Identification and characterisation of HHIP: 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 HHIP: A novel regulator of adipogenesis implicated in the modulation of local and systemic insulin sensitivity

Identification and characterisation of HHIP: A novel regulator of adipogenesis implicated in the modulation of local and systemic insulin sensitivity (#191)

Jingjing He 1 , Kevin Gillinder 1 , Daniel L Chen 2 , Graham Magor 1 , Dorit Samocha-Bonet 3 , Johanna Barclay 1 , Jerry Greenfield 3 , Andrew Perkins 1 , Jon Whitehead 1
  1. Mater Research Institute-University of Queensland, Brisbane
  2. Garvan Institute of Medical Research, Sydney
  3. 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 established FGF-1 as a driver of adipogenesis1 and diet-induced adipose tissue remodelling2.  Increased understanding of the mechanisms may reveal novel therapeutic targets.   Recent work identified BAMBI 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- 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 of which 131/31 were PPARγ-dependent.  Bioinformatics revealed several genes/clusters involved in Wnt, ECM, interferome and hedgehog pathways. 

Hedgehog Interacting Protein (HHIP), an inhibitor of the hedgehog axis (a negative regulator of adipogenesis) recently found to be associated with BMI and reduced incidence of type 2 diabetes in GWAS4, was stimulated by FGF-1 in a BAMBI/PPARγ-independent manner (p<0.05).  HHIP knockdown significantly reduced differentiation of SGBS preadipocytes, decreasing lipid accumulation/adipogenic markers expression consistent with a positive role in adipogenesis.  HHIP expression in shAT showed a trend towards an inverse correlation with ATIR (p=0.10) and correlated positively with GIR (p=0.005), but no correlation with BMI (p=0.37), which may suggest an association with insulin sensitivity independent of adiposity in obese people.

These findings increase our understanding of adipogenic networks, establishing HHIP as a novel positive regulator mediating the adipogenic effects of FGF-1 that may promote local and systemic insulin sensitivity by enhancing adipose tissue remodelling through increased preadipocyte differentiation.

  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)
  4. Locke, A. E. et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 518, 197-206, (2015)