摘要：SummaryLipid digestion and absorption are tightly regulated to cope with metabolic demands among tissues. How these processes are coordinated is not well characterized. Here, we found that mifepristone (RU486) prevents lipid digestion both in flies and mice. In flies, RU486 administration suppresses lipid digestion by transcriptional downregulatingMagroin guts. Similarly, intestinal lipid uptake in mice was also suppressed by RU486 through the glucocorticoid receptor (GR). Further studies showed that the pancreatic lipasePnlipis a direct transcriptional target of GR in pancreas tissues. Glucocorticoid levels in mice fed a high fat diet (HFD) are significantly lower than those fed on a conventional diet, and RU486 administration inhibits HFD-induced obesity both in mice and flies. Our findings identified a novel mechanism of RU486 functions as a GR antagonist systematically regulating lipid metabolism, providing new insight on the role of Glucocorticoid/GR in Cushing disease, diabetes, and other related metabolic syndromes.Graphical abstractDisplay OmittedHighlights•RU486 suppresses lipid digestion both in mice and flies.•In flies, lipaseMagrois transcriptionally suppressed by RU486 through dERR.•In mice, intestinal lipid digestion is inhibited by RU486 through (GR)/PTL pathway in pancreas.•RU486 alleviates high fat diet-induced obesity both in flies and mice.Lipid; Cellular physiology; Metabolic engineering
