Endocrine Abstracts

Endothelial dysfunction is a key step in the initiation of atherosclerosis, resulting from a decrease in bioavailability of nitric oxide (NO). IGF-1 may play a part in regulation of NO production via the PI3-kinase/Akt/eNOS pathway. We have investigated whether disturbances of this pathway occur in dietary-induced obesity.

Obesity was induced in mice fed a high fat diet for 20 weeks (n=12), compared to chow fed controls, with an age-related increase in systolic blood pressure in fat fed (19.2% from baseline) versus chow fed mice (7.6% from baseline). In glucose tolerance testing, blood glucose levels increased from 13.5 to 20 mmol/l at 120 min in fat fed mice, versus 5.7 to 7.3 mmol/l in the chow fed mice (P=0.009). In response to insulin, blood glucose fell by 72% in the chow fed group versus 48% in the fat fed group (P=0.0002). The fat fed mice were less sensitive to IGF-1 stimulation than the chow fed mice by IGF-1 tolerance testing (P=0.046 at 30 min). The basal aortic protein level of phosphorylated eNOS in fat fed mice was 40% of that in the chow fed mice and this increased by approximately 7% compared to 85% in the chow fed mice after IGF-1 stimulation. eNOS activity in aortae, measured by an ex-vivo L-citrulline assay, showed an increase of 1.6-fold in response to IGF-1 (100 nM; 10 minutes) as compared to the fat fed mice (n=5; P<0.01). Pre-incubation of aortae with the NOS inhibitor, L-NAME (1 mmol/L; 30 minutes) prior to stimulation with IGF-1 completely inhibited eNOS enzyme activity (n=5; P<0.05). Ex-vivo constriction curves from aortic rings showed phenylephrine induced constriction was blunted by IGF-1 causing vasorelaxation in chow fed mice. This relaxation effect was blocked in fat fed mice.

These data suggest that dietary-induced obesity results in resistance to IGF-1 via an endothelial/PI3-K/NO dependent mechanism.