title: Metformin ameliorates hepatic steatosis and inflammation without altering adipose phenotype in diet-induced obesity.
abstract: 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.
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Shih-Lung
authors.initials: SL
authors.lastname: Woo
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Hang
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Honggui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America; Department of Endocrinology, Union Hospital, Tongji College of Medicine, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America; Department of Stomatology, Union Hospital, Tongji College of Medicine, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Ting
authors.initials: T
authors.lastname: Guo
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Rachel
authors.initials: R
authors.lastname: Botchlett
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Ting
authors.initials: T
authors.lastname: Qi
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Ya
authors.initials: Y
authors.lastname: Pei
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America; Department of Endocrinology, Union Hospital, Tongji College of Medicine, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: An
authors.affiliation: Department of Endocrinology, Union Hospital, Tongji College of Medicine, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Stomatology, Union Hospital, Tongji College of Medicine, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Qifu
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; The Laboratory of Lipid & Glucose Metabolism, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Xiaoqiu
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America; Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Huo
authors.affiliation: Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Chaodong
authors.initials: C
authors.lastname: Wu
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000188:drug therapy / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D007333:Insulin Resistance; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose