Abstract
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.
Highlights
One-third of the global population is obese or overweight, and obesity is a major risk factor for type 2 diabetes (Roden and Shulman, 2019)
SUMMARY The eukaryotic translation initiation factor 2 a (eIF2a) phosphorylation-dependent integrated stress response (ISR) is a signaling pathway that maintains homeostasis in mammalian cells exposed to various stresses
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
Summary
One-third of the global population is obese or overweight, and obesity is a major risk factor for type 2 diabetes (Roden and Shulman, 2019). The cellular signaling pathways controlling adipokine production and regulating glucose and lipid metabolism are promising targets for managing obesity and preventing type 2 diabetes. A variety of stresses, including heme depletion, viral infection, endoplasmic reticulum (ER) stress, amino acid depletion, glucose depletion, hypoxia, and hyperosmosis, converge to phosphorylate eIF2a, which activates the ISR to restore cellular homeostasis (Pakos-Zebrucka et al, 2016). As shown in our recent study, four eIF2a kinases, namely, heme-regulated inhibitor (HRI), protein kinase R (PKR), PKR-like ER kinase, (PERK) and general control nondepressible 2 (GCN2), have overlapping functions and cooperatively activate the ISR in response to diverse stress stimuli (Taniuchi et al, 2016). As the ISR is a homeostatic program, the dysregulation of the ISR may be deleterious for cells and organisms
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