Metabolic Profiling Reveals Reprogramming of Lipid Metabolic Pathways in Treatment of Polycystic Ovary Syndrome with 3-Iodothyronamine

Objectives T1AM is an endogenous compound, and an analog of the thyroid hormone, shows a great potential as a human weight loss drug. Subchronic treatment at a low dose of T1AM results in a rapid lipolysis and weight loss without an apparent change in food consumption in obese mice. Polycystic ovary syndrome (PCOS) is a complex endocrine disease in women that is associated with intricate pathophysiological, hormonal and metabolic feedbacks, which makes the early diagnosis challenging, thus increasing the prevalence risks for infertility, obesity, cardiovascular and fatty liver diseases. Recently, we showed that women with PCOS exhibit significantly diminished lipid oxidation, and perturbed glucose and amino acid metabolism. Here, we investigated tissue specific effects of T1AM, a novel antihyperlipidemic agent, in the GC‐mice as a model for PCOS. This paper reveals T1AM action at the molecular level on metabolic pathways and associated transcriptional gene signaling in PCOS. Methods Two groups of spontaneously obese female GC mice were injected once daily with saline (n=5) and 25 mg/kg T1AM (n=5). Blood was drawn on study days ‐3, 4, and 7 and analyzed by 1H‐NMR. On day 7 of the study, animals were sacrificed and their organs were collected for 1H‐NMR metabolomics and real‐time PCR. Results Multivariate statistical analysis of the 1H ‐NMR based metabolomics data sets reveals increases in lipid oxidation pathways in plasma, muscle, and liver biomarkers by significantly increasing metabolites (glucogenic amino acids, carnitine and citrate) levels in T1AM treated mice compared to control mice. These metabolic changes are accompanied by significant reduction of liver cholesterol and triglycerides and with no differences in plasma glucose levels. T1AM administration induces lowering gene expression of key regulators of lipid metabolism, PTP1B and PLIN2 and increasing antioxidant levels. In contrast, T1AM has an opposing effect on the regulation of estrogenic pathways in the ovary by upregulating STAR, CYP11A1 and CYP17A1. Conclusions T1AM regulates cellular metabolism through tissue specific targeted gene signaling and metabolic cross talks by inducing a profound tissue specific anti‐lipogenic effect in liver and muscle, while reducing oxidative stress. In contrast, T1AM has an opposing effect on the regulation of estrogenic pathways in ovary pointing to the origin of dysregulation of these pathways in PCOS. This study opens up new avenues for the treatment regimes and understanding tissue specific mechanism of PCOS pathophysiology.