Metabolome Dynamics Platform Reveals Endocrine‐metabolic Crosstalk in PCOS and Its Reprogramming of Lipid Metabolic Pathways with 3‐Iodothyronamine

Abstract

ObjectivesPolycystic ovary syndrome (PCOS) is a complex metabolic and endocrine disorder, and a leading cause of infertility in women. The PCOS metabolic phenotype in women and mice is associated with defective lipid and glucose metabolism that is linked to dysregulation of steroidogenesis through unknown mechanism(s). Here, we investigated tissue specific treatment effects of 3‐Iodothyronamine (T1AM), a natural analog of thyroid hormone, action on metabolic pathways and associated transcriptional and gene signaling in vivo in order to understand the crosstalk between endocrine and lipid metabolism as drug targets in PCOS pathophysiology.MethodsWe analyzed plasma and tissue extracts using multidisciplinary omics and biochemical approaches. We used 1H‐NMR spectroscopy using metabolome dynamics platform (MDP) to analyze metabolomics profiles and complemented with monitoring transcription levels of major targeted metabolic regulatory genes and proteins.ResultsAdministering with the low sub‐chronic application of T1AM (10mg/Kg/Day) in vivo induces a profound anti‐lipogenic effect by lowering gene expression of key regulators of lipid metabolism, Ptpb1 and Plin2, and significant increased levels of metabolites (glucogenic amino acids, carnitine and acetate) in a tissue specific manner, while enhancing protection against oxidative stress in liver and muscle. In contrast, T1AM has an opposing effect on the regulation of estrogenic metabolic and gene pathways in the ovary by upregulating Star, Cyp11a1 and Cyp17a1s. Biochemical measurements provide further evidence of a significant reduction of plasma total cholesterol and triglycerides after T1AM treatment.ConclusionsOur MDP analysis indicate a novel mechanism for T1AM in regulating lipid metabolism, which untangles endocrine‐metabolic pathways, thus elucidating the intricacies within the pathophysiology of PCOS at the tissue specific level in contrast to overall systemic effect. This study opens new avenues to design new approaches for essential therapeutic targets in order to improve quality of life in complex diseases such as PCOS with endocrine‐metabolic dysfunction.Support or Funding InformationThis research was supported by RC4 EY021357 and a Wisconsin Institute of Discovery Grant (WID‐135A039) to F.A‐P. This study made use of the National Magnetic Resonance Facility at Madison for data collection, which is supported by NIH grant P41RR002301 (NIGMS).