Intestinal IRE1 Is Required for Increased Triglyceride Metabolism and Longer Lifespan under Dietary Restriction

• DOI: 10.1016/j.celrep.2016.10.003
• Publication Date: 2016-10-25T13:00:19Z
• Authors: Nuno Miguel Luis; Lifen Wang; Mauricio Ortega; Hansong Deng; Subhash D. Katewa; Patrick Wai-Lun Li; Jason Karpac; Heinrich Jasper; Pankaj Kapahi
• Keywords: 0303 health sciences; QH301-705.5; aging; Longevity; dietary restriction; metabolic adaptation; IRE1; DNA-Binding Proteins; 03 medical and health sciences; Drosophila melanogaster; Enterocytes; longevity; Starvation; Endoribonucleases; Animals; Drosophila Proteins; Homeostasis; Drosophila; Biology (General); Intestinal Mucosa; lipid turnover; Triglycerides; Caloric Restriction; Transcription Factors

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.