroidism-related clinical signs (hCS) together with TSH, FT4, FT3 and anti-thyroperoxidase antibodies values. hCS expression has been compared in patients with SCH vs euthyroidism in each age group. The number of hCS above 60y of age were found to be more elevated in the euthyroid population (1.9 vs 1.6, p<0.01) than in the SCH population (2.3 vs 2.6, p=0.41) while increase in hCS is limited to SCH subjects in the <60y group (p<0.01). The percentage of subjects with at least 3 signs increased with SCH in the <60y group (42.6% vs 25.0%, p<0.01) but not ≥60y (34.4% vs 33.9%, p=0.96). In older individuals, only three hCS could be related to both SCH and a decreased T3/T4-ratio (0.26 vs 0.27, p<0.01), suggesting either a reduced activity of TSH, or an adaptive response with aging. While hCS are clearly associated with SCH in patients <60y, they are not so informative in older subjects. TSH measurements carried out on the basis of hCS need to be interpreted with caution in aged patients. A reassessment of the TSH reference range in older patients is clearly needed and should be associated to more appropriate monitoring of thyroid dysfunction.
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