Postnatal overfeeding in rats causes childhood and adulthood obesity associated with vascular dysfunction in a mechanistic and sex-dependent manner

In recent years incidence of childhood obesity has increased globally, regardless of economic status. This phenomenon is a known risk factor for cardiovascular diseases. Here we hypothesized that postnatal overfeeding, a recognized model of childhood obesity, will induce vascular dysfunction in prepubertal and adult rats in a sex-dependent manner. For this, we used the animal model of postnatal overfeeding by litter size reduction. At postnatal day (PND) 1, Wistar rat were divided into a normal litter (NL, mothers were kept with 5 female and 5 male pups) or small litter (SL, mothers were kept with 2 male and 1 female pup). The ratss were evaluated at two time points prepubertal (PND 30 for females and 40 for males due to known sexual maturation differences), and in adulthood (120 for both sex). Body weight (g) and retroperitoneal adipose tissue (fat pad weight/100g of the body n=9-13) were evaluated. Aorta was removed for wall thickness measurements via histology (n=5, μm), and vascular function was performed via pin myograph. Concentration-response curves to phenylephrine [Phenyl, 1nM-10μM, n=6, gram force (gf)] or acetylcholine (ACh 0.1nM100μM, n=7 % relaxation) were performed. To understand the role of the NADPH-derived reactive oxygen species, angiotensin-II and aldosterone, apocynin (APO 10 μM), losartan (LOS 1 μM) or spironolactone (SPR 1 μM) were used respectively. Prepubertal SL rats had higher body weight (female: NL 76±2 vs SL 91±1, g, p<0.05; male: NL 148±2 vs. SL 185±4, g, p<0.05), and adipose tissue deposition (female: NL 0.09±0.01 vs. SL 0.17±0.01, p<0.05; male: NL 0.17±0.09 vs. SL 0.32±0.03, p<0.05] regardless of sex. Interestingly, there were no differences in these parameters at PND 120 for female NL and SL. In contrast, male SL at PND 120 had higher body weight (NL 419±9 vs SL 462±5, g, p<0.05) and retroperitoneal adipose tissue (NL 1.2±0.9 vs SL 1.6±0.1, p<0.05]). No differences were observed in phenyl-induced contraction in aortas from females at PND 30 and 120. On the other hand, endothelial dysfunction was observed at PND 120 in arteries from SL females rats [Maximum response (Rmax): NL 94±1 vs SL 84±2, % p<0.05]. LOS (Rmax: SL 77±1 vs LOS 90±1, % p<0.05) and APO (SL 77±1 vs APO 87±1, % p<0.05] restored endothelial function in these animals. No changes in endothelium-dependent relaxation were observed in arteries from male rats at PND 40 or 120. However, there was an increase in vascular contractility from SL males at PND 40 (Rmax: NL 1.17±0.40 vs SL 1.47±0.06, g, p<0.05), and SPR (SL 1.50 ±0.14 vs SPR 0.93±0.09, g, p<0.05) improved this response, but no differences were observed at PND 120. Further, the aortic thickness was similar between groups at PND 120 regardless of sex. In conclusion, postnatal overfeeding in rats causes childhood obesity associated with vascular dysfunction. These differences were observed in prepubescent and adult rats, and the respective mechanisms are sex-dependent. Coordination for the Improvement of Higher Education Personnel - Brazil (CAPES) (Finance code 001). Araucária Foundation for the Support of Scientific and Technological Development of the State of Paraná - Brazil (grant: 215/2022-PBA). National Institutes of Health - R00GM118885, R01HL149762, R00HL151889, and RO1DK132948. Fulbright Program - DDRA foundation. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.