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

被引：37

作者：

Miyake, Masato ^{[1
,2
,3
]}

Zhang, Jun ^{[1
,2
,4
]}

Yasue, Akihiro ^{[5
]}

Hisanaga, Satoshi ^{[1
,6
]}

Tsugawa, Kazue ^{[1
]}

Sakaue, Hiroshi ^{[2
,7
]}

Oyadomari, Miho ^{[1
]}

Kiyonari, Hiroshi ^{[8
]}

Oyadomari, Seiichi ^{[1
,2
,3
,4
]}

机构：

[1] Univ Tokushima, Inst Genome Res, Inst Adv Med Sci, Div Mol Biol, Tokushima 7708503, Japan

[2] Univ Tokushima, Inst Adv Med Sci, Diabet Therapeut & Res Ctr, Tokushima 7708503, Japan

[3] Univ Tokushima, Fujii Mem Inst Med Sci, Inst Adv Med Sci, Tokushima 7708503, Japan

[4] ER Stress Res Inst Inc, Tokushima 7708503, Japan

[5] Tokushima Univ, Inst Biomed Sci, Dept Orthodont & Dentofacial Orthoped, Grad Sch, Tokushima, Japan

[6] Kumamoto Univ, Dept Orthopaed Surg, Fac Life Sci, Kumamoto 8608556, Japan

[7] Tokushima Univ, Inst Biomed Sci, Dept Nutr & Metab, Grad Sch, Tokushima 7708503, Japan

[8] RIKEN Ctr Biosyst Dynam Res, Lab Anim Resources & Genet Engn, Kobe, Hyogo 6500047, Japan

来源：

ISCIENCE | 2021年 / 24卷 / 12期

关键词：

DIFFERENTIATION FACTOR 15; SELECTIVE-INHIBITION; BETA-CELLS; ACID; RECEPTOR; PHOSPHORYLATION; WEIGHT; DEPHOSPHORYLATION; PROTECTS; TRANS-10;

D O I：

10.1016/j.isci.2021.103448

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The eIF2 alpha 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 anal is 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 noncell-autonomous regulation of appetite.

引用

页数：22