title: Leptin improves fatty liver independently of insulin sensitization and appetite suppression in hepatocyte-specific Pten-deficient mice with insulin hypersensitivity.
abstract: Nonalcoholic fatty liver disease (NAFLD) is recognized as the hepatic component of the metabolic syndrome. Although NAFLD is a major cause of cirrhosis and cancer of the liver of unknown cause, no established pharmacological treatment for NAFLD has been established yet. It has been reported that leptin treatment improved fatty liver dramatically as well as insulin resistance and hyperphagia in patients with lipodystrophy. However, it is unclear whether leptin improves fatty liver independently of these metabolic improvements. We investigated the liver effect of leptin independently of insulin sensitization and appetite suppression using hepatocyte-specific Pten-deficient (AlbCrePtenff) mouse, a model of severe fatty liver with insulin hypersensitivity. Male AlbCrePtenff mice were infused subcutaneously with leptin (20 ng/g/h) for 2 weeks using osmotic minipumps. Leptin infusion effectively reduced liver weight, liver triglyceride content, and glutamate pyruvate transaminase (GPT) concentrations as well as food intake and body weight without the change of plasma insulin concentration in AlbCrePtenff mice. Pair-feeding also reduced body weight but not liver triglyceride content. Pair feeding reduced α1 and α2 AMP-activated protein kinase (AMPK) activities and PGC1α gene expression in the liver, while leptin infusion unchanged them. The present study clearly demonstrated that leptin improve fatty liver independently of insulin sensitization and suppression of food intake. It was suggested that leptin improves fatty liver by stimulation of β-oxidation in the liver. The present study might provide a further understanding on the mechanism of metabolic effect of leptin.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yamamoto-Kataoka
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.|Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ebihara
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.|Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Aizawa-Abe
authors.affiliation: Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nishio
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.|Medical Innovation Center, Kyoto University Graduate School of Medicine 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kusakabe
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.|Medical Innovation Center, Kyoto University Graduate School of Medicine 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Aotani
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sakai
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Ebihara
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: V M J
authors.initials: VMJ
authors.lastname: Gumbilai
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.|Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.|Department of Health and Science, Kyoto University Graduate School of Medicine 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hosoda
authors.affiliation: Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.|Medical Innovation Center, Kyoto University Graduate School of Medicine 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nakao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001066:Appetite / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D020738:Leptin / Q000008:administration & dosage*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism
chemical_list: D007328:Insulin; D020738:Leptin; D014280:Triglycerides; D055372:AMP-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse