Network analysis of adipose tissue gene expression highlights altered metabolic and regulatory transcriptomic activity in high-fat-diet-fed IL-1RI knockout mice

Abstract

A subacute inflammatory phenotype is implicated in the pathology of insulin resistance (IR) and type 2 diabetes mellitus. Interleukin (IL)-1α and IL-1β are produced by innate immune cells, including macrophages, and mediate their inflammatory response through the IL-1 type I receptor (IL-IRI). This study sought to understand the transcriptomic signature of adipose tissue in obese IL-1RI(-/-) mice. Following dietary intervention, markers of insulin sensitivity and inflammation in adipose tissue were determined, and gene expression was assessed with microarrays. IL-1RI(-/-) mice fed a high-fat diet (HFD) had significantly lower plasma inflammatory cytokine concentrations than wild-type mice. Metabolic network analysis of transcriptomic effects identified up-regulation and co-expression of genes involved in lipolysis, lipogenesis and tricarboxylic acid (TCA) cycle. Further assessment of gene expression in a network of protein interactions related to innate immunity highlighted Stat3 as a potential transcriptional regulator of IL-1 signalling. The complex, downstream effects of IL-1 signalling through the IL-1RI receptor remain poorly defined. Using network-based analyses of transcriptomic signatures in IL-1RI(-/-) mice, we have identified expression changes in genes involved in lipid cycling and TCA cycle, which may be more broadly indicative of a restoration of mitochondrial function in the context of HFD. Our results also highlight a potential role for Stat3 in linking IL-1 signalling to adipogenesis and IR.