Starvation-induced transcription factor CREBH negatively governs body growth by controlling GH signaling

Yoshimi Nakagawa*, Kae Kumagai, Song iee Han, Yuhei Mizunoe, Masaya Araki, Seiya Mizuno, Hiroshi Ohno, Kazuya Matsuo, Yasunari Yamada, Jun dal Kim, Takafumi Miyamoto, Motohiro Sekiya, Morichika Konishi, Nobuyuki Itoh, Takashi Matsuzaka, Satoru Takahashi, Hirohito Sone, Hitoshi Shimano*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

cAMP responsive element-binding protein H (CREBH) is a hepatic transcription factor to be activated during fasting. We generated CREBH knock-in flox mice, and then generated liver-specific CREBH transgenic (CREBH L-Tg) mice in an active form. CREBH L-Tg mice showed a delay in growth in the postnatal stage. Plasma growth hormone (GH) levels were significantly increased in CREBH L-Tg mice, but plasma insulin-like growth factor 1 (IGF1) levels were significantly decreased, indicating GH resistance. In addition, CREBH overexpression significantly increased hepatic mRNA and plasma levels of FGF21, which is thought to be as one of the causes of growth delay. However, the additional ablation of FGF21 in CREBH L-Tg mice could not correct GH resistance at all. CREBH L-Tg mice sustained GH receptor (GHR) reduction and the increase of IGF binding protein 1 (IGFBP1) in the liver regardless of FGF21. As GHR is a first step in GH signaling, the reduction of GHR leads to impairment of GH signaling. These data suggest that CREBH negatively regulates growth in the postnatal growth stage via various pathways as an abundant energy response by antagonizing GH signaling.

Original languageEnglish
Article numbere21663
JournalFASEB Journal
Volume35
Issue number6
DOIs
StatePublished - 2021/06

Keywords

  • CREBH
  • FGF21
  • GH resistance
  • GHR
  • IGFBP1
  • growth delay

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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