Several studies have established a link between excessive consumption of simple carbohydrates and the increased incidence of insulin resistance (IR) and obesity registered worldwide. Many of these patients also show a concomitant dysfunction of the hypothalamus pituitary adrenal (HPA) axis. We have previously reported that feeding rats a sucrose rich diet (SRD, 30% sucrose in the drinking water) was associated with the hyperactivation of the HPA axis, as early as 3 weeks after the initiation of the diet and IR after 7 weeks of treatment. Present experiments were designed to evaluate possible mechanisms involved in the HPA axis dysfunction after 3 weeks of SRD treatment. Our results showed that augmented levels of circulating ACTH and an increased expression of POMC were accompanied by changes in oxidative stress (OxS) and inflammatory parameters in pituitary tissues. Since a chronic low-grade inflammatory state has been associated with the development of IR, and several inflammatory cytokines have been shown to activate the HPA axis, we hypothesized the involvement of pituitary OxS and inflammation in the stimulation of ACTH production from corticotroph cells. To test this hypothesis we analyzed the effect of melatonin, a molecule with potent anti-oxidant and antiinflammatory properties, on POMC/ACTH production both in vivo and in vitro. Invivo experiments: Wistar rats were fed standard chow and water or a SRD. Melatonin pellets were surgically implanted in a group of animals. After 3 weeks of treatment pituitary glands were processed to obtain total proteins and RNA. Plasma ACTH levels were assessed by a chemiluminiscent assay and serum corticosterone concentration was determined by RIA. Expression of specific proteins and mRNAs were evaluated by western blot and RT-qPCR. Results showed that melatonin treatment prevented the increases in pituitary POMC expression levels and in circulating levels of ACTH and corticosterone observed in the SRD group. A closer examination into pituitary tissues showed an increase in the mRNA levels of TNFα, IL-1 beta and inflammasome components (NLRP3, ASC, Caspase-1), and also in the expression levels of Iba-1 and F4-80 as determined by immunofluorescence and immunoblot assays. These changes were prevented by melatonin treatment. In vitro experiments: AtT20 (murine corticotrophs) and J774 (murine macrophages) cells were used. Incubation of AtT20 cells with conditioned media obtained from control (CMC) or activated J774 cells (LPS 100ng/ml and glucose 7.5mM, CMLG) showed an increase in the reporter activity of POMC-LUC by CMLG that was not observed when conditioned media was obtained in the presence of 50nM melatonin. In summary, our results suggest that the early increase in the synthesis and secretion of ACTH, detected in SRD-treated rats, could involve inflammation-related pathways activated in addition to or as a consequence of the generation of OxS, as all these effects were prevented by melatonin treatment.