Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice
Open accessAbstract
During illness, major changes in thyroid hormone metabolism and regulation occur; these are collectively known as non-thyroidal illness and are characterized by decreased serum triiodothyronine (T(3)) and thyroxine (T(4)) without an increase in serum TSH. Whether alterations in the central part of the hypothalamus-pituitary-thyroid (HPT) axis precede changes in peripheral thyroid hormone metabolism instead of vice versa, or occur simultaneously, is presently unknown. We therefore studied the time-course of changes in thyroid hormone metabolism in the HPT axis of mice during acute illness induced by bacterial endotoxin (lipopolysaccharide; LPS).LPS rapidly induced interleukin-1beta mRNA expression in the hypothalamus, pituitary, thyroid and liver. This was followed by almost simultaneous changes in the pituitary (decreased expression of thyroid receptor (TR)-beta2, TSHbeta and 5'-deiodinase (D1) mRNAs), the thyroid (decreased TSH receptor mRNA) and the liver (decreased TRbeta1 and D1 mRNA). In the hypothalamus, type 2 deiodinase mRNA expression was strongly increased whereas preproTRH mRNA expression did not change after LPS. Serum T(3) and T(4) fell only after 24 h.Our results suggested almost simultaneous involvement of the whole HPT axis in the downregulation of thyroid hormone metabolism during acute illness.
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Illness results in marked downregulation of liver DIO1 both in humans and experimental animals.
“Illness results in marked downregulation of DIO1 both in humans and experimental animals [15, 20, 21].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [15]
The Liver and circulation section reports decreased liver D1 mRNA expression and activity after LPS administration in mice, supporting the experimental-animal part of the claim. The paper’s discussion of human illness concerns the hypothalamus, not liver D1, so this source does not support the human part. (LLM, conf=0.87)
Experimental — accuracy not yet measuredLiver TRα and TRβ expression in rodents decrease during acute illness but not during chronic inflammation and bacterial sepsis.
“Liver TRα and TRβ expression in rodents decrease during acute illness [15, 39] but not during chronic inflammation and bacterial sepsis.”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [15]
The Liver and circulation section reports decreased liver TR1 mRNA within eight hours of LPS administration in mice, supporting a decrease in one liver receptor transcript during acute illness. It does not report decreases in both liver TRα and TRβ. The citation precedes the chronic-inflammation and bacterial-sepsis clause, so that clause is not attributed to this source. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIllness results in increased hypothalamic DIO2 mRNA expression and activity while hypothalamic DIO3 decreases.
“Illness results in increased DIO2 mRNA expression and activity [12, 15–17] while hypothalamic DIO3 decreases [18, 19].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [15]
Liver TRβ1 expression decreases during acute inflammation in mice and limited availability of SRC-1 might be partly responsible for the illness induced decrease of liver DIO1.
“Indeed, liver TRβ1 expression decreases during acute inflammation in mice [15, 39, 77] and limited availability of SRC-1, a shared coactivator for TR and inflammatory signaling pathways, might be partly responsible for the illness induced decrease of liver DIO1 [78, 79].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [15]
The whole HPT axis is involved almost simultaneously in the downregulation of thyroid hormone metabolism during acute illness.
“Together, this suggested almost simultaneous involvement of the whole HPT axis in the downregulation of thyroid hormone metabolism during acute illness [15].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [15]
In mice with acute illness induced by LPS, serum T3 and T4 fall only after 24 h.
“Serum T3 and T4 fell only after 24 h.”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [15]
In mice with acute illness induced by LPS, D2 mRNA is strongly increased in the hypothalamus whereas preproTRH mRNA expression does not change.
“In the hypothalamus, D2 mRNA was strongly increased whereas preproTRH mRNA expression did not change after LPS.”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [15]
In mice with acute illness induced by LPS, the rapid induction of interleukin-1beta mRNA is followed by almost simultaneous molecular changes in the pituitary, thyroid gland and liver.
“This was followed by almost simultaneous molecular changes in the pituitary, the thyroid gland and the liver.”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [15]
In mice with acute illness induced by LPS, there is a rapid induction of interleukin-1beta mRNA expression in the hypothalamus, pituitary, thyroid and liver.
“Studies in mice on the time course of the changes in thyroid hormone metabolism in the HPT axis during acute illness induced by bacterial endotoxin (lipopolysaccharide; LPS) showed a rapid induction of interleukin-1beta mRNA expression in the hypothalamus, pituitary, thyroid and liver.”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [15]
Liver DIO3 is differentially regulated during illness: acute inflammation in mice results in decreased DIO3 levels but prolonged critical illness, both in patients and in rabbits, increases DIO3.
“Liver DIO3 is differentially regulated during illness: acute inflammation in mice results in decreased DIO3 levels [15] but prolonged critical illness, both in patients and in rabbits, increases DIO3 [21, 22].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [15]
The citation to this paper is attached to the claim that acute inflammation decreases liver DIO3 in mice. The Liver and circulation section reports decreased liver D1 expression and activity after LPS, not D3; the RNA isolation and real-time PCR section mentions D3 primers but gives no liver D3 result. Searches for liver D3 and type 3 deiodinase found no passage establishing the claimed decrease. (LLM, conf=0.78)
Experimental — accuracy not yet measuredLPS increases tanycyte D2 mRNA level and activity in the MBH about fourfold within 12 hours.
“LPS has a potent effect on tanycyte D2 gene expression and enzymatic activity, resulting in an approximately 4-fold increase of D2 mRNA level and activity in the MBH within 12 hours of administration (Figure 15, A and B) (197,200).”
From Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions (2014) · cites this paper as [200]
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A TRβ-selective agonist confers resistance to diet-induced obesity
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Self-citationPretranslational Regulation of Type 2 Deiodinase
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Self-citationTissue thyroid hormone metabolism is differentially regulated during illness in mice
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Metabolic and Functional Cross Talk Between the Thyroid and Liver
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Downregulation of Type 3 Deiodinase in the Hypothalamus During Inflammation
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Transient changes in thyroid functions tests after zoledronic acid infusion
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- Authors
- Boelen, A., Kwakkel, J., Thijssen-Timmer, D., Alkemade, A., Fliers, E., & Wiersinga, W.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Venue
- Journal of Endocrinology
- Publisher
- Bioscientifica
- Published
- 2004-08-01
- Volume
- 182
- Issue
- 2
- Pages
- 315-323
- ISSN
- 0022-0795 (ISSN-L)
- 1479-6805
- OpenAlex
- W2106664880
- Cited by
- 159
- References
- 28
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 8 · 2022: 9 · 2021: 4 · 2020: 5 · 2019: 5 · 2018: 9 · 2017: 6 · 2016: 7 · 2015: 8 · 2014: 9 · 2013: 5 · 2012: 2
- FWCI
- 5.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- hypothalamic-pituitary-thyroid axis, low T3 syndrome, lipopolysaccharide, acute illness, thyroid hormone metabolism, triiodothyronine, thyroxine, thyroid-stimulating hormone, type 2 deiodinase, thyroid hormone receptor beta, IL-1β, endotoxin, mice
- MeSH terms
- Acute Disease, Animals, Bacterial Infections, Female, Gene Expression Regulation, Hypothalamo-Hypophyseal System, Interleukin-1, Iodide Peroxidase, Lipopolysaccharides, Liver, Mice, Inbred BALB C, Receptors, Thyrotropin, RNA, Messenger, Thyroid Hormones, Thyroid Hormone Receptors beta, Thyrotropin, beta Subunit, Mice
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