WEIGHT LOSS WITH PRESERVED GLUCOSE HOMEOSTASIS DURING CHRONIC TREATMENT OF OBESE MICE WITH 3-IODOTHYRONAMINE (T1AM): ROLE OF THE SIRTUIN FAMILY

Objectives: T1AM, an endogenous thyroid hormone derivative, is regarded as a rapid modulator of metabolism. In a recent study we provided the first evidence that subchronic low doses of T1AM increased lipolysis determining significant weight loss without changes in food consumption. In the present work we investigated the effects of subchronic T1AM treat- ment on metabolism at the molecular level. To this aim, we performed Nuclear Magnetic Resonance (NMR)-based metabolomics on plasma samples from control and T1AM treated mice in conjunction with organ specific (liver and adipose tissue) gene and protein expression profiling. Methods: Three groups of spontaneously obese female CD-1 mice were injected once daily with saline (n = 5), 10 mg/kg T1AM (n = 5), or 25 mg/kg T1AM (n = 5). Blood was drawn on study days -3, 4, and 7 and analyzed by 1H-NMR. On day 7, animals were cervically dislocated and their organs were collected for real-time PCR and WB analyses. Results: Multivariate statistical analysis of the 1H-NMR data sets revealed increased plasma 3-hydroxybutyrate and acetate concentrations in T1AM-treated mice compared to control mice, whereas no differences were observed in plasma glucose levels. Mice treated with T1AM (25mg/kg/day) showed significant changes in gene expression. In liver we observed increased expression of SIRT6 and glucokinase (GCK), and decreased expression of SIRT4, whereas in adipose tissue only SIRT6 was increased. Protein expres- sion studies confirmed over-expression of SIRT6 and GCK in liver. Conclusions: Since SIRT6 functions as a master gene regulator of glucose levels by maintaining the normal processes by which cells convert glucose into energy, whereas SIRT4 function as a negative regulator of fatty acids oxi- dative metabolism, our results suggest that T1AM can act as a master regulator of both glucose and fat metabolism in obese mice.