Triiodothyronine and free thyroxine levels are differentially associated with metabolic profile and adiposity-related cardiovascular risk markers in euthyroid middle-aged subjects

Background: We previously showed that in healthy young men a less favorable body composition is associated with higher FT3 levels within the euthyroid range. Besides, a higher FT3-to-FT4 ratio has been related to a less favorable metabolic phenotype and more placental growth in pregnant women. In the present study, we therefore investigated whether serum TSH, thyroid hormone levels and the FT3-to-FT4 ratio are associated with metabolic and adiposity-related cardiovascular risk markers in a healthy population of middle-aged euthyroid men and women. Methods: Thyroid parameters were measured in 2524 generally healthy subjects from the Asklepios study (35-55yrs, mean age 46 years). Analyses were restricted to 2315 subjects (1138 women and 1177 men), not using thyroid medication, not having anti-TPO levels above clinical cut-off values nor TSH levels outside the reference range (0.27-4.2 mU/L). Twenty-seven percent of the women and 47.5% of the men were overweight, while 13% of women and 17% of men were obese. Twenty percent of the subjects were active smokers. Serum thyroid function parameters were determined by electrochemiluminescence. Results: (F) T3 and the FT3-to-FT4 ratio were positively related to BMI, waist circumference and components of the metabolic syndrome, i.e. triglycerides, systolic and diastolic blood pressure and fasting plasma glucose, and negatively with HDL-cholesterol levels, whereas FT4 was negatively associated to BMI, waist circumference and triglycerides (all p-values <0.001). TSH related positively to total cholesterol levels (p<0.01), triglycerides and to systolic and diastolic blood pressure (all p<0.001). The FT3-to-FT4 ratio was further positively associated to the adiposity-related inflammation markers interleukin-6 (IL6) and high-sensitive CRP (hs-CRP) and to pulse wave velocity. All associations were adjusted for sex, age, height and smoking and most associations persisted after additional adjustment for weight or waist circumference. Conclusion: In healthy euthyroid middle-aged men and women, higher (F) T3 levels, lower FT4 levels and thus a higher FT3-to-FT4 ratio are consistently associated with various markers of unfavorable metabolic profile and cardiovascular risk

Sex-specific phenotypes of hyperthyroidism and hypothyroidism in mice

Background Thyroid dysfunction is more common in the female population, however, the impact of sex on disease characteristics has rarely been addressed. Using a murine model, we asked whether sex has an influence on phenotypes, thyroid hormone status, and thyroid hormone tissue response in hyper- and hypothyroidism. Methods Hypo- and hyperthyroidism were induced in 5 -month-old female and male wildtype C57BL/6N mice, by LoI/MMI/ClO4 − or T4 i.p. treatment over 7 weeks, and control animals underwent sham treatment (N = 8 animals/sex/treatment). Animals were investigated for impact of sex on body weight, food and water intake, body temperature, heart rate, behaviour (locomotor activity, motor coordination, and strength), liver function, serum thyroid hormone status, and cellular TH effects on gene expression in brown adipose tissue, heart, and liver. Results Male and female mice showed significant differences in behavioural, functional, metabolic, biochemical, and molecular traits of hyper- and hypothyroidism. Hyperthyroidism resulted in increased locomotor activity in female mice but decreased muscle strength and motor coordination preferably in male animals. Hypothyroidism led to increased water intake in male but not female mice and significantly higher serum cholesterol in male mice. Natural sex differences in body temperature, body weight gain, food and water intake were preserved under hyperthyroid conditions. In contrast, natural sex differences in heart rate disappeared with TH excess and deprivation. The variations of hyper- or hypothyroid traits of male and female mice were not explained by classical T3/T4 serum state. TH serum concentrations were significantly increased in female mice under hyperthyroidism, but no sex differences were found under eu- or hypothyroid conditions. Interestingly, analysis of expression of TH target genes and TH transporters revealed little sex dependency in heart, while sex differences in target genes were present in liver and brown adipose tissue in line with altered functional and metabolic traits of hyper- and hypothyroidism. Conclusions These data demonstrate that the phenotypes of hypo- and hyperthyroidism differ between male and female mice and indicate that sex is an important modifier of phenotypic manifestations

Hypothyroidism in rats decreases peripheral glucose utilisation, a defect partially corrected by central leptin infusion

