Adaptive Thermogenesis Driving Catch-Up Fat Is Associated With Increased Muscle Type 3 and Decreased Hepatic Type 1 Iodothyronine Deiodinase Activities: A Functional and Proteomic Study

Refeeding after caloric restriction induces weight regain and a disproportionate recovering of fat mass rather than lean mass (catch-up fat) that, in humans, associates with higher risks to develop chronic dysmetabolism. Studies in a well-established rat model of semistarvation-refeeding have reported that catch-up fat associates with hyperinsulinemia, glucose redistribution from skeletal muscle to white adipose tissue and suppressed adaptive thermogenesis sustaining a high efficiency for fat deposition. The skeletal muscle of catch-up fat animals exhibits reduced insulin-stimulated glucose utilization, mitochondrial dysfunction, delayed in vivo contraction-relaxation kinetics, increased proportion of slow fibers and altered local thyroid hormone metabolism, with suggestions of a role for iodothyronine deiodinases. To obtain novel insights into the skeletal muscle response during catch-up fat in this rat model, the functional proteomes of tibialis anterior and soleus muscles, harvested after 2 weeks of caloric restriction and 1 week of refeeding, were studied. Furthermore, to assess the implication of thyroid hormone metabolism in catch-up fat, circulatory thyroid hormones as well as liver type 1 (D1) and liver and skeletal muscle type 3 (D3) iodothyronine deiodinase activities were evaluated. The proteomic profiling of both skeletal muscles indicated catch-up fat-induced alterations, reflecting metabolic and contractile adjustments in soleus muscle and changes in glucose utilization and oxidative stress in tibialis anterior muscle. In response to caloric restriction, D3 activity increased in both liver and skeletal muscle, and persisted only in skeletal muscle upon refeeding. In parallel, liver D1 activity decreased during caloric restriction, and persisted during catch-up fat at a time-point when circulating levels of T4, T3 and rT3 were all restored to those of controls. Thus, during catch-up fat, a local hypothyroidism may occur in liver and skeletal muscle despite systemic euthyroidism. The resulting reduced tissue thyroid hormone bioavailability, likely D1- and D3-dependent in liver and skeletal muscle, respectively, may be part of the adaptive thermogenesis sustaining catch-up fat. These results open new perspectives in understanding the metabolic processes associated with the high efficiency of body fat recovery after caloric restriction, revealing new implications for iodothyronine deiodinases as putative biological brakes contributing in suppressed thermogenesis driving catch-up fat during weight regain.

Deiodinases: how non-mammalian research helped shape our present view

Iodothyronine deiodinases are enzymes capable of activating and inactivating thyroid hormones (THs) and have an important role in regulating TH action in tissues throughout the body. Three types of deiodinases (D1, D2 and D3) were originally defined based on their biochemical characteristics. Cloning of the first cDNAs in the 1990s (Dio1 in rat and dio2 and dio3 in frog) allowed to confirm the existence of three distinct enzymes. Over the years, increasing genomic information revealed that deiodinases are present in all chordates, vertebrates and non-vertebrates, and that they can even be found in some mollusks and annelids, pointing to an ancient origin. Research in non-mammalian models has substantially broadened our understanding of deiodinases. In relation to their structure, we discovered for instance that biochemical properties such as inhibition by 6-propyl-2-thiouracil, stimulation by dithiothreitol and temperature optimum are subject to variation. Data from fish, amphibians and birds were key in shifting our view on the relative importance of activating and inactivating deiodination pathways, and in showing the impact of D2 and D3 not only in local but also whole body T3 availability. They also led to the discovery of new local functions such as the acute reciprocal changes in D2 and D3 in hypothalamic tanycytes upon photostimulation, involved in seasonal rhythmicity. With the present possibilities for rapid and precise gene silencing in any species of interest, comparative research will certainly further contribute to a better understanding of the importance of deiodinases for adequate TH action, also in humans.

