Identification and characterisation of the interferome: A novel regulator of adipogenesis implicated in the modulation of local and systemic insulin sensitivity — ASN Events
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  3. Identification and characterisation of the interferome: A novel regulator of adipogenesis implicated in the modulation of local and systemic insulin sensitivity

Identification and characterisation of the interferome: A novel regulator of adipogenesis implicated in the modulation of local and systemic insulin sensitivity (#159)

Jingjing He 1 , Kevin Gillinder 1 , Daniel L Chen 2 , Graham Magor 1 , Dorit Samocha-Bonet 2 , Johanna Barclay 1 , Jerry Greenfield 2 , Andrew Perkins 1 , Jon Whitehead 1
  1. Mater Research Institute-University of Queensland, Brisbane
  2. Garvan Institute of Medical Research, Sydney

Adipose tissue dysfunction links obesity with cardiometabolic disease.  Improved adipose tissue remodelling represents a strategy to enhance adipose tissue function.  Previous work has established FGF-1 as a driver of adipogenesis1 and diet-induced adipose tissue remodelling2.  Increased understanding of the mechanisms may reveal novel therapeutic targets.   A recent study identified BAMBI (BMP and Activin Membrane-Bound Inhibitor) as a negative regulator of adipogenesis, situated between FGF-1 and the master adipogenic regulator PPARγ3.

Here we used SGBS preadipocytes to perform (i) transcriptomics to define FGF-1, BAMBI and PPARγ networks, (ii) functional studies to characterise the role of candidate genes and (iii) correlations between candidate gene expression in subcutaneous human adipose tissue (shAT) with BMI, adipose tissue insulin resistance (ATIR-determined by fasting insulin * fasting NEFA) and glucose infusion rates (GIR) in obese subjects.

RNA-Seq of cells treated ±FGF-1, ±BAMBI siRNA, ±PPARγ siRNA revealed significant changes in 1526 genes. FGF-1/BAMBI knockdown altered expression of 598/54 genes respectively.  Of these, 131/31 were PPARγ-dependent.  Bioinformatics analysis revealed several genes/clusters involved in hedgehog, Wnt, ECM and interferome related pathways. 

Five interferome genes were selected for further investigation (IFI44L, IFIT1, IFI27, ISG15 and HERC6).  RNA-Seq/qRT-PCR indicated all 5 were reduced by FGF-1/BAMBI siRNA (all p<0.05).  Targeted knockdown of each gene enhanced differentiation, increasing lipid accumulation/expression of adipogenic markers (all p<0.05) consistent with a negative role in adipogenesis.  Expression levels of all 5 genes in shAT correlated with BMI (n=24) but, paradoxically, showed inverse correlations with ATIR (n=18) /positive correlations with GIR (n=24).

These findings increase our understanding of adipogenic networks and begin to integrate these observations at a tissue and systemic level.  Paradoxically, elevated shAT expression levels of interferome genes appear to protect local and systemic insulin sensitivity, highlighting the need for integrated approaches to afford identification of rational therapeutic strategies

  1. Hutley, L. J. et al. FGF-1 - a key regulator of human adipogenesis. Diabetes 53, 3097-3106 (2004)
  2. Jonker, J. W. et al. A PPARgamma-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis. Nature 485, 391-394 (2012)
  3. Luo, X. et al. Identification of BMP and Activin Membrane-Bound Inhibitor (BAMBI) as a Potent Negative Regulator of Adipogenesis and Modulator of Autocrine/Paracrine Adipogenic Factors. Diabetes 61, 124-136, (2012)