Mechanisms involved in cardiovascular and hydroelectrolytic balance changes induced by angiotensin II and central osmoreceptors in rats fed a high-fat diet

Abstract

Obesity is a noncommunicable disease that can lead to hypertension and changes in hydroelectrolytic balance. Dehydration is a common phenomenon that affects both humans and animals. Thus, one of the objectives of the thesis was to investigate the mechanisms involved in cardiovascular and hydroelectrolytic balance changes induced by water deprivation in animals fed a high-fat diet (HFD). Furthermore, the hypothalamic circuits that regulate food intake during obesity are not completely understood. Thus, the second objective was to carry out the anatomical mapping of hypothalamic circuits 'sensitive to angiotensin', since this peptide has been implicated in the regulation of food intake, as well as its implications in the neural control of energy balance in animals fed with HFD. To achieve the first objective, Holtzman rats (initial weight 290-310 g) were fed a standard diet (SD, 10% kcal from fat) or HFD (46% kcal from fat) for 6 weeks and dehydration was induced by water deprivation (WD) for 24 h. We observed the following results: a) In HFD rats, the animals drank less water and the urinary volume and sodium excretion were lower compared to the SD group; b) Baseline mean arterial pressure (MAP) was higher in the HFD group, but the increase in MAP after WD was similar for the both groups; c) The increase in MAP in HFD rats submitted to WD seems to have a greater angiotensinergic component compared to SD rats; d) There were no differences in FOS labeling in vasopressin-immunopositive neurons in the supraoptic nucleus; e) Renal denervation induced an increase in basal urinary volume in SD rats, which was reduced after WD, but still greater than HFD rats. In HFD animals, urinary volume did not change after renal denervation at baseline or during WD. In order to verify the hypothalamic circuits “sensitive to angiotensin II (ANG II)”, we used genetically modified mice, AT1a-Cre (8 weeks old) and we observed the following results: a) in AT1a-Cre mice that received bilaterally adeno-associated viral vectors in the paraventricular nucleus (PVN), we observed that the AT1aR containing neurons in the PVN (PVNAT1aR) are neurosecretory that synthesize corticotropin-releasing hormone (CRH) or thyrotropin-releasing hormone (TRH), moreover these neurons send projections to arcuate nucleus (ARC); b) In AT1aR-Cre mice, acute optogenetic activation of PVNAT1aR neurons can promote robust activation of pro-opiomelanocortin (POMC) neurons in the ARC and lead to a slight decrease in food intake without altering energy expenditure. In conclusion, the results demonstrated changes in cardiovascular, water intake and renal excretion in HFD animals 24 hours- water deprived. Cardiovascular changes seem to be associated with a greater renin angiotensin system (RAS) activation in HFD rats during WD. Vasopressin or renal nerves appear not to be involved with the greater decrease in urinary volume in water-deprived HFD-fed rats. Data from the literature suggest that the lower water intake in HFD water-deprived rats is due to the formation of metabolic water in this condition. Furthermore, preliminary data characterized the hypothalamic neurocircuit from the PVN to the ARC showing that PVNAT1aR neurons are neurosecretory and through their projections they can activate POMC anorexinergic neurons. Furthermore, functional data demonstrated a slight decrease in food intake with the optogenetic activation of these neurons, thus corroborating, in parts, with the anatomical data.