Aims/hypothesis: The aims of this work were to determine the effect of hypothyroidism on insulin-stimulated glucose turnover and to unravel the potential mechanisms involved in such an effect. Methods: Hypothyroidism was induced by administration of propylthiouracil, with partial T4 substitution. Euglycaemic-hyperinsulinaemic clamps, associated with the labelled 2-deoxy-d-glucose technique for measuring tissue-specific glucose utilisation, were used. To assess a possible involvement of leptin in the modulation of glucose metabolism by hypothyroidism, leptin was infused intracerebroventricularly for 6 days. A group of leptin-infused rats was treated with rT3 to determine a potential role of T3 in mediating the leptin effects. Results: Compared with euthyroid rats, hypothyroid animals exhibited decreased overall glucose turnover and decreased glucose utilisation indices in skeletal muscle and adipose tissue. Leptinaemia in hypothyroid rats was lower while resistin mRNA expression in adipose tissue was higher than in euthyroid animals. Intracerebroventricular leptin infusion in hypothyroid rats partially restored overall, muscle and adipose tissue insulin-stimulated glucose utilisation and improved the reduced glycaemic response observed during insulin tolerance tests. The leptin effects were due neither to the observed increase in plasma T3 levels nor to changes in the high adipose tissue resistin expression of hypothyroid rats. The administration of leptin to hypothyroid animals was accompanied by increased expression of muscle and adipose tissue carnitine palmitoyl transferases, decreased plasma NEFA levels and reduced muscle triglyceride content. Conclusions/interpretation: Hypothyroidism is characterised by decreased insulin responsiveness, partly mediated by an exaggerated glucose-fatty acid cycle that is partly alleviated by intracerebroventricular leptin administratio

PARTIAL THYROCYTE-SPECIFIC Gαs DEFICIENCY LEADS TO RAPID-ONSET HYPOTHYROIDISM, HYPERPLASIA, AND PAPILLARY THYROID CARCINOMA-LIKE LESIONS IN MICE

Hypothyroidism is a condition where thyroid gland is not producing enough thyroid hormone, thyroxine, which regulates development, growth, and energy metabolism. The production of thyroxine is regulated by thyrotropin (TSH), a hormone secreted from the pituitary gland. TSH stimulates thyroid via thyrotropin receptor (TSHR). TSHR is a G-protein-coupled receptor and the stimulation of the receptor activates different intracellular signaling pathways. The main signaling pathway in thyrocytes is Gs-pathway, which stimulates the production of cyclic adenosine monophosphate (cAMP). G-proteins are composed out of α- and β-subunits. It is still not known how different G-proteins effect to thyroid pathophysiology. The aim of the study is to investigate if deletion of thyroid specific Gs-protein α-subunit (Gαs) leads to hypothyroidism in a tamoxifen induced Gαs knock-out mouse model (iTGasKO). Genotyping of the mice was performed from DNA isolated from skin tissue. Serum TSH and thyroxin levels were measured from blood samples. cAMP, qPCR, histological and immunohistochemical experiments were done from thyroid tissue samples collected from the mice. The mice were weighted and measured every two weeks. EchoMRI was used to measure body composition and runners were used to measure the activity of the mice. Statistical analyses were done using Prism7 software. In general, iTGasKO mice were less active and in addition, weight loss and a lower amount of white adipose tissue were seen only in males. Unlike in human, in rodents it is typical to lose weight in hypothyroidism. In iTGasKO mice the serum thyroxine levels were lower and TSH levels higher compared to control mice (P<0.01) and cAMP production was decreased both in basal level and after stimulation (P<0.01). Gαs was expressed in small amounts in iTGasKO mice, but thyroid specific transcription factors and genes regulating thyroid hormone synthesis were downregulated. As an unexpected result, 6 months old iTGasKO mice were diagnosed to have papillary thyroid cancer-like lesions in histopathological studies. These areas were also shown to express Gαs-protein. This leads to conclusion of high TSH levels and partial Gαs expression leading to cancer-like lesions. This mouse model is a new way to show how TSHR’s Gs-pathway knock-out leads to hypothyroidism. However, different species carry different signaling pathways, so the changes may not be identical in human pathophysiology

