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 (Pparg, 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.