Differential Regulation of Thyroid Hormone Metabolism Target Genes during Non-thyroidal Illness Syndrome Triggered by Fasting or Sepsis in Adult Mice

Abstract

Fasting and sepsis induce profound changes in thyroid hormone (TH) central and peripheral metabolism. These changes affect TH action and are called the non-thyroidal illness syndrome (NTIS). To date, it is still debated whether NTIS represents an adaptive response or a real hypothyroid state at the tissue level. Moreover, even though it has been considered the same syndrome, we hypothesized that fasting and sepsis induce a distinct set of changes in thyroid hormone metabolism. Herein, we aimed to evaluate the central and peripheral expression of genes involved in the transport (MCT8/Slc16a2 and MCT10/Slc16a10), metabolism (Dio1, Dio2, and Dio3) and action (Thra and Thrb) of TH during NTIS induced by fasting or sepsis. Male mice were subjected to a 48 h period of fasting or cecal ligation and puncture (CLP)-induced sepsis. At the peripheral level, fasting led to: (1) reduced serum thyroxine (T4) and triiodothyronine (T3), expression of Dio1, Thra, Slc16a2, and MCT8 protein in liver; (2) increased hepatic Slc16a10 and Dio3 expression; and (3) decreased Slc16a2 and Slc16a10 expressions in the thyroid gland. Fasting resulted in reduction of Tshb expression in the pituitary and increased expression of Dio2 in total hypothalamus, arcuate (ARC) and paraventricular (PVN) nucleus. CLP induced sepsis resulted in reduced: (1) T4 serum levels; (2) Dio1, Slc16a2, Slc16a10, Thra, and Thrb expression in liver as well as Slc16a2 expression in the thyroid gland (3) Thrb and Tshb mRNA expression in the pituitary; (4) total leukocyte counts in the bone marrow while increased its number in peritoneal and pleural fluids. In summary, fasting- or sepsis-driven NTIS promotes changes in the set point of hypothalamus-pituitary-thyroid axis through different mechanisms. Reduced hepatic THRs expression in conjunction with reduced TH transporters expression in the thyroid gland may indicate, respectively, reduction in the peripheral action and in the secretion of TH, which may contribute to the low TH serum levels observed in both models.

Association of thyroid hormones and thyroid-stimulating hormone with mortality in adults admitted to the intensive care unit: A systematic review and meta-analysis

“…45,46 When the levels of circulating THs are low, high levels of local T3 in hypothalamic cells inhibit the expression of TRH and downregulate TSH activity directly. 47,48…”

“…45,46 When the levels of circulating THs are low, high levels of local T3 in hypothalamic cells inhibit the expression of TRH and downregulate TSH activity directly. 47,48 Although a decrease in THs may be an adaptive response to critical illness, like fasting, 36 low levels of THs have been demonstrated to be associated with high mortality. Researchers have tried to give patients T3, LT4, TRH, GH-releasing peptide-2, and growth hormone-releasing hormone as TH replacement.…”

Thyroid Hormone Transporters

“…Although other specific factors and pathways that regulate MCT8 (and MCT10) expression, especially in physiological relevant tissues, remain to be identified, several studies may provide some guidance for identifying such mechanisms. Recent studies in rodents indicated that expression both of Mct8 and Mct10 is responsive to feeding status and systemic inflammation because pronounced downregulation of hepatic and hypothalamic Mct8 expression levels was found during fasting (225)(226)(227) and reduced Mct8 expression in liver and brain vasculature during systemic inflammation (111,225).…”

Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

“…The relative sequence and importance of these various mechanisms in depressing the HPT axis and thyroid hormone function in different tissues and phases of critical illness are the subject of most NTIS publications ( 10 , 104 , 105 ). Notwithstanding the effect of other mechanisms, alterations in the activity of the deiodinase enzymes lead to a decrease in T3 and an increase in rT3 and thus a reduction in thyroid hormone function in peripheral tissues during prolonged critical illness [based on biopsies on ICU patients who died ( 142 ) and studies on mice ( 143 , 144 )]. Circulating thyroid hormone concentrations, however, only reveal the “tip of the iceberg” of the alterations occurring at the tissue level ( 141 , 145 ), which thus are often missed altogether in clinical settings ( 146 ).…”