Deciphering the potential of 3-iodothyronamine (T1AM) in regulating lipid metabolism

3-iodothyronamine (T1AM) is a novel chemical messenger that has been reported to regulate energy metabolism and body weight. To better characterize its effects in a subacute model, we treated obese mice with two different dosages of T1AM for seven days, and analyzed plasma and tissue extracts using multidisciplinary approaches. Three groups of spontaneously obese female CD-1 mice (n = 6) were injected once a day i.p. with saline, 10 mg/Kg T1AM, or 25 mg/ kg T1AM. Blood was drawn on study days - 3, 4, and 7 and analyzed by 1H-NMR metabolomics. On day 7, animals were sacrificed and their organs collected for NMR-metabolomics and real-time qPCR targeted at major metabolic regulatory genes. Tissue T1AM concentration was determined by tandem mass spectrometry coupled to liquid chromatography. At both dosages, T1AM treatment produced a significant increase in plasma triglycerides (61.1 – 4.1 and 67.3 – 2.0 vs 49.0 – 2.4 mg/dL, P < 0.05) and a significant decrease in total plasma cholesterol (79.2 – 1.6 and 77.7 – 2.0 vs 90.8 – 3.7 mg/dL, P < 0.05), without any significant change in glycemia. 1H-NMR analysis of liver extracts showed that T1AM induced lipid mobilization and inhibited lipid synthesis and storage. Treatment with 10 mg/Kg T1AM increased glycerol, 3-hydroxybutyrate and acetone concentration, while at 25 mg/Kg glucogenic aminoacids, carnitine and acetate were also increased. In the liver, the highest T1AM dose stimulated the expression of sirtuin 6 and glucokinase, and inhibited the expression of sirtuin 4; in adipose tissue, only sirtuin 6 expression was increased. After treatment with 10 mg/kg/day, T1AM concentration increased over the baseline by about 3-fold in adipose tissue and by about 40- fold in liver, while a 50 to 100-fold increase over the baseline was observed in both tissues in mice treated with 25 mg/Kg/day T1AM. Our multidisciplinary approaches provide evidence that treatment with exogenous T1AM affects lipid metabolism in a dose-dependent and tissue-specific manner. T1AM might play a physiological role in the regulation of metabolism and might provide a novel therapeutic tool for metabolic diseases.