Obesity-associated adipose tissue dysfunction contributes to cardiometabolic disease. Coordinated adipogenesis and adipose tissue remodelling are required for healthy adipose tissue. We previously reported that FGF-1 (Fibroblast growth factor-1) primes human preadipocytes via a novel BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor)/PPARg-dependent pathway. Here, we combined RNA-Seq, functional investigations in preadipocytes and studies in humans to identify novel downstream regulators of adipogenesis implicated in the modulation of adipose tissue and systemic insulin sensitivity. FGF-1 significantly altered the expression of 598 genes. Five interferome genes (IFI44L, IFIT1, IFI27, ISG15 and HERC6) were selected for detailed characterization based on literature, bioinformatics and preliminary investigations. All five were regulated in an FGF-1/BAMBI/PPARg-dependent manner. Moreover, siRNA mediated knockdown showed that all five genes were negative regulators of adipogenesis as evidenced by increased lipid accumulation and expression of adipogenic markers (PPARg, AdipoQ, AdipoR2 and Glut4). Conversely, Hedgehog Interacting Protein (HHIP), an inhibitor of the hedgehog axis (a negative regulator of adipogenesis) recently associated with BMI and reduced incidence of type 2 diabetes in GWAS, was induced by FGF-1 in a BAMBI/PPARγ-independent manner and functional (siRNA-based) studies indicated HHIP is a positive regulator of adipogenesis. In subcutaneous human adipose tissue (shAT) expression of all five interferome genes correlated positively with BMI but, paradoxically, inversely with adipose tissue insulin resistance (ATIR) and positively with glucose infusion rate (GIR – measured during a hyperinuslinaemic euglycaemic clamp). HHIP expression in shAT correlated positively with GIR and showed a trend towards an inverse correlation with ATIR, but no correlation with BMI. Collectively these findings increase our understanding of the molecular networks that regulate adipogenesis and suggest that elevated activity of the interferome axis and reduced activity of the hedgehog axis in shAT may help to protect both local and systemic insulin sensitivity.