NMR-based metabolomics and breath studies show lipid and protein catabolism during low dose chronic T1AM treatment
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author notes may be found in the online version of this article.
Funding agencies: This research was supported by the Rodale Foundation, the Farmers Advocating for Organics (FAFO) fund, grant R01 DC009018 from NIH, and the Wisconsin Institute of Discovery Grant (WID-135A039). This work was supported in part by funds from the following: the Rodale Foundation; the Farmers Advocating for Organics (FAFO) fund to W.P.P.; grants R01 DC009018 from NIH; the Wisconsin Institute of Discovery Grant (WID-135A039) to F.M.A.P. This study made use of the National Magnetic Resonance Facility at Madison, which is supported by NIH grants P41RR02301 (BRTP/ NCRR) and P41GM66326 (NIGMS). Additional equipment was purchased with funds from the University of Wisconsin, the NIH (RR02781, RR08438), the NSF (DMB-8415048, OIA-9977486, BIR-9214394), and the USDA.
3-Iodothyronamine (T1AM), an analog of thyroid hormone, is a recently discovered fast-acting endogenous metabolite. Single high-dose treatments of T1AM have produced rapid short-term effects, including a reduction of body temperature, bradycardia, and hyperglycemia in mice.
Design and Methods
The effect of daily low doses of T1AM (10 mg/kg) for 8 days on weight loss and metabolism in spontaneously overweight mice was monitored. The experiments were repeated twice (n = 4). Nuclear magnetic resonance (NMR) spectroscopy of plasma and real-time analysis of exhaled 13CO2 in breath by cavity ring down spectroscopy (CRDS) were used to detect T1AM-induced lipolysis.
CRDS detected increased lipolysis in breath shortly after T1AM 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 T1AM include both lipolysis and protein breakdown. After discontinuation of T1AM treatment, mice regained only 1.8% of the lost weight in the following 2 weeks, indicating lasting effects of T1AM on weight maintenance.
CRDS in combination with NMR and 13C-metabolic tracing constitute a powerful method of investigation in obesity studies for identifying in vivo biochemical pathway shifts and unanticipated debilitating side effects.