NMR-based metabolomics and breath studies show lipid and protein catabolism during low dose chronic T(1)AM treatment

OBJECTIVE: 3-iodothyronamine (T(1)AM), an analog of thyroid hormone, is a recently discovered fast-acting endogenous metabolite. High single dose treatments of T(1)AM have produced rapid short-term effects, including a reduction of body temperature, bradycardia, and hyperglycemia in mice. DESIGN AND METHODS: The present study monitored the effect of daily low doses of T(1)AM (10mg/Kg) for eight-days on weight loss and metabolism in spontaneously overweight mice. The experiments were repeated twice (n=4). Nuclear magnetic resonance (NMR) spectroscopy of plasma and real-time analysis of exhaled (13)CO(2) in breath by cavity ringdown spectroscopy (CRDS) were used to detect T(1)M-induced lipolysis. RESULTS: CRDS detected increased lipolysis in breath shortly after T(1)AM administration that was associated with a significant weight loss but independent of food consumption. NMR spectroscopy revealed alterations in key metabolites in serum: valine, glycine, and 3-hydroxybutyrate, suggesting that the subchronic effects of T(1)AM include both lipolysis and protein breakdown. After discontinuation of T(1)AM treatment, mice regained only 1.8% of the lost weight in the following two weeks, indicating lasting effects of T(1)AM on weight maintenance. CONCLUSIONS: CRDS in combination with NMR and (13)C-metabolic tracing constitute a powerful method of investigation in obesity studies for identifying in vivo biochemical pathway shifts and unanticipated debilitating side effects.