Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Identification of an interferome nexus as a paradoxical negative regulator of adipogenesis and positive regulator of local and systemic insulin sensitivity (#239)

Jon Whitehead 1
  1. Mater Research Institute, University of Queensland, Brisbane, QLD, Australia

Coordinated adipogenesis helps maintain adipose tissue function and reduce obesity-associated complications including type 2 diabetes.  We previously demonstrated that FGF-1 promotes adipogenesis via a novel BAMBI/PPARg-dependent pathway.  Here, we employed a combination of RNA-Seq, functional investigations and association studies to identify novel downstream regulators of adipogenesis implicated in the modulation of local and systemic insulin sensitivity.  FGF-1 altered the expression of 598 genes, including 49 ‘interferome’ genes, of which 11 were downstream of BAMBI and PPARg.  In silico analysis of known and predicted protein-protein interactions revealed a nexus that included all 11 FGF-1/BAMBI/PPARg-dependent genes.  Functional characterization of five nexus genes revealed all were negative regulators of adipogenesis.  Determination of the expression profile of the nexus genes in subcutaneous human adipose tissue from a cohort of obese males with varying degrees of insulin sensitivity showed expression of all five nexus genes correlated with local (adipose) and systemic (skeletal muscle) insulin sensitivity.  This contrasted with a classic inflammatory gene signature which showed the expected inverse correlation with insulin sensitivity.  Moreover, in a cohort of subjects without overt metabolic dysfunction expression of both interferome nexus genes and inflammatory genes showed a positive correlation with BMI.  Collectively these findings increase our understanding of the molecular networks that regulate adipogenesis and, somewhat paradoxically, reveal the interferome nexus as a potential positive regulator of both local and systemic insulin sensitivity.  Further studies are warranted to explore the molecular mechanisms and define potential therapeutic opportunities.