Clinical and laboratory aspects of 3,3′,5′-triiodothyronine (reverse T3)

Reverse T3 (3,3′,5′-triiodothyronine or rT3) is the third most abundant iodothyronine circulating in human blood and is produced by the inner ring deiodination of the pro-hormone thyroxine (T4). Unlike the more abundant and active metabolite T3, the measurement of serum rT3 is yet to find a routine clinical application. As rT3 binds weakly to the T3 thyroid nuclear hormone receptors, it is thought to represent an inactive end-product of thyroid hormone metabolism, diverting T4 away from T3 production. The analysis of serum rT3 has, up until recently, been measured by competitive radioimmunoassay, but these methods have been superseded by mass-spectrometric methods which are less susceptible to interference from other more abundant iodothyronines. Serum rT3 concentration is increased as part of the non-thyroidal illness syndrome, and by administration of common medications such as amiodarone which inhibit the metabolism of rT3. Serum rT3 concentration is also affected by genetic conditions that affect the iodothyronine deiodinases, as well as thyroid transporters and transport proteins. Analysis of rT3 can provide a useful diagnostic fingerprint for these conditions. rT3 has been shown to bind extra-nuclear iodothyronine receptors with a potential role in cell proliferation; however, the clinical relevance of these findings awaits further study.

The Role of Selenium in Oxidative Stress and in Nonthyroidal Illness Syndrome (NTIS): An Overview

Selenium is a trace element, nutritionally classified as an essential micronutrient, involved in maintaining the correct function of several enzymes incorporating the selenocysteine residue, namely the selenoproteins. The human selenoproteome including 25 proteins is extensively described here. The most relevant selenoproteins, including glutathione peroxidases, thioredoxin reductases and iodothyronine deiodinases are required for the proper cellular redox homeostasis as well as for the correct thyroid function, thus preventing oxidative stress and related diseases. This review summarizes the main advances on oxidative stress with a focus on selenium metabolism and transport. Moreover, thyroid-related disorders are discussed, considering that the thyroid gland contains the highest selenium amount per gram of tissue, also for future possible therapeutic implication.

Selenium in Hyperthyroidism

Introduction: Thyroid gland has the highest selenium content compare with other endocrine organs. Enzyme that catalyzing thyroid hormone activation, iodothyronine deiodinases, were identified as selenocysteine-containing proteins. Selenium levels in soil and rice consumed in Indonesia were lower than in several other countries, which can increase the risk of selenium deficiency.Methods: This is an article review of the current literatures published up to November 2018 about the role of selenium in hyperthyroid.Result: Several studies have shown that selenium supplementation can be beneficial in patients with Graves disease and autoimmune thyroiditis. Selenium has an important immunomodulatory effect, but the effects of selenium supplementation in hyperthyroid has not been conclude. Data regarding selenium intake, prevalence of deficiency, and the relationship between selenium and thyroid disease in Indonesia are limited. Various studies of selenium supplementation in thyroid disease provide controversial results, so there are no guidelines that include selenium as standard therapy hyperthyroid. Selenium supplementation can enhance the restoration of biochemical euthyroidism in Graves disease and was associated with a significant decrease in the levels of thyroid peroxidase antibodies in autoimmune thyroiditis.Conclusions: Micronutrients that play a role in thyroid hormone synthesis and maintain thyroid function in addition to selenium are iodine, iron, zinc, and vitamin A. By correcting the deficit of selenium, and meeting other micronutrient requirements may provide health benefits in patient with hyperthyroid.

Structure and Mechanism of Iodothyronine Deiodinases – What We Know, What We Don’t Know, and What Would Be Nice to Know

Deiodinases catalyze the specific removal of iodine atoms from one of the two iodinated phenyl rings in iodothyronines. They thereby fine-regulate local thyroid hormone concentrations in organs or cells. The chemical reaction is unique in the sense that in metazoans the reductive elimination of iodide depends on the rare amino acid selenocysteine in the enzymes’ active centers. While there is no prokaryotic homologue of such deiodinases, the solution of the crystal structure of a catalytic domain of mouse deiodinase 3 has revealed that the ancient peroxiredoxin structure has been repurposed, and improved using selenocysteine, as a deiodinase during metazoan evolution. Likewise, many biochemical findings obtained over decades can now be interpreted in light of the molecular structure. Despite this leap in our understanding of deiodinase structure, there are still several open questions that need to be addressed in order to fully understand substrate binding, catalytic mechanism, and regulation of deiodinases. We surmise that these issues as well as differences between the three highly homologous isoenzymes must be understood in order to develop modulators of deiodinases that could be valuable in clinical use.