CREBH Improves Diet-Induced Obesity, Insulin Resistance, and Metabolic Disturbances by FGF21-Dependent and FGF21-Independent Mechanisms

Aoi Satoh; Song-iee Han; Masaya Araki; Yoshimi Nakagawa; Hiroshi Ohno; Yuhei Mizunoe; Kae Kumagai; Yuki Murayama; Yoshinori Osaki; Hitoshi Iwasaki; Motohiro Sekiya; Morichika Konishi; Nobuyuki Itoh; Takashi Matsuzaka; Hirohito Sone; Hitoshi Shimano

iScience (Mar 2020)

CREBH Improves Diet-Induced Obesity, Insulin Resistance, and Metabolic Disturbances by FGF21-Dependent and FGF21-Independent Mechanisms

Aoi Satoh,
Song-iee Han,
Masaya Araki,
Yoshimi Nakagawa,
Hiroshi Ohno,
Yuhei Mizunoe,
Kae Kumagai,
Yuki Murayama,
Yoshinori Osaki,
Hitoshi Iwasaki,
Motohiro Sekiya,
Morichika Konishi,
Nobuyuki Itoh,
Takashi Matsuzaka,
Hirohito Sone,
Hitoshi Shimano

Affiliations

Aoi Satoh: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
Song-iee Han: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
Masaya Araki: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
Yoshimi Nakagawa: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Corresponding author
Hiroshi Ohno: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
Yuhei Mizunoe: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
Kae Kumagai: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
Yuki Murayama: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
Yoshinori Osaki: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
Hitoshi Iwasaki: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
Motohiro Sekiya: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
Morichika Konishi: Laboratory of Microbial Chemistry, Kobe Pharmaceutical University, 4-19-1, Motoyamakitamachi, Higashinada-Ku, Kobe, Hyogo, 658-8558, Japan
Nobuyuki Itoh: Department of Genetic Biochemistry, Graduate School of Pharmaceutical Science, Kyoto University, 46-29 Yoshida-Shimoadachi-Cho, Sakyo-ku, Kyoto, Kyoto 606-8501, Japan
Takashi Matsuzaka: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
Hirohito Sone: Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, 757 Asahimachi, Niigata, Niigata 951-8510, Japan
Hitoshi Shimano: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan; Japan Agency for Medical Research and Development–Core Research for Evolutional Science and Technology (AMED-CREST), 1-7-1 Otemachi, Chiyoda-ku, Tokyo, Japan; Corresponding author

Journal volume & issue: Vol. 23, no. 3

Abstract

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Summary: Mice overexpressing the nuclear form of CREBH mainly in the liver (CREBH-Tg) showed suppression of high-fat high-sucrose (HFHS) diet-induced obesity accompanied by an increase in plasma fibroblast growth factor 21 (FGF21) levels. CREBH overexpression induced browning in inguinal white adipose tissue (WAT) and whole-body energy expenditure, which was canceled in Fgf21−/− mice. Deficiency of FGF21 in CREBH-Tg mice mostly canceled the improvement of obesity, but the suppression of inflammation of epidermal WAT, amelioration of insulin resistance, and improvement of glucose metabolism still sustained. Kisspeptin 1 (Kiss1) was identified as a novel hormone target for CREBH to explain these FGF21-independent effects of CREBH. Knockdown of Kiss1 in HFHS-fed CREBH-Tg Fgf21−/− mice showed partially canceled improvement of glucose metabolism. Taken together, we propose that hepatic CREBH pleiotropically improves diet-induced obesity-mediated dysfunctions in peripheral tissues by improving systemic energy metabolism in FGF21-dependent and FGF21-independent mechanisms. : Obesity Medicine; Molecular Genetics Subject Areas: Obesity Medicine, Molecular Genetics

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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