L-Thyronine

Since the realization that the cellular homologs of a gene found in the retrovirus that contributes to erythroblastosis in birds (v-erbA), i.e. the proto-oncogene c-erbA encodes the nuclear receptors for thyroid hormones (THs), most of the interest for THs focalized on their ability to control gene transcription. It was found, indeed, that, by regulating gene expression in many tissues, these hormones could mediate critical events both in development and in adult organisms. Among their effects, much attention was given to their ability to increase energy expenditure, and they were early proposed as anti-obesity drugs. However, their clinical use has been strongly challenged by the concomitant onset of toxic effects, especially on the heart. Notably, it has been clearly demonstrated that, besides their direct action on transcription (genomic effects), THs also have non-genomic effects, mediated by cell membrane and/or mitochondrial binding sites, and sometimes triggered by their endogenous catabolites. Among these latter molecules, 3,5-diiodo-L-thyronine (3,5-T2) has been attracting increasing interest because some of its metabolic effects are similar to those induced by T3, but it seems to be safer. The main target of 3,5-T2 appears to be the mitochondria, and it has been hypothesized that, by acting mainly on mitochondrial function and oxidative stress, 3,5-T2 might prevent and revert tissue damages and hepatic steatosis induced by a hyper-lipid diet, while concomitantly reducing the circulating levels of low density lipoproteins (LDL) and triglycerides. Besides a summary concerning general metabolism of THs, as well as their genomic and non-genomic effects, herein we will discuss resistance to THs and the possible mechanisms of action of 3,5-T2, also in relation to its possible clinical use as a drug.

Overweight and obesity related metabolic disorders, commonly sharing a pathogenic excess of body adiposity, are world-wide epidemic leading to increasing morbidity and mortality. The related conditions include, among the others, liver steatosis, insulin resistance, and cardiovascular risk. Effective and safe anti-obesity drugs are still needed. Likely without undesirable side effects, an ideal treatment should be able to counteract the numerous causes associated with excess of body adiposity putatively modulating the delicate balance between feeding and energy expenditure, untimely controlling the adipose mass. In the past, thyroid hormones have been tested in reducing weight and lipid accumulation, however, the concomitant induction of a thyrotoxicosis state limited their use. Recent studies in rodents revealed that 3,5- diiodo-L-thyronine (T2), an endogenous metabolite of thyroid hormones, exhibits interesting metabolic activities. Specifically, when exogenously administered, T2 increases the resting metabolic rate and elicits short-term beneficial hypolipidemic effects, without being thyrotoxic, at lest in high fat diet fed rats. Now, a matter of interest is whether T2 can be considered or not a potential anti-obesity pharmacological agent. Actually, very few studies have been performed as far as it concerns the effects of T2 in humans and further analyses on larger cohorts to test time of use- and dose-dependent actions as well as the putative occurrence of T2 induced undesirable side effects, are needed. Here, an updated overview of the current literature on T2 bioactivity is furnished with a particular focus on those effects which may be defined "beneficial" vs. "deleterious" ones above all in view of its putative pharmacological use.

In vertebrates and, specifically, in mammals, energy homeostasis is achieved by the integration of metabolic and neuroendocrine signals linked to one another in an intricate network hierarchically responding to the tight modulating action of hormones among which thyroid hormones (THs) play a central role. At the cellular level, 3,5,3'-triiodo-L-thyronine (T3) acts mainly by binding to specific nuclear receptors (TRs) but actually it is becoming more and more evident that some T3- actions are independent of TRs and that other iodothyronines, such as 3,5-diiodo-L-thyronine (T2), affect energy metabolism and adiposity. In the postgenomic era, clinical and basic biological researches are increasingly benefiting from the recently developed new omics approaches including, among the others, proteomics. Considering the recognized value of proteins as excellent targets in physiology, the functional and simultaneous analysis of the expression level and the cellular localization of multiple proteins can actually be considered fundamental in the understanding of complex mechanisms such as those involved in thyroid control of metabolism. Here, we will discuss new leads (i.e., target proteins and metabolic pathways) emerging in applying proteomics to the actions of T3 and T2 in conditions of altered energy metabolism in animal tissues having a central role in the control of energy balance.