Metformin Ameliorates Hepatic Steatosis and Inflammation without Altering Adipose Phenotype in Diet-Induced Obesity

Woo, Shih Lung; Xu, Huaxi; Li, Honggui; Zhao, Yan; Hu, Xiang; Zhao, Jiajia; Guo, Xin; Guo, Ting; Botchlett, Rachel; Qi, Ting; Pei, Ya; Zheng, Juan; Xu, Yiming; An, Xiaofei; Chen, Lulu; Chen, Lili; Li, Qifu; Xiao, Xiaoqiu; Huo, Yuqing; Wu, Chaodong

doi:10.1371/journal.pone.0091111

Cited by 166 publications

(132 citation statements)

References 49 publications

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“…Thus, metformin is not recommended as a specific treatment for NAFLD in clinical practice guidelines (Chalasani et al 2012). By contrast, the data based on animal studies have shown that metformin improves hepatic steatosis, liver inflammation, and to a certain degree fibrosis (Lin et al 2000, Woo et al 2014, Tripathi et al 2015. These results are consistent with the data of this study.…”

Section: Discussionsupporting

confidence: 88%

Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis

Hong

Zhou

Liu

et al. 2016

Journal of Endocrinology

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Nonalcoholic fatty liver disease and cirrhosis are strongly associated with insulin resistance and glucose intolerance. To date, the influence of metformin on glycogen synthesis in the liver is controversial. Limited studies have evaluated the effect of metformin on hepatic insulin signaling pathway in vivo. In this study, an insulin-resistant rat model of nonalcoholic steatohepatitis and cirrhosis was developed by high-fat and high-sucrose diet feeding in combination with subcutaneous injection of carbon tetrachloride. Liver tissues of the model rats were featured with severe steatosis and cirrhosis, accompanied by impaired liver function and antioxidant capacity. The glucose tolerance was impaired, and the index of insulin resistance was increased significantly compared with the control. The content of hepatic glycogen was dramatically decreased. The expression of insulin receptor β (IRβ); phosphorylations of IRβ, insulin receptor substrate 2 (IRS2), and Akt; and activities of phosphatidylinositol 3-kinase (PI3K) and glycogen synthase (GS) in the liver were significantly decreased, whereas the activities of glycogen synthase kinase 3α (GSK3α) and glycogen phosphorylase a (GPa) were increased. Metformin treatment remarkably improved liver function, alleviated lipid peroxidation and histological damages of the liver, and ameliorated glucose intolerance and insulin resistance. Metfromin also significantly upregulated the expression of IRβ; increased the phosphorylations of IRβ, IRS2, and Akt; increased the activities of PI3K and GS; and decreased GSK3α and GPa activities. In conclusion, our study suggests that metformin upregulates IRβ expression and the downstream IRS2/PI3K/Akt signaling transduction, therefore, to increase hepatic glycogen storage and improve insulin resistance. These actions may be attributed to the improved liver histological alterations by metformin.

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Section: Discussionsupporting

confidence: 88%

Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis

Hong

Zhou

Liu

et al. 2016

Journal of Endocrinology

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“…The main molecular mediator of these effects is regarded as adenosine monophosphate-activated protein kinase (AMPK) (Browning & Horton 2004, Woo et al 2014, Zheng et al 2015. By activation of AMPK, metformin improved hepatic lipid metabolism via decreasing activities of ACC-1 and hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase, promoting β-oxidation, and inhibiting SREBP 1-c, a master transcription factor that induces the expression of lipogenic genes including FAS , leading to decreased steatosis levels.…”

