Effect of IL-6 Trans-Signaling Blockade by sgp130 overexpression on hepatic gene expression in the context of mature-onset obesity in mice

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 mice overexpressing sgp130 (SGP mice), which specifically blocks IL-6 trans-signaling. Transgenic SGP mice engineered to block IL-6 trans-signaling and wild-type (WT) littermates were raised to 6 and 14 months of age. RNA-seq analyses were performed on liver samples as a function of age and genotype. 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. IL-6/sIL-6R blockade strongly reduced STAT3 phosphorylation in the liver. RNA-seq analyses of mouse livers revealed 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. These findings reveal the crucial functions of IL-6 trans-signaling in preventing mature-onset body fat accumulation induced by certain intestinal microbiota.