Fat, High Sugar And Its Molecular Mechanisms Of Hpa Axis Function

Objective Hippocampus controls HPA axis negative feedback. The current study aimed to test the hypothesis whether the activation of the HPA axis response to high FFA was due to the lesions of hippocampus, which was associated with the altered expression of GR, MR, 11β-HSD1 or iNOS in hippocampus.Methods After baseline (0 minute) sample was obtained, 20% Intralipid (FFA group, n=10) or 0.9% saline (as control, NS group, n=10) was infused IV (2ml/h) into Sprague-Dawley rats for 180 minutes. Rats were killed by decapitation after injection, and trunk blood were stored for future measures. For in situ hybridization and immunohistochemistry, whole brains from animals were dissected and immediately frozen.Results (1)Infusion of Intralipid into rats elevated plasma FFA up to 5.1-fold above basal values (preinfusion) at 180 min. There was no influence on FFA levels after saline infusion(.2)There was no significantly difference in basal ACTH and corticosterone levels between FFA and NS groups. The net change in ACTH (ΔACTH: FFA,15.6±10.2 pg/ml; NS, 2.6±3.9 pg/ml, respectively)during infusion was higher in FFA group than that in NS group. In comparison with basal corticosterone levels, plasma corticosterone levels at 180 min were lower in the two groups. However, the magnitude of decrease in corticosterone levels was significantly less in FFA group compared with NS group (Δcorticosterone: FFA, 104.6±193.1 ng/ml; NS, 187.2±167.3 ng/ml, respectively). The current study showed that administering Intralipid mildly activated the axis compared with NS group.(3)In FFA group, 11β-HSD1 mRNA and protein levels were significantly decreased in the pyramidal cells in hippocampal CA4 subregion compared with NS group. However, Intralipid infusion significantly increased iNOS mRNA and protein levels in the pyramidal cells in the CA4 field of hippocampus.(4)Neither GR mRNA nor protein levels in the hippocampal formation differed between FFA and NS group. Moreover, there was no significant effect on MR mRNA and protein levels in the hippocampal formation after Intralipid infusion.Conclusion Our findings support the hypothesis that FFA would impair hippocampus and then stimulate the HPA axis. The mechanism of the action of FFA might be attributable to down-regulation of 11β-HSD1 and up-regulation of iNOS expression in hippocampus. Objective To measure the basal levels of cortisol in patients with Polycystic Ovarian Syndrome (PCOS), analyze its associations with correlative factors, investigate the effects of short-term hyperglycemia or hyperinsulinemia per se on their plasma cortisol concentrations, and evaluate isletβ-cell function in women with PCOS.Methods 84 PCOS patients divided into two groups (obese group, n=34; non-obese group, n=50) and 21 age-matched healthy women were recruited. All subjects received oral glucose tolerance test (OGTT). After an overnight fasting, an acute 60-minute glucose stimulation was performed by intravenous glucose tolerance test followed by a 120-minute euglycemic hyperinsulinemic clamp. Basal glucose, insulin, and cortisol during IVGTT and euglycemic clamp at 0, 60 and 180 minute (cortisol0, cortisol60 and cortisol180) were measured. The net change in cortisol during IVGTT and euglycemic clamp was calculated asΔcortisolx= cortisol0-cortisolx (x meaned time). Insulin sensitivity (IS) calculated as the glucose infusion rate during the euglycemic clamp phase (M value, mg﹒kg-1﹒min-1). Isletβ-cell function was reflected through acute insulin response (AIR) of IVGTT. Glucose disposition index (DI) = IS×AIR.Results 1)Basal cortisol levels were similar between the non-obese PCOS group and control groups, and significantly higher than that in the obese PCOS group. 2)The cortisol-60 levels after short-term hyperglycemic challenges were lower in the obese PCOS group than that in the control group, Whereas the net change in cortisol during IVGTT did not significantly differ among the groups. 3)Although the cortisol-180 levels after euglycemic clamp were similar among the groups, the magnitude of the net change in cortisol was significantly less in the obese PCOS group than that in the other groups. 4)In the group of 84 PCOS subjects, simple Pearson correlations showed a negative relationship between basal cortisol with either M value, BMI, or fasting glucose (r=-0.241, -0.230, -0.253 , respectively; all p value <0.05). A shady correlation was found between basal cortisol and fasting insulin (r=0.200; p=0.071). However, with basal cortisol as the independent variable, M value, BMI, fasting glucose and fasting insulin as dependent variables, multiple regression analysis showed that the significance of fasting glucose on basal cortisol was removed when fasting insulin was added as a covariate. 5)AIR was similar in three groups, but there was a trend of increase in women with PCOS patients, especially for the obese(P=0.08). DI was lower in non-obese and obese PCOS patients than that in healthy women, and no significant difference was found between the non-obese and obese PCOS group.Conclusion Our data suggest that basal level of cortisol correlates not only with body weight, but also with insulin sensitivity and fasting insulin level in patients with PCOS. In present study we did not observe changes in cortisol concentrations after short-term hyperglycemic challenges. Although basal cortisol levels decreased in the obese or overweight patients with PCOS, the cortisol180 levels after short-term hyperinsulinemic challenges were similar among the groups. It suggested that a rise in plasma insulin might moderately activate the HPA axis of obese PCOS patients. Acute insulin response to glucose in women with PCOS doesn't decrease, but compensatory ability of isletβ-cell for insulin resistance is deficient.