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

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.

• Authors: 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
• Journal: iScience (iScience) Vol. 23 Issue 3 Pg. 100930 (Mar 27 2020) ISSN: 2589-0042 [Electronic] United States
• PMID: 32151974 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.