Metabolic Reprogramming by 3-Iodothyronamine (T1AM): A New Perspective to Reverse Obesity through Co-Regulation of Sirtuin 4 and 6 Expression

Abstract

Obesity is a complex disease associated with environmental and genetic factors. 3-Iodothyronamine (T1AM) has revealed great potential as an effective weight loss drug. We used metabolomics and associated transcriptional gene and protein expression analysis to investigate the tissue specific metabolic reprogramming effects of subchronic T1AM treatment at two pharmacological daily doses (10 and 25 mg/kg) on targeted metabolic pathways. Multi-analytical results indicated that T1AM at 25 mg/kg can act as a novel master regulator of both glucose and lipid metabolism in mice through sirtuin-mediated pathways. In liver, we observed an increased gene and protein expression of Sirt6 (a master gene regulator of glucose) and Gck (glucose kinase) and a decreased expression of Sirt4 (a negative regulator of fatty acids oxidation (FAO)), whereas in white adipose tissue only Sirt6 was increased. Metabolomics analysis supported physiological changes at both doses with most increases in FAO, glycolysis indicators and the mitochondrial substrate, at the highest dose of T1AM. Together our results suggest that T1AM acts through sirtuin-mediated pathways to metabolically reprogram fatty acid and glucose metabolism possibly through small molecules signaling. Our novel mechanistic findings indicate that T1AM has a great potential as a drug for the treatment of obesity and possibly diabetes.

3-Iodothyronamine and Derivatives: New Allies Against Metabolic Syndrome?

“…Also, minor alterations in BMR lasted for more than 24 h. Consistently with a metabolic rerouting toward mobilization and utilization of lipids, a rise in urine ketone body content was observed 8 h after T1AM treatment, while body weight substantially dropped [43]. T1AM has been similarly reported to induce weight loss in several studies [41,[44][45][46].…”

“…It thus follows that the selective augmentation of some of T1AM actions can represent an attractive strategy for the treatment of metabolic disturbances [97]. Substantial data described in the last two decades provide compelling evidence of the action of T1AM as a multitarget modulator of metabolism and behavior in several experimental models and pathophysiological conditions [41,44,46,89,90], raising hope for increasing therapeutic option in the treatment of a wide variety of diet-and age-related diseases, such as obesity and neurodegeneration.…”

Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-Like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents through the Modulation of SIRT6

“…Recently, evidence was provided that 3-iodothyronamine (T1AM), an endogenous component of the thyroid endocrine system [9,10], reprogrammed altered metabolism when exogenously administered to obese mice at pharmacological doses (10 and 25 mg/kg) [11]. This effect was based on the activation of SIRT6-mediated pathways [12], which in turn actively rescued fatty acid and glucose metabolism. We found that these effects led to a significant weight loss, which was independent from food consumption [11,12].…”

“…This effect was based on the activation of SIRT6-mediated pathways [12], which in turn actively rescued fatty acid and glucose metabolism. We found that these effects led to a significant weight loss, which was independent from food consumption [11,12]. Notably, our group also provided the first evidence that when systemically administered to mice at submicromolar doses T1AM and recently developed thyronamine-like analogs were able to improve learning and memory [13].…”

“…Thus, the present work was designed to investigate in more detail the molecular mechanisms through which T1AM and recently developed thyronamine-like analogs (namely, SG-1 and SG-2, Figure 1), could produce a SIRT6 activation bridging autophagy, weight loss and neuroprotection [12,13]. The present investigation was further motivated by recent findings, which indicate that the two major clearing pathways, namely autophagy and ubiquitine proteasome (UP), considered as independent for long time, converge at the level of single organelles named autophagoproteasomes following mTOR inhibition.…”