摘要：SummaryThe 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.Graphical abstractDisplay OmittedHighlights•Activation of ISR in adipocytes suppresses intake of high-fat diet and prevents obesity•ATF4 and DDIT3 induced by ISR directly regulate GDF15 expression•GDF15-GFRAL axis mediates the control of appetite for high-fat diet by ISR activation•One of conjugated linoleic acids induces ISR and GDF15 expression in adipocytesBiological sciences; Human metabolism; Cell biology
