title: Transcriptomic effects of metformin in skeletal muscle arteries of obese insulin-resistant rats.
abstract: We 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 = 9) or without ( n = 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. Impact statement 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.
authors.affiliation: 1 Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, USA.|2 Child Health, University of Missouri, Columbia, MO 65211, USA.|3 Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Jaume
authors.initials: J
authors.lastname: Padilla
authors.affiliation: 4 Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Pamela K
authors.initials: PK
authors.lastname: Thorne
authors.affiliation: 5 Department of Cell Biology and Physiology, Edward Via College of Osteopathic Medicine, Auburn, AL 36832, USA.|6 School of Kinesiology, Auburn University, Auburn, AL 36849, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Martin
authors.affiliation: 1 Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, USA.|7 Research Service-Harry S Truman Memorial VA Medical Center, Columbia, MO 65211, USA.|8 Medicine-Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65211, USA.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Rector
authors.affiliation: 9 MU Informatics Institute, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Sadia
authors.initials: S
authors.lastname: Akter
authors.affiliation: 9 MU Informatics Institute, University of Missouri, Columbia, MO 65211, USA.|10 Health Management and Informatics, University of Missouri, Columbia, MO 65211, USA.|11 Statistics, University of Missouri, Columbia, MO 65211, USA.
authors.forename: J Wade
authors.initials: JW
authors.lastname: Davis
authors.affiliation: 3 Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA.|4 Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA.|12 Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65211, USA.
authors.forename: M Harold
authors.initials: MH
authors.lastname: Laughlin
authors.affiliation: 13 Kinesiology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Nathan T
authors.initials: NT
authors.lastname: Jenkins
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000098:blood supply*; D009765:Obesity / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D011922:Rats, Mutant Strains
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin
keywords: RNA sequencing; diabetes; gene expression; skeletal muscle resistance arteries