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Original article (peer-reviewed)

Journal Cell Metabolism
Volume (Issue) 28(6)
Page(s) 907 - 921
Title of proceedings Cell Metabolism
DOI 10.1016/j.cmet.2018.08.005

Open Access

Type of Open Access Publisher (Gold Open Access)


Caloric 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 increase beige fat development and ameliorate 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.