Page 100 - GTM-4-2

Global Translational Medicine Thyroid status in obesity

are essential for thyroid hormone synthesis. The authors receiving HCD. Previously, we demonstrated that 16 weeks
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suggested that the decrease in NIS activity could be due of HCD led to increased serum TSH levels and heightened
to lipotoxicity. The decrease in TPO activity in obesity 5′-deiodinase type 1 (DI-1) activity in the liver. Since DI-1
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may also be attributable to proinflammatory IL, including catalyzes the conversion of T4 to the active hormone T3,
IL-6. Our previous studies revealed that IL-6 levels in these findings suggest an adaptive response to prolonged
2
thyroid tissue were significantly reduced almost twofold overnutrition, aimed at increasing metabolic activity under
in HCD-fed rats compared to the control. However, upon excessive caloric intake. 22
switching to StD, IL-6 levels began to normalize, with the Notably, thyroid follicles store large amounts of thyroid
most substantial recovery observed in rats subjected to a hormones, which can be released into the blood circulation
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combined intervention of StD and moderate treadmill under the influence of TSH, despite the inhibition of T4
exercise (“HCD/StD + running”). IL-6 is known to play and T3 synthesis. However, a decrease in TPO activity,
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a pleiotropic role in activating intracellular signaling along with morphological signs of thyroid hypofunction,
pathways, including phosphatidylinositol 3-kinase, AMP- indicates an incipient trend towards hypothyroidism.
activated protein kinase, and Janus kinase pathways, all
of which are necessary for the regulation of intracellular A prolonged high-fat diet may eventually lead to overt
metabolism. This suggests that IL-6 reduction may thyroid dysfunction, as demonstrated by Shao et al., who
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contribute to metabolic suppression in the thyroid gland, reported decreased T4 levels and persistently high TSH
14
while dietary and physical interventions can restore levels in rats fed a high-fat diet for 24 – 30 weeks. This
metabolic function. Interestingly, our data indicate that reduction in T4 was accompanied by downregulation of
exercise alone (even without dietary changes) led to partial thyroid hormone synthesis-related proteins in thyroid
normalization of IL-6 levels, suggesting that physical tissue, suggesting a progressive decline in thyroid function.
activity may directly stimulate energy metabolism within Similarly, studies in genetically obese mouse models reveal
the thyroid gland, potentially mitigating HCD-induced pronounced thyroid dysfunction with reduced circulating
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hypofunction. thyroid hormone levels. Thyroid hypofunction has also
been reported in obese rats with streptozotocin-induced
Our findings indicate that the decrease in TPO type 2 diabetes (T2DM). Patients with T2DM often
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activity in thyroid tissue occurs against a background of manifest hypothyroidism. Insulin resistance has been
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reduced MDA levels, a fact that deserves special attention. shown to play a crucial role in both T2DM and thyroid
Generally, obesity is associated with increased lipid dysfunction. 26
peroxidation, leading to elevated MDA levels in various
tissues. We previously demonstrated this phenomenon in Several molecular mechanisms underlie the interplay
muscle tissue homogenates of rats subjected to a 16-week between insulin resistance and thyroid dysfunction.
HCD. However, in the thyroid gland, we observed the Insulin resistance in subclinical hypothyroidism is linked
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opposite trend—a decrease in MDA levels despite visceral to decreased insulin-stimulated glucose transport, likely
obesity. This paradox can be explained by the specificity caused by impaired translocation of glucose transporter
of TPO, a hemin peroxidase. Only the oxidized form of type 2. The Thr92Ala polymorphism in the gene encoding
this enzyme can oxidize the substrate. Efficient thyroid DI-2 reduces T3 activation, leading to intrathyroidal
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hormone synthesis depends on the adequate production deiodination defects and contributing to insulin
of hydrogen peroxide (H O ), which serves as an oxidant resistance. 27
2
2
in the synthesis of T4 and T3. H O is produced by a According to Shpakov, altered adenylate cyclase
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2
2
member of the NADPH oxidase (NOX) family—double signaling is the most important mechanism linking
oxidase 2 (DUOX2). Studies indicate that a deficient thyroid disorders to T2DM; in T2DM, there is reduced
reactive oxygen species production, due to insufficient sensitivity of the thyrocyte adenylate cyclase signaling
NOX/DUOX activity, can lead to thyroid hypofunction in system in thyrocytes to TSH, along with decreased thyroid
rodent models. In this study, the observed reduction in hormone receptor expression in peripheral tissues and
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MDA content in thyroid tissue and the positive correlation dysregulated deiodinase activity. A decreased activity of
between TPO activity and MDA levels in males suggest DI-2, a deiodinase that converts T4 into the active form
a potential decrease in H O production at the apical of T3, is associated with insulin resistance. A decreased
2
2
membrane of thyrocytes. However, the precise mechanisms activity of DI-3, a deiodinase that catalyzes T3 inactivation
underlying reduced TPO activity in obesity remain poorly in pancreatic β-cells, suppresses insulin secretion and leads
understood. to insulin deficiency. Together, these findings highlight
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Analysis of thyroid status parameters revealed a the bidirectional relationship between thyroid dysfunction
statistically significant increase in blood T4 levels in rats and insulin resistance, where thyroid hormone imbalances
Volume 4 Issue 2 (2025) 92 doi: 10.36922/GTM025080020