title: Intestinal IRE1 Is Required for Increased Triglyceride Metabolism and Longer Lifespan under Dietary Restriction.
abstract: Dietary restriction (DR) is one of the most robust lifespan-extending interventions in animals. The beneficial effects of DR involve a metabolic adaptation toward increased triglyceride usage. The regulatory mechanism and the tissue specificity of this metabolic switch remain unclear. Here, we show that the IRE1/XBP1 endoplasmic reticulum (ER) stress signaling module mediates metabolic adaptation upon DR in flies by promoting triglyceride synthesis and accumulation in enterocytes (ECs) of the Drosophila midgut. Consistently, IRE1/XBP1 function in ECs is required for increased longevity upon DR. We further identify sugarbabe, a Gli-like zinc-finger transcription factor, as a key mediator of the IRE1/XBP1-regulated induction of de novo lipogenesis in ECs. Overexpression of sugarbabe rescues metabolic and lifespan phenotypes of IRE1 loss-of-function conditions. Our study highlights the critical role of metabolic adaptation of the intestinal epithelium for DR-induced lifespan extension and explores the IRE1/XBP1 signaling pathway regulating this adaptation and influencing lifespan.
authors: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA. Electronic address: nuno.luis@univ-amu.fr.
authors: Nuno Miguel
authors: NM
authors: Luis
authors: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA.
authors: Lifen
authors: L
authors: Wang
authors: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA.
authors: Mauricio
authors: M
authors: Ortega
authors: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA.
authors: Hansong
authors: H
authors: Deng
authors: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA.
authors: Subhash D
authors: SD
authors: Katewa
authors: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA.
authors: Patrick Wai-Lun
authors: PW
authors: Li
authors: Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843, USA.
authors: Jason
authors: J
authors: Karpac
authors: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena 07745, Germany. Electronic address: hjasper@buckinstitute.org.
authors: Heinrich
authors: H
authors: Jasper
authors: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA. Electronic address: pkapahi@buckinstitute.org.
authors: Pankaj
authors: P
authors: Kapahi
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D004268:DNA-Binding Proteins / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster; D004722:Endoribonucleases / Q000378:metabolism; D020895:Enterocytes / Q000378:metabolism; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism*; D008136:Longevity / Q000502:physiology*; D013217:Starvation / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D014157:Transcription Factors; D014280:Triglycerides; C517798:Xbp1 protein, Drosophila; C469740:sug protein, Drosophila; D004722:Endoribonucleases; C511918:inositol requiring enzyme-1, Drosophila
keywords: Drosophila; IRE1; aging; dietary restriction; lipid turnover; longevity; metabolic adaptation