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      Short treatment of metformin attenuated insulin resistance and hepatic steatosis in obese mice by mechanisms independents of PPAR-alpha

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      1 , , 1 , 1 , 1 , 1
      Cancer & Metabolism
      BioMed Central
      Metabolism, Diet and Disease 2014: Cancer and metabolism
      28-30 May 2014

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          Abstract

          Background Nonalcoholic steatohepatitis (NASH) is characterized by accumulation of fat in the liver without excessive alcohol intake [1]. The optimal treatment for this disease is not well established, however, metformin is described as an efficient treatment for NASH and hepatic inflammation [2]. Based on these data, the present study aimed to evaluate the possible immune-metabolic effects of metformin in high-fat diet wild type (C57) and knockout for PPAR-alpha (KO) mice. Materials and methods C57 and KO mice were submitted to a balanced or high fat diet (HFD) for 12 weeks, after 10 weeks these animals were treated with metformin or phosphate buffered saline by gavage. The insulin tolerance test (ITT) and glucose tolerance test (GTT) were performed. Histological slices of the liver, cored by hematoxilin and eosin were obtained, and the concentration of triacylglycerols and the cytokines levels were determined by ELISA. Results Animals submitted to HFD showed higher gain of weight (C57 p<0.001;KO p<0.05), that in C57 was represented by a greater gain of adipose tissue (p<0.001), while the weight of the liver did not change. This diet promotes insulin resistance in C57 and KO, as observed by reduction of glycemia in ITT (p<0.05) and by an increase in GTT (p<0.001). Although no differences in liver weight were observed in KO, these animals showed higher hepatic deposition of triacylglycerols (p<0.01) and more severe steatosis without an increase of pro-inflammatory cytokines levels. After 7 days, both C57 and KO treated with metformin showed an improvement in glucose tolerance in the GTT (p<0.05), and after 10 days metformin reduced the steatosis as evidenced by histology. Controversially, the liver of C57 mice submitted to HFD and treated with metformin showed higher levels of IL1-β (p<0.05), IL-8 and IL-12 (p<0.01). Conclusion The treatment with metformin improves glucose tolerance and decreases steatosis in mice submitted to high fat diet. However, the treatment was not able to reverse the inflammation in C57 mice. The mechanism of metformin is independent of PPAR-alpha.

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          Hepatocytes: critical for glucose homeostasis.

          Maintaining blood glucose levels within a narrow range is a critical physiological function requiring multiple metabolic pathways and involving several cell types, including a prominent role for hepatocytes. Under hormonal control, hepatocytes can respond to either feeding or fasting conditions by storing or producing glucose as necessary. In the fasting state, the effects of glucagon avoid hypoglycemia by stimulating glucogenesis and glycogenolysis and initiating hepatic glucose release. Postprandially, insulin prevents hyperglycemia, in part, by suppressing hepatic gluconeogenesis and glycogenolysis and facilitating hepatic glycogen synthesis. Both transcriptional regulation of rate limiting enzymes and modulation of enzyme activity through phosphorylation and allosteric regulation are involved. Type 2 diabetes mellitus is the most common serious metabolic condition in the world, and results from a subnormal response of tissues to insulin (insulin resistance) and a failure of the insulin-secreting beta cells to compensate. In type 2 diabetes, glucose is overproduced by the hepatocyte and is ineffectively metabolized by other organs. Impairments in the insulin signal transduction pathway appear to be critical lesions contributing to insulin resistance and type 2 diabetes.
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            Metformin Prevents and Reverses Inflammation in a Non-Diabetic Mouse Model of Nonalcoholic Steatohepatitis

            Background Optimal treatment for nonalcoholic steatohepatitis (NASH) has not yet been established, particularly for individuals without diabetes. We examined the effects of metformin, commonly used to treat patients with type 2 diabetes, on liver pathology in a non-diabetic NASH mouse model. Methodology/Principal Findings Eight-week-old C57BL/6 mice were fed a methionine- and choline-deficient plus high fat (MCD+HF) diet with or without 0.1% metformin for 8 weeks. Co-administration of metformin significantly decreased fasting plasma glucose levels, but did not affect glucose tolerance or peripheral insulin sensitivity. Metformin ameliorated MCD+HF diet-induced hepatic steatosis, inflammation, and fibrosis. Furthermore, metformin significantly reversed hepatic steatosis and inflammation when administered after the development of experimental NASH. Conclusions/Significance These histological changes were accompanied by reduced hepatic triglyceride content, suppressed hepatic stellate cell activation, and the downregulation of genes involved in fatty acid metabolism, inflammation, and fibrogenesis. Metformin prevented and reversed steatosis and inflammation of NASH in an experimental non-diabetic model without affecting peripheral insulin resistance.
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              Author and article information

              Conference
              Cancer Metab
              Cancer Metab
              Cancer & Metabolism
              BioMed Central
              2049-3002
              2014
              28 May 2014
              : 2
              : Suppl 1
              : P73
              Affiliations
              [1 ]Department of Cell and Developmental Biology, Biomedical Sciences Institute, São Paulo, São Paulo, Brazil
              Article
              2049-3002-2-S1-P73
              10.1186/2049-3002-2-S1-P73
              4073080
              049ece76-8da5-4bab-ad6d-5375703fa544
              Copyright © 2014 Teixeira et al; licensee BioMed Central Ltd.

              This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

              Metabolism, Diet and Disease 2014: Cancer and metabolism
              Washington DC, USA
              28-30 May 2014
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