Blockade of Interleukin-6 Trans-signaling in the Presence of Certain Gut Microbiota Induces Mature-onset Obesity in Mice.

Background and Aims: Interleukin-6 (IL-6) performs multiple roles in regulating metabolic pathways in both mice and man. Here, we examined the age-dependent metabolic phenotype of SGP mice-mice overexpressing sgp130, a factor that specifically blocks IL-6 trans-signaling-that were housed in distant vivaria. Methods: Transgenic SGP mice engineered to block IL-6 trans-signaling and wild-type littermates were raised in a Jerusalem animal facility to up to 14 months of age and assessed for weight gain, body composition, and metabolic determinants of energy expenditure in young Results: At ∼6 months of age, weight gain, body fat accumulation, hepatosteatosis, hyperglycemia, and macrophage recruitment to adipose tissue emerged and progressed with age in SGP mice maintained in the Jerusalem animal facility, but not in 3 other vivaria. IL-6/sIL-6R blockade strongly reduced signal transducer and activator of transcription 3 phosphorylation in the liver, and hepatocyte-targeted ablation of signal transducer and activator of transcription 3 recapitulated the IL-6 trans-signaling blockade phenotype. Multiomics analyses of mouse livers revealed age- and genotype-related changes in gene expression profiles attributable to bacterial byproducts. Depletion of the gut microbiota by antibiotic treatment from the age of 6 months reversed the obese phenotype in transgenic mice, confirming the crucial role of the microbiome in the phenotype. Accordingly, the microbiome of mice from the Jerusalem animal facility differed significantly from that of mice from animal facilities in Kiel and Hamburg, Germany, where the same mice did not develop a metabolic phenotype. Conclusion: These findings reveal the crucial functions of IL-6 trans-signaling in preventing mature-onset body fat accumulation induced by certain intestinal microbiota.