Modulation of Gene Expression by 3-Iodothyronamine: Genetic Evidence for a Lipolytic Pattern

Abstract

3-Iodothyronamine (T1AM) is an endogenous biogenic amine, structurally related to thyroid hormone, which is regarded as a novel chemical messenger. The molecular mechanisms underlying T1AM effects are not known, but it is possible to envisage changes in gene expression, since delayed and long-lasting phenotypic effects have been reported, particularly with regard to the modulation of lipid metabolism and body weight. To test this hypothesis we analysed gene expression profiles in adipose tissue and liver of eight rats chronically treated with T1AM (10 mg/Kg twice a day for five days) as compared with eight untreated rats. In vivo T1AM administration produced significant transcriptional effects, since 378 genes were differentially expressed in adipose tissue, and 114 in liver. The reported changes in gene expression are expected to stimulate lipolysis and beta-oxidation, while inhibiting adipogenesis. T1AM also influenced the expression of several genes linked to lipoprotein metabolism suggesting that it may play an important role in the regulation of cholesterol homeostasis. No effect on the expression of genes linked to toxicity was observed. The assay of tissue T1AM showed that in treated animals its endogenous concentration increased by about one order of magnitude, without significant changes in tissue thyroid hormone concentration. Therefore, the effects that we observed might have physiological or pathophysiological importance. Our results provide the basis for the reported effectiveness of T1AM as a lipolytic agent and gain importance in view of a possible clinical use of T1AM in obesity and/or dyslipidaemia.

The Possible Role of 3-lodothyronamine in Browning of Inguinal White Adipose Tissue in Mice

“…Mitchel et al [30] performed RT-PCR with rat TAAR1 specific primers and noticed that TAAR1 mRNA was present in various rat tissues including adipose tissue and that T1AM induced some of its lipolytic effects by activating this receptor [30]. This is further supported by Marrioti et al [18], who used chronic T1AM treatment (the same dose as our study twice a day for five days) in a rat model and looked for gene expression changes [18]. They discovered elevated lipolysis and gene expression of beta-oxidation markers coupled with the decreased expression of adipogenesis markers in adipose tissue.…”

“…The subchronic T1AM treatment causes ketonuria and a significant loss of body fat indicating a shift in the metabolic pathways from carbohydrate to lipid oxidation. The treatment also triggers lipolytic pattern in rat adipose tissue and modulates mitochondrial FoF1-ATP synthase activity [16][17][18][19][20]. Taken together, these modulations in lipid metabolism provide a balance in energy homeostasis and thus have a great potential in therapeutic applications (especially for treating obesity).…”

“…This makes T1AM a high potency metabolic hormone. The molecular targets of T1AM are currently unknown but Mariotti et al [18] have shown a greater responsiveness of adipose tissue compared to the liver by the fifth day of T1AM administration (18). They also established that a high number of genes was altered in rat subcutaneous adipose tissue, especially the ones related to lipoprotein function and cholesterol homeostasis.…”

3-Iodothyronamine: A High Potency Metabolic Hormone and its Potential for Therapeutic Applications

“…Uptake of T1AM appears to be mediated via facilitated diffusion, but the specific transporters which are responsible for this have yet to be identified [26], however due to its association with ApoB100 in circulation, LDL receptors may likely facilitate for cellular internalization of T1AM [25]. This internalization, and subsequent unknown intracellular interaction, may mediate long term alterations in gene expression patterns, as confirmed by Mariotti et al in rat adipose and liver [27], and possibly account for the persistence of effects observed in chronic T1AM administration [3] (Figure 2). …”

“…This response was thought to be mediated through α2A adrenergic receptor interaction, whereby T1AM possesses adrenergicblocking properties [31]. This interaction with α2A may present an additional ubiquitous receptor target of T1AM than just GCPRs as it has also been speculated that T1AM interacts with α2A in pancreatic beta-cells [27]. ICV administration of T1AM was able to improve learning capacity and served as a memory enhancer in mice [28].…”