Esther Kemper, Gijs Goossens, Ellen Blaak, Michiel Adriaens and Ruth Meex

Department of Human Biology, Maastricht University Medical Centre+, Maastricht, The Netherlands. ruth.meex@maastrichtuniversity.nl

Objective: Fetuin B is a hepatokine that is increased in individuals with liver steatosis and insulin resistance. We previously found that fetuin B induced glucose intolerance in mice, and that fetuin B content in adipose tissue was positively associated with skeletal muscle insulin resistance in both mice and humans. Furthermore, we found that fetuin B induced an inflammatory response in cultured adipocytes, suggesting a role for the adipose tissue in the development of peripheral insulin resistance. The current study aimed to investigate the link between plasma fetuin B and the adipose tissue transcriptome and plasma proteome in humans.

Methods: Baseline data was used from the DiOGenes study, a large European, multi-center, dietary intervention study. Continuous linear regression analysis in R was applied to investigate the link between plasma fetuin B with the adipose tissue transcriptome (n=207) and plasma proteome (n=558) in individuals, after adjustment for centre, sex and age (model 1), model 1 + BMI (model 2), and model 2 + MATSUDA-index (model 3). An overrepresentation analysis was then performed on the differentially expressed proteins and genes, utilizing the ClusterProfiler package in R.

Results: Plasma fetuin B was associated with >100 genes in white adipose tissue. Pathways that were significantly enriched in both model 1 and model 2 include pathways related to chemokine and cytokine signaling. Notably, two pathways were significantly enriched in all three models, and these were related to insulin signaling. Plasma fetuin B was associated with >146 plasma proteins. Among others, these pathways were related to the complement system and coagulation cascades, insulin signaling, cytokine signaling and a number of inflammatory pathways (all models).

Conclusion: Plasma fetuin B is related to adipose tissue genes and plasma proteins, involved in metabolic processes and insulin signaling. This study supports the notion that white adipose tissue may play a role in the development of fetuin B-induced insulin resistance.