The multifaceted role of ATF4 in regulating glucose-stimulated insulin secretion

Mitsuaki Sobajima; Masato Miyake; Yoshimasa Hamada; Kazue Tsugawa; Miho Oyadomari; Ryota Inoue; Jun Shirakawa; Hiroshi Arima; Seiichi Oyadomari

doi:10.1016/j.bbrc.2022.04.038

The multifaceted role of ATF4 in regulating glucose-stimulated insulin secretion

Biochem Biophys Res Commun. 2022 Jun 30:611:165-171. doi: 10.1016/j.bbrc.2022.04.038. Epub 2022 Apr 16.

Authors

Mitsuaki Sobajima¹, Masato Miyake², Yoshimasa Hamada², Kazue Tsugawa³, Miho Oyadomari³, Ryota Inoue⁴, Jun Shirakawa⁴, Hiroshi Arima⁵, Seiichi Oyadomari⁶

Affiliations

¹ Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan; Department of Molecular Physiology, Diabetes Therapeutics and Research Center, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan; Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan; Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, 371-8512, Japan.
² Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan; Department of Molecular Physiology, Diabetes Therapeutics and Research Center, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan; Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
³ Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
⁴ Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, 371-8512, Japan.
⁵ Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan.
⁶ Division of Molecular Biology, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan; Department of Molecular Physiology, Diabetes Therapeutics and Research Center, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan; Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan. Electronic address: oyadomar@genome.tokushima-u.ac.jp.

PMID: 35489203
DOI: 10.1016/j.bbrc.2022.04.038

Abstract

Stress-inducible transcription factor ATF4 is essential for survival and identity of β-cell during stress conditions. However, the physiological role of ATF4 in β-cell function is not yet completely understood. To understand the role of ATF4 in glucose-stimulated insulin secretion (GSIS), β-cell-specific Atf4 knockout (βAtf4KO) mice were phenotypically characterized. Insulin secretion and mechanistic analyses were performed using islets from control Atf4f/f and βAtf4KO mice to assess key regulators for triggering and amplifying signals for GSIS. βAtf4KO mice displayed glucose intolerance due to reduced insulin secretion. Moreover, βAtf4KO islets exhibited a decrease in both the insulin content and first-phase insulin secretion. The analysis of βAtf4KO islets showed that ATF4 is required for insulin production and glucose-stimulated ATP and cAMP production. The results demonstrate that ATF4 contributes to the multifaceted regulatory process in GSIS even under stress-free conditions.

Keywords: ATF4; ATP production; GSIS; ISR; Islet; Knockout mouse; β-cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Glucose / metabolism
Glucose / pharmacology
Glucose Intolerance* / genetics
Glucose Intolerance* / metabolism
Insulin / metabolism
Insulin Secretion
Insulin-Secreting Cells* / metabolism
Islets of Langerhans* / metabolism
Mice
Mice, Knockout

Substances

Insulin
Glucose