Han Jiao1,2,3,4,11, Jarne Jermei1,2,3,4,11, Xian Liang5,11, Hendrik J.P. van der Zande6,11, Frank Vrieling6, Valentina Sophia Rumanova1,2,3,4,7, Milan Dorscheidt1,2,3,4, Anhui Wang1,2,3,4, Ewout Foppen1,2,3,4, Bob Ignacio8, Dirk Jan Stenvers1,2, Tiemin Liu9, Kimberly Bonger8, Rinke Stienstra6,10, Zhi Zhang9, Andries Kalsbeek1,2,3,4, Chun-Xia Yi1,2,3,4,12, *
1. Department of Endocrinology and Metabolism, Amsterdam University Medical Center, location AMC, University of Amsterdam, Amsterdam, The Netherlands. 2. Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam, The Netherlands. 3. Department of Clinical Chemistry, Laboratory of Endocrinology, Amsterdam University Medical Centers, location AMC, Amsterdam, The Netherlands. 4. Netherlands Institute for Neuroscience, Amsterdam, The Netherlands. 5. Human Phenome Institute, Fudan University, Shanghai, China. 6. Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands. 7. Department of Animal Physiology and Physiology, Comenius University, Bratislava, Slovakia. 8. Institute for Molecules and Materials, Radboud University, Nijmegen, The Netherlands. 9. State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China. 10. Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. 11. These authors contributed equally. 12 Lead contact
Abstract: Time-restricted eating has shown great promise for improving metabolic health in obese humans, but its mechanism is still not completely resolved. In this study, we investigated how time-restricted feeding (TRF) affects microglial immunometabolism using Wistar rats. High-fat diet (HFD)-fed animals became obese, but restricting food intake to the active phase reduced fat mass, reinforced the rhythmicity of the microglial transcriptome, and prevented an increase of hypothalamic microglial cell numbers. However, TRF failed to reverse HFD-induced microglial immune dysfunction and metabolic disturbances, including suppressed electron transport chain activity, increased lipid metabolism gene expression, and impaired metabolic flexibility. These findings suggest that obesity-driven microglial immunometabolic reprogramming persists despite TRF-induced weight loss and may contribute to obesogenic memory and weight regain after weight loss induced by dietary interventions.