Abstract
BackgroundThe interface between environmental risk factors and genetic factors could contribute to the pathogenesis of hyperandrogenism and insulin resistance in polycystic ovary syndrome (PCOS); however, the underlying complex mechanism remains to be elucidated.MethodsWe used dehydroepiandrosterone (DHEA)-induced PCOS-like rat model to measure circadian clock genes and insulin resistance-related genes. Additionally, we performed in vitro experiments in mature adipocytes to verify the molecular mechanisms.ResultsDHEA-induced PCOS-like rats exhibited insulin resistance and arrhythmic expression of circadian clock genes in the liver and adipose tissues, particularly showing decreased brain and muscle ARNT-like protein 1 (BMAL1) expression. In addition, hyperandrogenism gave rise to negative regulation of BMAL1 expression to nicotinamide phosphoribosyltransferase and sirtuin 1, which further inhibited downstream glucose transporter type 4, leading to insulin resistance in mature adipocytes, which was consistent with our previous results in HepG2 cells.ConclusionsDecreased BMAL1 expression in the liver and adipose played a potentially novel role in the contribution of hyperandrogenism to insulin resistance, which might be a possible mechanism accounting for the pathogenesis of PCOS.
Highlights
The interface between environmental risk factors and genetic factors could contribute to the pathogenesis of hyperandrogenism and insulin resistance in polycystic ovary syndrome (PCOS); the underlying complex mechanism remains to be elucidated
We aimed to investigate the role of circadian clock genes in the contribution of hyperandrogenism to insulin resistance, which might aid in determining appropriate interventions for PCOS patients
DHEA treatment resulted in both reproductive and metabolic abnormalities in PCOS-like rats To verify the potential relationship among hyperandrogenism, insulin resistance, and the circadian clock, DHEA was used as a trigger in female SD rats for 4 weeks
Summary
The interface between environmental risk factors and genetic factors could contribute to the pathogenesis of hyperandrogenism and insulin resistance in polycystic ovary syndrome (PCOS); the underlying complex mechanism remains to be elucidated. The state in which more insulin is required to maintain glucose homeostasis, is a common phenotype of PCOS patients and contributes to the. Any changes in the process, such as phosphorylation of insulin receptors, insulin receptor substrate-1, or the phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) pathway and the subsequent expression of glucose transporter 4 (GLUT4), may play a role in the insulin-resistant state of PCOS [3]. Circadian clock is the biochemical oscillator that synchronizes human activities with solar time, and this internally synchronized circadian clock enables humans to coordinate their biology and behavior with daily environmental changes corresponding to the day–night cycle. Circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like protein 1 (BMAL1) heterodimers bind to cis-acting E-box elements to drive the transcription of cryptochrome (CRY) and period (PER), which subsequently return to the nucleus and repress their own transcription [6]
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