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

Background: An in-depth understanding of the fundamental principles that regulate thyroid hormone homeostasis is critical for the development of new diagnostic and treatment ap-proaches for patients with thyroid disease. Summary: Important clinical practices in use today for the treatment of patients with hypothy-roidism, hyperthyroidism, or thyroid cancer, are the result of laboratory discoveries made by scientists investigating the most basic aspects of thyroid structure and molecular biology. In this document, a panel of experts commissioned by the American Thyroid Association makes a se-ries of recommendations related to the study of thyroid hormone economy and action. These recommendations are intended to promote standardization of study design, which should in turn increase the comparability and reproducibility of experimental findings. Conclusions: It is expected that adherence to these recommendations by investigators in the field will facilitate progress towards a better understanding of the thyroid gland and thyroid hormone dependent processes

Alterations of thyroid function in overweight and obese children: An update

Background: Children with simple overweight and obesity may have alterations in the function of various endocrine organs. Abnormal function of the thyroid gland is seen in about one-fifth of children with obesity. The underlying mechanisms of obesity-associated thyroid dysfunction are still unclear, and hence, the specific treatment with levothyroxine (LT4) is controversial. This review discusses the causes of thyroid dysfunction and its management in pediatric obesity. Methods of Evidence Acquisition: The literature search for this narrative review was performed using international databases including PubMed/Medline, EMBASE, SCOPUS, and Google Scholar and relevant information was extracted from articles on thyroid dysfunction in obesity with an emphasis on the most recent studies. Results: The most common thyroid function abnormality in children with obesity is an isolated increase in thyroid-stimulating hormone (TSH) followed by minor changes in the ratios of triiodothyronine (T3) and thyroxine (T4). Several mechanisms have been proposed for the thyroid dysfunction in obesity, but none explains it fully, and hence, the clinical implications remain unclassified, and the specific treatment with levothyroxine is controversial. There are a few studies in children with obesity-related thyroid dysfunction and the effect of normalization of thyroid function on weight. However, there are limited data on the effect of normalization of thyroid function by either weight loss or levothyroxine (LT4) treatment on the various metabolic consequences closely associated with thyroid dysfunction in obesity. Conclusions: Further research is needed to elucidate the exact mechanisms of thyroid dysfunction in childhood obesity. In addition, larger studies are required to understand the beneficial effects of specific LT4 treatment on weight and on the other thyroid related metabolic derangements in childhood obesity, especially in view of the recent findings of induction of browning of white adipose tissue by thyroid hormones. Until new research establishes its benefits, specific LT4 treatment of thyroid dysfunction in childhood obesity should be avoided

Effects of hypothyroidism on pancreatic islet development and tissue insulin signalling pathways in the ovine fetus

Thyroid hormones are important regulators of fetal growth and maturation, although their mechanism of action and interactions with other hormones are unclear. The overall aim of the project was to elucidate the effects of hypothyroidism on the growth and development of the sheep fetus in late gestation. Specifically, the project investigated the extent to which the changes in fetal growth induced by thyroid hormone deficiency were mediated by changes in pancreatic islet development and insulin signalling in fetal tissues. In nineteen twin-bearing pregnant ewes at 105-110 days of gestation (dGA; term~145dGA) and under general anaesthesia, one fetus was thyroidectomised, while the other was sham-operated. At either 129 or 143dGA, umbilical blood samples and a variety of fetal tissues were collected after euthanasia. Hypothyroidism in utero did not affect fetal bodyweight but impaired skeletal growth and led to disproportionate patterns of organ growth. A 30-40% increase in pancreatic β-cell mass was observed in the thyroid deficient fetuses, compared to sham controls, and this was associated with increased plasma insulin and leptin concentrations. In studies using isolated fetal ovine pancreatic islets, β-cell proliferation in vitro was inhibited by T3 in a dose-dependent manner but was stimulated by the highest dose of insulin. Pancreatic β-cell proliferation was inhibited at low, and stimulated at high, leptin concentrations. Perirenal adipose tissue was enlarged in the hypothyroid fetuses due to an increase in the proportion of unilocular adipocytes, characteristic of white adipose tissue. The greater relative unilocular adipocyte mass was caused by hyperplasia in association with upregulation of the insulin signalling pathway. Kidneys of hypothyroid fetuses had no apparent changes in glomerular or tubular structure, but a greater water content may have accounted for the increased kidney mass seen in the thyroid deficient fetuses, compared to sham controls. No changes in insulin signalling or sodium transporter expression were seen in the kidneys of the hypothyroid fetuses. This research demonstrates that the thyroid hormones are required in the ovine fetus during late gestation for the normal development of the endocrine pancreas, adipose tissue and kidney. Alterations in organ development in response to hypothyroidism may have short and long term consequences for carbohydrate metabolism, obesity and renal function