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

Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity and insulin resistance. To better understand the pathophysiology of obesity-associated NAFLD, the present study examined the involvement of liver and adipose tissues in metformin actions on reducing hepatic steatosis and in...

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Main Authors:	Woo, Shih-Lung, Xu, Hang, 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
Format:	Online
Language:	English
Published:	Public Library of Science 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956460/

id	pubmed-3956460
recordtype	oai_dc
spelling	pubmed-39564602014-03-18 Metformin Ameliorates Hepatic Steatosis and Inflammation without Altering Adipose Phenotype in Diet-Induced Obesity Woo, Shih-Lung Xu, Hang 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 Research Article Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity and insulin resistance. To better understand the pathophysiology of obesity-associated NAFLD, the present study examined the involvement of liver and adipose tissues in metformin actions on reducing hepatic steatosis and inflammation during obesity. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity-associated NAFLD and treated with metformin (150 mg/kg/d) orally for the last four weeks of HFD feeding. Compared with HFD-fed control mice, metformin-treated mice showed improvement in both glucose tolerance and insulin sensitivity. Also, metformin treatment caused a significant decrease in liver weight, but not adiposity. As indicated by histological changes, metformin treatment decreased hepatic steatosis, but not the size of adipocytes. In addition, metformin treatment caused an increase in the phosphorylation of liver AMP-activated protein kinase (AMPK), which was accompanied by an increase in the phosphorylation of liver acetyl-CoA carboxylase and decreases in the phosphorylation of liver c-Jun N-terminal kinase 1 (JNK1) and in the mRNA levels of lipogenic enzymes and proinflammatory cytokines. However, metformin treatment did not significantly alter adipose tissue AMPK phosphorylation and inflammatory responses. In cultured hepatocytes, metformin treatment increased AMPK phosphorylation and decreased fat deposition and inflammatory responses. Additionally, in bone marrow-derived macrophages, metformin treatment partially blunted the effects of lipopolysaccharide on inducing the phosphorylation of JNK1 and nuclear factor kappa B (NF-κB) p65 and on increasing the mRNA levels of proinflammatory cytokines. Taken together, these results suggest that metformin protects against obesity-associated NAFLD largely through direct effects on decreasing hepatocyte fat deposition and on inhibiting inflammatory responses in both hepatocytes and macrophages. Public Library of Science 2014-03-17 /pmc/articles/PMC3956460/ /pubmed/24638078 http://dx.doi.org/10.1371/journal.pone.0091111 Text en © 2014 Woo et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Woo, Shih-Lung Xu, Hang 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
spellingShingle	Woo, Shih-Lung Xu, Hang 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 Metformin Ameliorates Hepatic Steatosis and Inflammation without Altering Adipose Phenotype in Diet-Induced Obesity
author_facet	Woo, Shih-Lung Xu, Hang 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
author_sort	Woo, Shih-Lung
title	Metformin Ameliorates Hepatic Steatosis and Inflammation without Altering Adipose Phenotype in Diet-Induced Obesity
title_short	Metformin Ameliorates Hepatic Steatosis and Inflammation without Altering Adipose Phenotype in Diet-Induced Obesity
title_full	Metformin Ameliorates Hepatic Steatosis and Inflammation without Altering Adipose Phenotype in Diet-Induced Obesity
title_fullStr	Metformin Ameliorates Hepatic Steatosis and Inflammation without Altering Adipose Phenotype in Diet-Induced Obesity
title_full_unstemmed	Metformin Ameliorates Hepatic Steatosis and Inflammation without Altering Adipose Phenotype in Diet-Induced Obesity
title_sort	metformin ameliorates hepatic steatosis and inflammation without altering adipose phenotype in diet-induced obesity
description	Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity and insulin resistance. To better understand the pathophysiology of obesity-associated NAFLD, the present study examined the involvement of liver and adipose tissues in metformin actions on reducing hepatic steatosis and inflammation during obesity. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity-associated NAFLD and treated with metformin (150 mg/kg/d) orally for the last four weeks of HFD feeding. Compared with HFD-fed control mice, metformin-treated mice showed improvement in both glucose tolerance and insulin sensitivity. Also, metformin treatment caused a significant decrease in liver weight, but not adiposity. As indicated by histological changes, metformin treatment decreased hepatic steatosis, but not the size of adipocytes. In addition, metformin treatment caused an increase in the phosphorylation of liver AMP-activated protein kinase (AMPK), which was accompanied by an increase in the phosphorylation of liver acetyl-CoA carboxylase and decreases in the phosphorylation of liver c-Jun N-terminal kinase 1 (JNK1) and in the mRNA levels of lipogenic enzymes and proinflammatory cytokines. However, metformin treatment did not significantly alter adipose tissue AMPK phosphorylation and inflammatory responses. In cultured hepatocytes, metformin treatment increased AMPK phosphorylation and decreased fat deposition and inflammatory responses. Additionally, in bone marrow-derived macrophages, metformin treatment partially blunted the effects of lipopolysaccharide on inducing the phosphorylation of JNK1 and nuclear factor kappa B (NF-κB) p65 and on increasing the mRNA levels of proinflammatory cytokines. Taken together, these results suggest that metformin protects against obesity-associated NAFLD largely through direct effects on decreasing hepatocyte fat deposition and on inhibiting inflammatory responses in both hepatocytes and macrophages.
publisher	Public Library of Science
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956460/
_version_	1612068389544525824

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

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