Transcriptomic effects of metformin in skeletal muscle arteries of obese insulin-resistant rats

Abstract

This study provides evidence that metformin treatment produces artery-specific gene expression effects. The genes whose expression was modulated with metformin do not appear to have a clear connection with its known mechanisms of action. AbstractWe examined the effects of metformin, a commonly used antidiabetic drug, on gene expression in multiple arteries. Specifically, transcriptional profiles of feed arteries and second branch order arterioles in the soleus, gastrocnemius, and diaphragm muscles as well as aortic endothelial scrapes were examined from obese insulin-resistant Otsuka Long-Evans Tokushima Fatty rats treated with (n ¼ 9) or without (n ¼ 10) metformin from 20 to 32 weeks of age. Metformin-treated rats exhibited a reduction in body weight, adiposity, and HbA1c (P < 0.05). The greatest number of differentially expressed genes (FDR < 15%) between those treated with and without metformin was found in the red gastrocnemius 2a arterioles (93 genes), followed by the diaphragm 2a arterioles (62 genes), and soleus 2a arterioles (15 genes). We also found that two genes were differentially expressed in aortic endothelial cells (LETMD1 and HMGCS2, both downregulated), one gene in the gastrocnemius feed artery (BLNK, downregulated), and no genes in the soleus and diaphragm feed arteries and white gastrocnemius 2a arterioles. No single gene was altered by metformin across all vessels examined. This study provides evidence that metformin treatment produces distinct gene expression effects throughout the arterial tree in a rat model of obesity and insulin resistance. Genes whose expression was modulated with metformin do not appear to have a clear connection with its known mechanisms of action. These findings support the notion that vascular gene regulation in response to oral pharmacological therapy, such as metformin, is vessel specific.

Metformin strongly affects transcriptome of peripheral blood cells in healthy individuals

“…Likewise, microarray analysis of mice liver and muscle tissues revealed the ability of metformin to mimic the calorie restriction-like transcriptome[28]. Furthermore, a distinct gene expression profile related to cardiovascular benefits of metformin, was observed in a rat model of obesity and insulin resistance[29]. Meanwhile, cell culture studies of adrenal H295R cell and MCF7 breast cancer cell transcriptome have revealed the association of metformin with complex cellular processes related with energy metabolism, steroidogenesis and the immune system as well as glycolysis and cancer-related pathways[30, 31].…”

Role of Genetic and Environmental Factors in Determining the Response to Metformin

“…Об этом может свидетельствовать тот факт, что метформин оказывает влияние на уровень метилирования более 100 генов, причем основные функции большинства из них связаны с хорошо известными мишенями для терапии метформином как в случае нарушения углеводного обмена, так и при других физиологических и патофизиологических процессах (в том числе регуляция энергетического гомеостаза, воспалительные реакции, онкогенез и нейродегенеративные процессы) [67]. Влияние метформина на экспрессию генов подтверждается данными транскриптомного анализа [10, [68][69][70]. M.R.…”

Whole-blood transcriptome profiling reveals signatures of metformin and its therapeutic response

“…RNA-Seq has revealed various novel effects and therapeutic targets of metformin, such as enrichment of the transcriptional regulator forkhead box O3a ( FOXO3a ) in primary human fibroblasts [ 14 ], upregulation of activating transcription factor 3 ( ATF3 ) in primary human hepatocytes [ 15 ], downregulation of cell division control protein 42 homolog ( CDC42 ) in breast cancer cells [ 16 ], upregulation of krüppel-like factor 4 ( KLF4 ) resulting in suppressed endothelial dysfunction [ 17 ], and even modulated alternative splicing in embryonic stem cells [ 18 ]. Moreover, multiple animal-based studies have reported metformin-specific signatures in gene expression profiles of rat arteries and mice epididymal fat, liver and muscle tissue, nevertheless, they still do not explain many beneficial effects of the drug [ 19 – 21 ].…”