Abstract
Metformin is an antidiabetic drug, which inhibits mitochondrial respiratory-chain-complex I and thereby seems to affect the cellular metabolism in many ways. It is also used for the treatment of the polycystic ovary syndrome (PCOS), the most common endocrine disorder in women. In addition, metformin possesses antineoplastic properties. Although metformin promotes insulin-sensitivity and ameliorates reproductive abnormalities in PCOS, its exact mechanisms of action remain elusive. Therefore, we studied the transcriptome and the metabolome of metformin in human adrenal H295R cells. Microarray analysis revealed changes in 693 genes after metformin treatment. Using high resolution magic angle spinning nuclear magnetic resonance spectroscopy (HR-MAS-NMR), we determined 38 intracellular metabolites. With bioinformatic tools we created an integrated pathway analysis to understand different intracellular processes targeted by metformin. Combined metabolomics and transcriptomics data analysis showed that metformin affects a broad range of cellular processes centered on the mitochondrium. Data confirmed several known effects of metformin on glucose and androgen metabolism, which had been identified in clinical and basic studies previously. But more importantly, novel links between the energy metabolism, sex steroid biosynthesis, the cell cycle and the immune system were identified. These omics studies shed light on a complex interplay between metabolic pathways in steroidogenic systems.
Highlights
Androgens are crucial steroid hormones for normal sexual development and reproduction in males and females
Microarray studies on starved H295R cells treated with metformin for 48 hours were performed using GeneChip Human Gene 1.0 ST arrays
Data were further analyzed for hierarchical clustering using the complete linkage algorithm of Cluster 3.0 and a heat map was created for visualization of the data by JTreeView (Fig. 1)
Summary
Androgens are crucial steroid hormones for normal sexual development and reproduction in males and females. Two common hyperandrogenic conditions, premature adrenarche and the polycystic ovary syndrome (PCOS), are still poorly understood. Adrenarche is characterized by lower HSD3B2 activity and increased CYP17-lyase activity for higher androgen production[2,3,4]. PCOS has very often important metabolic consequences including insulin resistance bearing an increased risk for type 2 diabetes[8]. Metformin was widely adopted as therapy for PCOS12, its mechanism of action on androgen production was unknown. Additional effects of the metformin altered AMP/ATP ratio include an improved lipid metabolism by suppressing hepatic lipid synthesis[16] and an increased fatty acid oxidation through the AMPK-dependent phosphorylation of acetyl CoA carboxylase (ACC)[17]. Metformin inhibits mitochondrial glycerophosphate dehydrogenase (mGPD), which results in reduced conversion of glycerol to glucose and an altered redox state; enhanced cytosolic NADH feeds back on lactate dehydrogenase activity[20]
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