Abstract 086: Insulin Receptor Signaling in the Subfornical Organ Protects Against the Development of Metabolic Syndrome

Abstract

Metabolic syndrome encompasses a combination of conditions including obesity, diabetes, dyslipidemia and hypertension. Brain insulin resistance has emerged as a contributor to the development of metabolic syndrome, although the neural regions involved remain unclear. While most studies have focused on hypothalamic areas, recent evidence suggests that the subfornical organ (SFO), a circumventricular organ well-known for cardiovascular control, is also involved in metabolic regulation. We therefore hypothesized that the SFO insulin receptor protects against the development of metabolic syndrome. Male mice (6.5 wks) harboring a conditional allele of the insulin receptor gene ( INSR) underwent SFO-targeted delivery of an adenovirus encoding a control vector (AdLacZ, n=7) or Cre-recombinase (AdCre, n=11) for selective removal of the SFO insulin receptor. Both groups remained on normal chow for 10 wks. Removal of the SFO insulin receptor did not influence food intake, but resulted in an ~40% greater increase in body weight (AdLacZ vs AdCre: Δ2.2±0.3 vs. 3.8±0.4 g; p<0.05). Consistent with the increased body weight, SFO insulin receptor deletion was associated with overall elevations in adiposity (e.g., abdominal fat, AdLacZ vs AdCre: 0.19±0.04 vs. 0.33±0.05 g; p<0.05). Analysis of the liver revealed substantial hepatic triglyceride accumulation in SFO-targeted AdCre mice (AdLacZ vs. AdCre: 62 ± 16 vs. 209 ± 29 mg/dl; p<0.05), with histological examinations (Oil Red O) revealing large lipid droplet accumulation following removal of the SFO insulin receptor. Parallel elevations in circulating triglycerides were also found (AdLacZ vs. AdCre: 1.4 ± 0.2 vs. 3.3 ± 0.6 mg/dl; p=0.05). These data demonstrate that ablation of SFO insulin receptors resulted in an overall deleterious metabolic state including increases in body weight, elevations in adiposity, hepatic steatosis and hypertriglyceridemia. These findings suggest that impairments in insulin signaling within the SFO contribute to the development of metabolic syndrome. Studies are ongoing to investigate the effect of SFO insulin receptor removal on blood pressure.