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

doi:10.1016/j.isci.2020.100930

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

iScience. 2020 Mar 27;23(3):100930. doi: 10.1016/j.isci.2020.100930. Epub 2020 Feb 21.

Authors

Affiliations

¹ Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
² 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.
³ 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. Electronic address: ynakagawa@md.tsukuba.ac.jp.
⁴ Laboratory of Microbial Chemistry, Kobe Pharmaceutical University, 4-19-1, Motoyamakitamachi, Higashinada-Ku, Kobe, Hyogo, 658-8558, Japan.
⁵ Department of Genetic Biochemistry, Graduate School of Pharmaceutical Science, Kyoto University, 46-29 Yoshida-Shimoadachi-Cho, Sakyo-ku, Kyoto, Kyoto 606-8501, Japan.
⁶ Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, 757 Asahimachi, Niigata, Niigata 951-8510, Japan.
⁷ 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. Electronic address: hshimano@md.tsukuba.ac.jp.

Abstract

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.

Keywords: Molecular Genetics; Obesity Medicine.