title: Bio-informatics analysis of a gene co-expression module in adipose tissue containing the diet-responsive gene Nnat.
abstract: BACKGROUND
  Obesity causes insulin resistance in target tissues - skeletal muscle, adipose tissue, liver and the brain. Insulin resistance predisposes to type-2 diabetes (T2D) and cardiovascular disease (CVD). Adipose tissue inflammation is an essential characteristic of obesity and insulin resistance. Neuronatin (Nnat) expression has been found to be altered in a number of conditions related to inflammatory or metabolic disturbance, but its physiological roles and regulatory mechanisms in adipose tissue, brain, pancreatic islets and other tissues are not understood.
  
  
  RESULTS
  We identified transcription factor binding sites (TFBS) conserved in the Nnat promoter, and transcription factors (TF) abundantly expressed in adipose tissue. These include transcription factors concerned with the control of: adipogenesis (Pparγ, Klf15, Irf1, Creb1, Egr2, Gata3); lipogenesis (Mlxipl, Srebp1c); inflammation (Jun, Stat3); insulin signalling and diabetes susceptibility (Foxo1, Tcf7l2). We also identified NeuroD1 the only documented TF that controls Nnat expression. We identified KEGG pathways significantly associated with Nnat expression, including positive correlations with inflammation and negative correlations with metabolic pathways (most prominently oxidative phosphorylation, glycolysis and gluconeogenesis, pyruvate metabolism) and protein turnover. 27 genes, including; Gstt1 and Sod3, concerned with oxidative stress; Sncg and Cxcl9 concerned with inflammation; Ebf1, Lgals12 and Fzd4 involved in adipogenesis; whose expression co-varies with Nnat were identified, and conserved transcription factor binding sites identified on their promoters. Functional networks relating to each of these genes were identified.
  
  
  CONCLUSIONS
  Our analysis shows that Nnat is an acute diet-responsive gene in white adipose tissue and hypothalamus; it may play an important role in metabolism, adipogenesis, and resolution of oxidative stress and inflammation in response to dietary excess.
authors.affiliation: National Heart and Lung Institute, Medicine Department, Imperial College London, South Kensington, Exhibition Road, London SW7 2AZ, UK. xinzhong.li@imperial.ac.uk
authors.forename: Xinzhong
authors.initials: X
authors.lastname: Li
authors.forename: Peter A
authors.initials: PA
authors.lastname: Thomason
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Withers
authors.forename: James
authors.initials: J
authors.lastname: Scott
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D019295:Computational Biology / Q000379:methods*; D004032:Diet; D004285:Dogs; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D023281:Genomics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D025941:Protein Interaction Mapping; D014158:Transcription, Genetic
chemical_list: D008565:Membrane Proteins; C490237:NNAT protein, human; D009419:Nerve Tissue Proteins