Fat body Ire1 regulates lipid homeostasis through the Xbp1s-FoxO axis in Drosophila

Abstract

Summary The endoplasmic reticulum (ER)-resident transmembrane protein kinase/RNase Ire1 is a conserved sensor of the cellular unfolded protein response and has been implicated in lipid homeostasis, including lipid synthesis and transport, across species. Here we report a novel catabolic role of Ire1 in regulating lipid mobilization in Drosophila . We found that Ire1 is activated by nutrient deprivation, and, importantly, fat body-specific Ire1 deficiency leads to increased lipid mobilization and sensitizes flies to starvation, whereas fat body Ire1 overexpression results in the opposite phenotypes. Genetic interaction and biochemical analyses revealed that Ire1 regulates lipid mobilization by promoting Xbp1s-associated FoxO degradation and suppressing FoxO-dependent lipolytic programs. Our results demonstrate that Ire1 is a catabolic sensor and acts through the Xbp1s-FoxO axis to hamper the lipolytic response during chronic food deprivation. These findings offer new insights into the conserved Ire1 regulation of lipid homeostasis.

Xbp1 targets canonical UPRER and non-canonical pathways in separate tissues to promote longevity

“…Importantly, the two pro-longevity TFs appear to share a large number of target genes and have highly similar transcriptional outcomes in the fat body. This adds an additional layer to previous findings where Xbp1 was observed to negatively regulate FOXO 41 , 42 , 43 ; or our previous work that identified a TF relay where transient activation of dfoxo results in subsequent Xbp1 induction. 15 Note that Xbp1 induction was not observed during chronic activation of dFOXO.…”

Macrophage‐derived insulin antagonist ImpL2 induces lipoprotein mobilization upon bacterial infection

“…Given that FOXO nuclear translocation is controlled by PI3K activity in situations of metabolic stress (Zhao et al , 2021), we analyzed the effect of Mφ‐ ImpL2 manipulations on PI3K activity in the fat body. For this purpose, we employed a fly strain carrying in vivo PI3K reporter based on pleckstrin homology domain fused with GFP (tGPH; Britton et al , 2002).…”

The landscape of aging

“…Moreover, activation of the IRE1-XBP1 axis has been shown to mediate the metabolic adaptation upon caloric restriction by promoting lipid synthesis and storage in enterocytes of the midgut, which is essential for extending longevity in flies (Luis et al, 2016). It is worth noting that abrogation of IRE1-Xbp1 signaling in the fat body can increase FoxO stability and the expression of its target genes, including dATGL/ Bmm, leading to elevated lipid mobilization with reduced starvation resistance (Zhao et al, 2021a). It remains to be deciphered, however, whether fat body IRE1-Xbp1 pathway can respond to caloric restriction and contribute to the control of longevity.…”