Thyroid hormone (TH) homeostasis depends on peripheral activation and inactivation of iododthyronines by selenoenzymes of the deiodinase (Dio) family. We genetically inactivated hepatic selenoenzyme expression, including Dio1, in order to determine the contribution of hepatic Dio to circulating TH levels. Serum levels of TSH, total T4, and total T3 were not different from controls. We measured Dio1 and Dio2 in kidney, skeletal muscle, heart, brown adipose tissue, and brain, but did not find compensatory up-regulation in these tissues. Finally, we determined expression in the liver of the following T3 target genes: Spot14, α-glycerophosphate dehydrogenase (αGPD), and malic enzyme (ME). On the transcript level, both Spot14 and αGPD were reduced in Dio deficient liver to about 60–70% of controls. However, mRNA and activity of ME were significantly increased in the same mice. Further studies are directed to elucidate changes in lipid or carbohydrate metabolism in these mice. Together, our results indicate that hepatic Dio1 activity is not absolutely required to sustain the euthyroid state in mice. Our findings are compatible with results from Dio1-KO mice, however, T4 levels are increased in Dio1-KO mice possibly indicating a role of Dio1 in the pituitary.

The thyroid gland is rich in selenium (Se) and expresses a variety of selenoproteins that are involved in antioxidative defense and metabolism of thyroid hormones (TH). Se deficiency impairs regular synthesis of selenoproteins and adequate TH metabolism. We recently generated mice that lack the plasma Se carrier, selenoprotein P (SePP). SePP-knockout mice display decreased serum Se levels and manifest growth defects and neurological abnormalities partly reminiscent of thyroid gland dysfunction or profound hypothyroidism. Thus, we probed the TH axis in developing and adult SePP-knockout mice. Surprisingly, expression of Se-dependent 5'-deiodinase type 1 was only slightly altered in liver, kidney, or thyroid at postnatal d 60, and 5'-deiodinase type 2 activity in brain was normal in SePP-knockout mice. Thyroid gland morphology, thyroid glutathione peroxidase activity, thyroid Se concentration, and serum levels of TSH, T4, or T3 were within normal range. Pituitary TSHbeta transcripts and hepatic 5'-deiodinase type 1 mRNA levels were unchanged, indicating regular T3 bioactivity in thyrotropes and hepatocytes. Cerebellar granule cell migration as a sensitive indicator of local T3 action during development was undisturbed. Collectively, these findings demonstrate that low levels of serum Se or SePP in the absence of other challenges do not necessarily interfere with regular functioning of the TH axis. 5'-deiodinase isozymes are preferentially supplied, and Se-dependent enzymes in the thyroid are even less-dependent on serum levels of Se or SePP than in brain. This indicates a top priority of the thyroid gland and its selenoenzymes with respect to the hierarchical Se supply within the organism.

Selenium (Se) represents an essential trace element in mammals and is essential for the activity of selenoenzymes including the family of thyroid hormone deiodinases, glutathione peroxidases or thioredoxin reductases. Se-deficiencies have been implicated to predispose to certain malignancies including cancer, inflammatory diseases, thyroid dysfunction, cardiovascular, infectious or neurological diseases or infertility. The different tissues and organs are supplied with Se in a hierarchical manner, i.e., the brain, the endocrine glands and testes are preferentially served and retain their Se efficiently in times of deficiency.

Thyroid hormone (TH) homeostasis depends on peripheral activation and inactivation of iodothyronines by selenoenzymes of the deiodinase (Dio) family. We genetically inactivated hepatic selenoenzyme expression, including Dio1, in order to determine the contribution of hepatic Dio to circulating TH levels. Serum levels of TSH, total T(4), and total T(3) were not different from controls. We measured Dio1 and Dio2 in kidney, skeletal muscle, heart, brown adipose tissue, and brain, but did not find compensatory up-regulation in these tissues. Finally, we determined expression in the liver of the following T(3) target genes: Spot14, alpha-glycerophosphate dehydrogenase (alphaGPD), and malic enzyme (ME). On the transcript level, both Spot14 and alphaGPD were reduced in Dio-deficient liver to about 60-70% of controls. However, mRNA and activity of ME were significantly increased in the same mice. Together, our results indicate that hepatic Dio1 activity is not absolutely required to sustain the euthyroid state in mice.

Mice deficient in selenoprotein P exhibit a disturbed selenium distribution and reduced activities of other selenoenzymes and display defects in growth and motor co-ordination. We have normalized selenoenzyme activities and rescued the phenotype of mutant mice by supplementing their nursing mothers with sodium selenite. Our results indicate that selenium from inorganic sources can be transferred efficiently via mother's milk to the developing offspring in a form that is both highly bioavailable by target tissues and yet sufficiently safe to prevent overdosages.

Selenium (Se) is an essential trace element for mammals and highly enriched in brain, the reproductive and endocrine organs. We have genetically inactivated the gene for the Se-transport protein selenoprotein P (SePP). SePP-KO mice are characterised by a growth defect, a disturbed Se distribution and an altered expression of selenoproteins. Since activation of the prohormone T4 and inactivation of biologically active T3 and T4 are mediated by Se-dependent enzymes, we studied expression of Type I (5'DIO1) and Type II (5'DIO2) 5'deiodinase activities using 125-I-labeled rT3 as substrate. In parallel, serum thyroid hormone and TSH concentrations were analysed by RIAs adapted to mouse serum and Se concentrations were analysed by the DAN-fluorimetric method.

Severe selenium (Se) deficiency impairs growth in rodents and farm animals. Selenoprotein P (SePP) has recently been identified as the main transport protein for the essential trace element Se in plasma. SePP is mainly synthesised in liver and contains up to 10 selenocysteine residues per protein chain. It is secreted into the blood where it may serve to supply Se to different target tissues. We have recently established SePP null mice that contain increased amounts of Se in liver and reduced levels of Se in e.g. blood and kidney. Most strikingly, SePP null mice display a drastic persisting growth defect (postnatal day 35: reduced body length from 15.9 to 13.0cm, tail length from 7.6 to 6.7cm and reduced body weight from 19.2 to 9.0g, P<0.001). In a first attempt to characterise this growth defect on a molecular level we employed a transcriptome wide screening method using arrays containing gene-specific oligonucleotides. Comparative hybridisation experiments with total RNA from the livers of SePP null and control mice revealed potential candidates that might be relevant to the observed growth phenotype. Signals for the insulin-like growth factors (IGF-1 and IGF-2) did not differ significantly while signals for growth hormone receptor mRNA were reduced to 60% of control. GH mRNA levels in the pituitaries were not different among the genotypes as determined by Northern blot analysis. Isoform specific differences were observed for hepatic mRNA expression of insulin-like growth factor binding proteins 1, 2, 3, 5, 6 and 10, respectively. Here, the main growth inhibitory isoform, i.e. IGFBP-2, was increased 2-fold in the SePP null mice. Together these data imply that hepatic expressions of GH-receptor and IGFBP-2 are affected by altered Se levels thereby contributing to the observed growth defects.