Integrated stress response regulates GDF15 secretion from adipocytes, preferentially suppresses appetite for a high-fat diet and improves obesity

Masato Miyake; Jun Zhang; Akihiro Yasue; Satoshi Hisanaga; Kazue Tsugawa; Hiroshi Sakaue; Miho Oyadomari; Hiroshi Kiyonari; Seiichi Oyadomari

doi:10.1016/j.isci.2021.103448

Integrated stress response regulates GDF15 secretion from adipocytes, preferentially suppresses appetite for a high-fat diet and improves obesity

iScience. 2021 Nov 15;24(12):103448. doi: 10.1016/j.isci.2021.103448. eCollection 2021 Dec 17.

Authors

Masato Miyake^{1

2

3}, Jun Zhang^{1

2

4}, Akihiro Yasue⁵, Satoshi Hisanaga^{1

6}, Kazue Tsugawa¹, Hiroshi Sakaue^{2

7}, Miho Oyadomari¹, Hiroshi Kiyonari⁸, Seiichi Oyadomari^{1

2

3

4}

Affiliations

¹ Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.
² Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.
³ Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.
⁴ ER Stress Research Institute Inc., Tokushima 770-8503, Japan.
⁵ Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, 770-8504, Japan.
⁶ Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
⁷ Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
⁸ Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan.

Abstract

The eIF2α phosphorylation-dependent integrated stress response (ISR) is a signaling pathway that maintains homeostasis in mammalian cells exposed to various stresses. Here, ISR activation in adipocytes improves obesity and diabetes by regulating appetite in a non-cell-autonomous manner. Adipocyte-specific ISR activation using transgenic mice decreases body weight and improves glucose tolerance and obesity induced by a high-fat diet (HFD) via preferential inhibition of HFD intake. The transcriptome analysis of ISR-activated adipose tissue reveals that growth differentiation factor 15 (GDF15) expression is induced by the ISR through the direct regulation of the transcription factors ATF4 and DDIT3. Deficiency in the GDF15 receptor GFRAL abolishes the adipocyte ISR-dependent preferential inhibition of HFD intake and the anti-obesity effects. Pharmacologically, 10(E), 12(Z)-octadecadienoic acid induces ISR-dependent GDF15 expression in adipocytes and decreases the intake of the HFD. Based on our findings the specific activation of the ISR in adipocytes controls the non-cell-autonomous regulation of appetite.

Keywords: Biological sciences; Cell biology; Human metabolism.