Influence of thyroid hormones on brown adipose tissue activity and browning of white adipose tissues in mice

Administration of thyroid hormones (TH) to mammals leads to an increase in basal metabolic rate and thermogenesis. These effects have been attributed to direct actions of TH on metabolically active tissues, such as brown adipose tissue (BAT). Furthermore, TH might stimulate “browning”, i.e. conversion of existing white fat cells to ''brite'' or ''beige'' adipocytes with features of brown adipocytes. However, the impact of TH on BAT activity and “browning” of white adipocytes has not been analyzed under well-controlled conditions in the same experimental setting.
Therefore, it was assessed how thyroid dysfunction, i.e. hyper- and hypothyroidism, affects 1) activity of BAT by ¹⁸F-FDG PET/MRI, and 2) affects gene expression of brown and beige adipose tissue differentiation markers in white adipose tissues (inguinal and epididymal, iWAT and eWAT, respectively) and interscapular BAT (iBAT) in mice. We randomized female C57BL/6NTac mice and rendered them hyper- or hyperthyroid (n = 20 per group) according to ATA guidelines (Bianco et al. Thyroid 2014). After 4 weeks of treatment, small animal PET/MR analysis revealed that hypothyroid mice had significantly decreased and hyperthyroid mice had significantly increased interscapular BAT (iBAT) ¹⁸F-FDG uptake as compared to euthyroid controls (SUV 3.5 ± 0.7 vs. 6.2 ± 0.6 and SUV 78.0 ± 2.1 vs. 6.16 ± 0.6, respectively). In addition to the findings in iBAT, hypothyroid mice also had significantly diminished glucose disposal in skeletal muscle as compared to both other groups. However, despite the iBAT of hypothyroid mice showing low metabolic activity, significantly higher levels of Ucp1 mRNA was found in iBAT when compared with hyper- and euthyroid animals (p < 0.05 for both). In accordance with these findings, other thermogenic markers including Prdm16, Fgf21, Cidea, Elovl3 and Cox7a1 were all overexpressed in the hypothyroid iBAT. In contrast, the thermogenic genes Ucp1, Prdm16, Fgf21, Cidea, Pgc1α were upregulated in eWAT in hyperthyroid mice as compared to hypothyroid and euthyroid mice. In addition, also markers for beige adipocytes (Cd137, Tmem26), and adipocyte recruitment (Zfp423) were significantly increased in the eWAT of hyperthyroid mice as compared hypo-and euthyroid mice.
In conclusion, these data suggest that TH induce both BAT activity and the thermogenic program in white adipose tissues possibly leading to the browning of white fat depots.