Abstract
Evidence from clinical and experimental data suggests that thyrotropin receptor (TSHR) signaling is involved in energy expenditure through its impact on white adipose tissue (WAT) and brown adipose tissue (BAT). TSHR expression increases during mesenchymal stem cell (MSC) differentiation into fat. We hypothesize that TSHR activation [TSHR*, elevated thyroid-stimulating hormone, thyroid-stimulating antibodies (TSAB), or activating mutation] influences MSC differentiation, which contributes to body composition changes seen in hypothyroidism or Graves’ disease (GD). The role of TSHR activation on adipogenesis was first investigated using ex vivo samples. Neck fat (all euthyroid at surgery) was obtained from GD (n = 11, TSAB positive), toxic multinodular goiter (TMNG, TSAB negative) (n = 6), and control patients with benign euthyroid disease (n = 11, TSAB negative). The effect of TSHR activation was then analyzed using human primary abdominal subcutaneous preadipocytes (n = 16). Cells were cultured in complete medium (CM) or adipogenic medium [ADM, containing thiazolidinedione (TZD), PPARγ agonist, which is able to induce BAT formation] with or without TSHR activation (gain-of-function mutant) for 3 weeks. Adipogenesis was evaluated using oil red O (ORO), counting adipogenic foci, qPCR measurement of terminal differentiation marker (LPL). BAT [PGC-1α, uncoupling protein 1 (UCP1), and ZIC1], pre-BAT (PRDM16), BRITE− (CITED1), or WAT (LEPTIN) markers were analyzed by semiquantitative PCR or qPCR. In ex vivo analysis, there were no differences in the expression of UCP1, PGC-1α, and ZIC1. BRITE marker CITED1 levels were highest in GD followed by TMNG and control (p for trend = 0.009). This was associated with higher WAT marker LEPTIN level in GD than the other two groups (p < 0.001). In primary cell culture, TSHR activation substantially enhanced adipogenesis with 1.4 ± 0.07 (ORO), 8.6 ± 1.8 (foci), and 5.5 ± 1.6 (LPL) fold increases compared with controls. Surprisingly, TSHR activation in CM also significantly increased pre-BAT marker PRDM16; furthermore, TZD-ADM induced adipogenesis showed substantially increased BAT markers, PGC-1α and UCP1. Our study revealed that TSHR activation plays an important role in the adipogenesis process and BRITE/pre-BAT formation, which leads to WAT or BAT phenotype. It may contribute to weight loss as heat during hyperthyroidism and later transforms into WAT posttreatment of GD when patients gain excess weight.
Highlights
Excess thyrotropin receptor (TSHR) activation occurs in two common conditions, Graves’ disease (GD) in which thyroidstimulating antibodies (TSAB) mimic thyroid-stimulating horm one (TSH) causing hyperthyroidism and primary hypothyroidism when elevated circulating TSH compensates for low thyroid hormone (T4/T3) levels resulting from the failing gland [1]
Expression levels of TSHR did not differ in control, toxic multinodular goiter (TMNG), or GD groups (Figure 1A); we analyzed the potential effect of TSAB/TSHR* on fat phenotype
Higher transcript levels of LEPTIN (WAT marker) were detected in GD samples compared to TMNG and control (p < 0.001) (Figure 1C), which indicates that adipogenesis in the white adipose tissue (WAT) compartment is ongoing in GD
Summary
Excess thyrotropin receptor (TSHR) activation occurs in two common conditions, Graves’ disease (GD) in which thyroidstimulating antibodies (TSAB) mimic thyroid-stimulating horm one (TSH) causing hyperthyroidism and primary hypothyroidism when elevated circulating TSH compensates for low thyroid hormone (T4/T3) levels resulting from the failing gland [1]. Both confer alterations in body composition, e.g., more than 90% of people with GD lose weight, mainly muscle mass and fat [2], while hypothyroidism increases fat and bone mineral density. The above evidence led us to hypothesize that TSHR activation per se may contribute to changes in body composition separately from the effects of thyroid hormone levels, exerting a direct impact on adipose tissues metabolism [25]
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