Polycystic ovarian syndrome (PCOS), with its range of symptoms from dysregulated menses to infertility, is a huge burden to bear on its own. Unfortunately, in many cases, this disorder also predisposes patients to co-morbidities such as hypertension, type 2 diabetes and dyslipidemia1. Excessive fat deposition in the liver is known to drive non-alcoholic fatty liver disease (NAFLD) pathology. Studies have shown the coexistence of NAFLD and PCOS in 20-30% of PCOS patients2. Conversely, women with NAFLD are also at risk of developing PCOS. Metabolic pathway disturbances and hormonal changes in PCOS patients lead to abnormal lipid metabolism in the liver3. The molecular mechanisms underpinning this phenomenon have not been elucidated thus far.

A Novel PCOS Mouse Model

Researchers at the University of Wisconsin-Madison and Johns Hopkins University developed a mouse model that closely reflects the metabolic and endocrine changes seen in women with PCOS. They discovered that exposing mice prenatally to high levels of glucocorticoids (GCs) translates to metabolic dysfunction in adult female mice, similar to that observed in women with PCOS. However, some inhibitory effects of PCOS on the reproductive system could not be successfully captured.

Metabolomic Profiling Reveals Abnormal Amino Acid and Lipid Metabolism in PCOS Mice

Using nuclear magnetic resonance (NMR), the authors of this publication conducted metabolomic profiling of the liver tissue of vehicle control and T1AM treated GC mice. T1AM is an endogenous thyroid hormone analog that has been previously shown to reduce body weight, maintain glucose homeostasis and promote efficient lipid utilization in obese mice with metabolic dysfunctions4. The NMR data provided evidence that T1AM treatment considerably altered the levels of amino acid metabolism intermediates in the liver. Increased levels of glutathione, a molecule that protects against oxidative stress, were also observed. Specific lipid species, including triglycerides and cholesterol, were significantly reduced in the livers of the T1AM group compared to the controls. These results were further confirmed by biochemical measurements using RT-PCR.

T1AM Protects the Liver from Oxidative Stress

Antioxidants protect against oxidative stress caused by free radicals, as a consequence of lipid oxidation and peroxidation. P53, a gene that is expressed at normal levels in healthy tissue but is elevated in the case of activated oncogenes or oxidative stress, was found to be decreased in T1AM treated mice with PCOS. This corresponded to an increase in the amount of glutathione detected by NMR.

Linking PCOS and NAFLD

Taken together, the findings in this paper indicate that PCOS mice have altered metabolic pathways that lead to a detrimental increase in lipid synthesis and oxidative stress in the liver. These characteristics are also observed in the case of NAFLD pathology. This study helps provide new molecular insights into the links between PCOS and NAFLD. T1AM, owing to its antioxidant effects and lipid pathway alterations, could potentially have beneficial effects in women with PCOS.

Link to the original publication: Metabolic profiling reveals reprogramming of lipid metabolic pathways in treatment of polycystic ovary syndrome with 3-iodothyronamine

References:

1. Gilbert, E. W., Tay, C. T., Hiam, D. S., Teede, H. J. & Moran, L. J. Comorbidities and complications of polycystic ovary syndrome: An overview of systematic reviews. Clin. Endocrinol. (Oxf). 89, 683–699 (2018).

2. Paschou, S. A. et al. Nonalcoholic fatty liver disease in women with polycystic ovary syndrome. Endocrine vol. 67 (2020).

3. Macut, D. et al. Non-alcoholic fatty liver disease is associated with insulin resistance and lipid accumulation product in women with polycystic ovary syndrome. Hum. Reprod. 31, 1347–1353 (2016).

4. Braulke, L. J. et al. 3-Iodothyronamine: A novel hormone controlling the balance between glucose and lipid utilisation. J. Comp. Physiol. B Biochem. Syst. Environ. Physiol. 178, 167–177 (2008).