Section: Discussionmentioning

confidence: 99%

Metformin increases hepatic leptin receptor and decreases steatosis in mice

Tang

Xiang

et al. 2016

Journal of Endocrinology

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In addition to the ascertained efficacy as antidiabetic drug, metformin is increasingly being used as weight-loss agent in obesity, and as insulin sensitizer in nonalcoholic fatty liver disease (NAFLD). However, the mechanisms underlying these effects are still incompletely understood. Emerging evidence suggest metformin as leptin sensitizer to mediate the weight-loss effect in the brain. In this study, we investigated effects of metformin on expression of leptin receptors in liver and kidney in mice. C57BL/6 mice were fed with chow diet (CD) or high-fat diet (HF) for 5 months. Afterward, mice were treated with metformin (50 mg/kg or 200 mg/kg) for 15 days. Metabolic parameters and hepatic gene expression were analyzed at the end of the treatment. We also tested the effects of metformin on plasma-soluble leptin receptor (sOB-R) levels in newly diagnosed type 2 diabetes mellitus (T2DM) patients, and assessed its effect on hepatosteatosis in mice. Results showed that metformin upregulates the expression of leptin receptors (OB-Ra, -Rb, -Rc, and -Rd) in liver but not kidney. The stimulation effect is dosedependent in both chow and HF mice. Upregulation of OB-Rb, long signaling isoform, needs a relatively higher dose of metformin. This effect was paralleled by increased sOBR levels in mice and T2DM patients, and decreased hepatic triglyceride (TG) content and lipogenic gene expression, including sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthase (FAS) and acetyl-CoA carboxylase-1 (ACC-1). Taken together, these data identify hepatic leptin receptor as target gene being upregulated by metformin which may enhance leptin sensitivity in liver to alleviate steatosis.

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“…The direct anti-inflammatory action of metformin has been reported in several animal experimental studies, both in the liver (69,54,47) and in circulating polymorphonuclear cells (9). In contrast to these experimental findings, metformin efficiency in human NASH treatment is the subject of open debate (58,60).…”

Section: Discussionmentioning

confidence: 99%

Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation

Cahová

Páleníčková

Daňková

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Z, Oliyarnyk O, Kazdova L. Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation. Am J Physiol Gastrointest Liver Physiol 309: G100 -G111, 2015. First published June 4, 2015; doi:10.1152/ajpgi.00329.2014.-Nonalcoholic fatty liver disease is associated with chronic oxidative stress. In our study, we explored the antioxidant effect of antidiabetic metformin on chronic [high-fat diet (HFD)-induced] and acute oxidative stress induced by short-term warm partial ischemia-reperfusion (I/R) or on a combination of both in the liver. Wistar rats were fed a standard diet (SD) or HFD for 10 wk, half of them being administered metformin (150 mg·kg body wt Ϫ1 ·day Ϫ1 ). Metformin treatment prevented acute stress-induced necroinflammatory reaction, reduced alanine aminotransferase and aspartate aminotransferase serum activity, and diminished lipoperoxidation. The effect was more pronounced in the HFD than in the SD group. The metformin-treated groups exhibited less severe mitochondrial damage (markers: cytochrome c release, citrate synthase activity, mtDNA copy number, mitochondrial respiration) and apoptosis (caspase 9 and caspase 3 activation). Metformin-treated HFD-fed rats subjected to I/R exhibited increased antioxidant enzyme activity as well as attenuated mitochondrial respiratory capacity and ATP resynthesis. The exposure to I/R significantly increased NADH-and succinate-related reactive oxygen species (ROS) mitochondrial production in vitro. The effect of I/R was significantly alleviated by previous metformin treatment. Metformin downregulated the I/R-induced expression of proinflammatory (TNF-␣, TLR4, IL-1␤, Ccr2) and infiltrating monocyte (Ly6c) and macrophage (CD11b) markers. Our data indicate that metformin reduces mitochondrial performance but concomitantly protects the liver from I/R-induced injury. We propose that the beneficial effect of metformin action is based on a combination of three contributory mechanisms: increased antioxidant enzyme activity, lower mitochondrial ROS production, and reduction of postischemic inflammation. metformin; oxidative stress; mitochondrial respiration; liver injury; 31 P MR spectroscopy METFORMIN IS AN ORAL ANTIHYPERGLYCEMIC drug widely used in the treatment of Type 2 diabetes (T2D) (7). There is evidence that metformin also protects against oxidative stress in various tissues, although the antioxidant activity of metformin is not well understood. It has been shown that hyperglycemia is associated with increased reactive oxygen species (ROS) formation due to superoxide overproduction from the mitochondrial electron transport chain as a consequence of increased glycolysis (8). It has been hypothesized that the antioxidative effect of metformin is simply the consequence of its glucoselowering effect and subsequent decrease in superoxide anion production (3). Nevertheless, metformin has also displayed antioxidative characteristics in several models of oxidative stress without hyperglycemia (2,19,20,2...

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Metformin Ameliorates Hepatic Steatosis and Inflammation without Altering Adipose Phenotype in Diet-Induced Obesity

Cited by 166 publications

References 49 publications

Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis

Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis

Metformin increases hepatic leptin receptor and decreases steatosis in mice

Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation

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