Autophagy and oxidative stress contribute to the functional remodeling of the anterior pituitary gland in diet-induced insulin resistance

MERCAU M; REPETTO EM; CALANNI JS; BOGNI E; VECINO C; CALDARERI L; FINKIELSTEIN CV; CYMERYNG CB

Bariloche

Simposio; The Third South American Symposium in Signal Transduction and Molecular Medicine - SISTAM 2015; 2015

SISTAM

The aim of this study was to evaluate the effects of a sucrose-rich diet (SRD, 30% w/v sucrose in the drinking water) on the activity of the hypothalamic-pituitary-adrenal axis (HPA). Male Wistar rats were provoked insulin resistance by SRD treatment and this conditionwas confirmed by an insulin tolerance test on the 7th week of treatment. Statistical analyses were performed using either Student?s t test or ANOVA and significant differences were studied with Tukey?s post hoc test.In order to analyzethe functionality of the pituitary glandanimals were randomized into control and SRD-groups (C-S and SRD-S, n=5).Results showed that serum metabolites including fasting serum glucose, triglycerides and total cholesterol levels, along with the weight of fat depots, were increased in SRD-S animals by the end of the 15th week of treatment. Animals from the SRD-S group showed significantly lower plasma levels of ACTH, decreased pituitary POMC mRNA levels, and lower serum corticosterone concentrations than those from the C-S group. Analysis of pituitary expression of antioxidant enzymes (e.g. HO-1 and catalase) and of markers ofendoplasmic reticulum stress (e.g. GRP78 and p58PKImRNAs) and autophagy (e.g. p62 and LC-3 II) suggested the activation of these cellular pathways in the SRD-S group. In a second set of experiments we analyzed the effect of a common insulin-sensitizing treatment, a moderate exercise protocol, on the above mentioned parameters. Animals were randomly assigned tocontrol and SRD-fed sedentary (C-S, SRD-S), and control and SRD-fed exercised(C-E, SRD-E) groups (n=5). Rats in the E groups were exercised once a day, 5 days a week throughout the 15 weeks of the dietary intervention. Interestingly, autophagy and antioxidant defense systems (e.g. HO-1 and catalase) do not appear to be activated in the pituitary gland of SRD-E animals. Analysis of POMC mRNA and ACTH protein levels and of serum corticosterone concentrations showed that application of a moderate exercise protocol prevented the effects of SRD on the basal activity of the HPA axis. In summary, administration of a SRDshows a significant effect on various cellular mechanisms that influence POMC transcription and ACTH production in pituitary corticotrophs. We propose a role for autophagy and oxidative stress in the sucrose-induced pituitary dysfunction.