Functional Gut Microbiota Remodeling Contributes to the Caloric Restriction-Induced Metabolic Improvements

Summary

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 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.

Graphical Abstract

Highlights

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  CR-microbiota transplantation improves glycemic control and insulin sensitivity

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  CR microbiota promotes beige fat development and reduces weight gain

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  CR suppresses key microbial genes for LPS biosynthesis and dictates the immune tone

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  LPS-TLR4 inhibition in bone marrow-derived cells improves metabolism and browning

Abstract

Fabbiano et al. show that gut microbiota remodeling is important for the metabolic improvements associated with caloric restriction, including fat browning and improved glycemic control. They link the systemic beneficial metabolic effects to reduced endotoxin production, leading to increased type 2 immune response in the adipose tissue.