Fabbiano, SalvatoreSalvatoreFabbianoSuárez-Zamorano, NicolasNicolasSuárez-ZamoranoChevalier, ClaireClaireChevalierLazarević, VladimirVladimirLazarevićKieser, SilasSilasKieserRigo, DorothéeDorothéeRigoLeo, StefanoStefanoLeoVeyrat-Durebex, ChristelleChristelleVeyrat-DurebexGaïa, NadiaNadiaGaïaMaresca, MarcelloMarcelloMarescaMerkler, DoronDoronMerklerGomez de Agüero Tamargo, Maria de la MercedesMaria de la MercedesGomez de Agüero TamargoMacpherson, AndrewAndrewMacpherson0000-0002-7192-0184Schrenzel, JacquesJacquesSchrenzelTrajkovski, MirkoMirkoTrajkovski2024-10-072024-10-072018-12-04https://boris-portal.unibe.ch/handle/20.500.12422/61433Caloric restriction (CR) stimulates development of functional beige fat and extends healthy lifespan. Here we show that compositional and functional changes in the gut microbiota contribute to a number of CR-induced metabolic improvements and promote fat browning. Mechanistically, these effects are linked to a lower expression of the key bacterial enzymes necessary for the lipid A biosynthesis, a critical lipopolysaccharide (LPS) building component. The decreased LPS dictates the tone of the innate immune response during CR, leading to increased eosinophil infiltration and anti-inflammatory macrophage polarization in fat of the CR animals. Genetic and pharmacological suppression of the LPS-TLR4 pathway or transplantation with Tlr4 bone-marrow-derived hematopoietic cells increases beige fat development and ameliorates diet-induced fatty liver, while Tlr4 or microbiota-depleted mice are resistant to further CR-stimulated metabolic alterations. These data reveal signals critical for our understanding of the microbiota-fat signaling axis during CR and provide potential new anti-obesity therapeutics.enTLR4 beige fat browning caloric restriction fatty liver gut microbiota innate immunity insulin sensitivity600 - Technology::610 - Medicine & healtharticle10.7892/boris.1223773017430810.1016/j.cmet.2018.08.005