Restoration of mRNA Expression of Solute Carrier Proteins in Liver of Diet-Induced Obese Mice by Metformin.

Jiamei Le,Peixian Pi,Yifan Chen,Houlin Ji,Xinjie Lin,Qiuqin Han,Jianping Ye,Jilei Li,Xindong Wei,Yong Zhang,Qiuying Wang,Yi Fu,Xiaoying Zhang

doi:10.3389/fendo.2021.720784

Abstract

Metformin (MET), the most common medicine for type 2 diabetes (T2DM), improves insulin sensitivity by targeting the liver, intestine and other organs. Its impact on expression of the solute carrier (Slc) transporter genes have not been reported in the mechanism of insulin sensitization. In this study, we examined Slc gene expression in the liver and colon of diet-induced obese (DIO) mice treated with MET by transcriptomic analysis. There were 939 differentially expressed genes (DEGs) in the liver of DIO mice vs lean mice, which included 34 Slc genes. MET altered 489 DEGs in the liver of DIO mice, in which 23 were Slc genes. Expression of 20 MET-responsive Slc DEGs was confirmed by qRT-PCR, in which 15 Slc genes were altered in DIO mice and their expressions were restored by MET, including Slc2a10, Slc2a13, Slc5a9, Slc6a14, Slc7a9, Slc9a2, Slc9a3, Slc13a2, Slc15a2, Slc26a3, Slc34a2, Slc37a1, Slc44a4, Slc51b and Slc52a3. While, there were only 97 DEGs in the colon of DIO mice with 5 Slc genes, whose expression was not restored by MET. The data suggest that more genes were altered in the liver over the colon by the high fat diet (HFD). There were 20 Slc genes with alteration confirmed in the liver of DIO mice and 15 of them were restored by MET, which was associated with improvement of insulin sensitivity and obesity. The restoration may improve the uptake of glucose, amino acids, mannose, fructose, 1,5-anhydro-D-glucitol and bumetanide in hepatocytes of the liver of DIO mice. The study provides new insight into the mechanism of metformin action in insulin sensitization and obesity.

Highlights

Metformin (MET), a guanidine derivative initially extracted from the plant Galega officinalis (French lilac), is the first-line medicine in the treatment of type 2 diabetes (T2DM) [1]
It was reported that Slc22A1, Slc22A2, Slc22A3, Slc47A1 played an important role in the kidney, fat and liver for bioavailability, clearance, and pharmacological action of metformin in T2DM [10,11,12]
The diet-induced obese (DIO) mice were generated in C57BL/6 mice with high fat diet (HFD) feeding for 16 wks

Summary

Introduction

Metformin (MET), a guanidine derivative initially extracted from the plant Galega officinalis (French lilac), is the first-line medicine in the treatment of type 2 diabetes (T2DM) [1]. MET activity has been reported in the treatment of many other diseases, such as cancer, obesity, nonalcoholic fatty liver disease (NAFLD) and inflammation [2]. In the treatment of T2DM, MET is considered to act in the liver by inhibition of gluconeogenesis through a couple of mechanisms, such as inhibition of mitochondrial redox shuttle [3], suppression of the Complex I of mitochondrial respiratory chain [4], activation of the cellular energy sensor AMP-activated protein kinase (AMPK) [5]. MET is reported to act in the intestine to regulate bile acids [6], microbiota [7] and GLP-1 secretion [8] in the improvement of insulin sensitivity. The relative importance of liver and intestine remains to be established in the mechanism of insulin sensitization by MET. Systemic examination of Slc genes has not been reported in obesity

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Conclusion