Abstract 10695: Early Overnutrition in Rats Induces Premature Cardiac Alterations Independently of Blood Pressure: Leptin-TRH Pathway Involvement

Abstract

Animal models are an interesting tool to evaluate future consequences of early nutritional insults. We described in adult mice that: leptin induces cardiac cTRH, leading to cardiac damage regardless of blood pressure in hyperleptinemic Agouti. Conversely, cTRH in the ob/ob lacking leptin is similar to control and even do not have Left Ventricular Hypertrophy (LVH). Moreover, leptin restitution induces cTRH and later LVH. Also, in C57BL/6 a 3-week subanorexigenic leptin dose induced cTRH and sequent LVH. All this suggests that heart damage in obesity depends on the novel leptin-cTRH pathway. Plus, Leptin directly induces TRH in cell culture (Aisicovich 2019, AHA) To further investigate the impact of early dietary interventions in childhood, we studied rat litter size reduction, a model with a reported increase in body weight, fat, leptin, insulin and cholesterol levels (Stefanidis A, 2012) We hypothesize that leptin rise increases cTRH leading to cardiac damage, independently of hypertension. On postnatal day 4, Wistar rat litters of 11 pups at birth were adjusted to 4 male pups (overnourished ON) or 11 (control C). At weaning, we individualized rats with free access to water and standard diet up to 7 weeks old. The rise in body weight, food consumption, and fat in ON vs C (p<0.02 n=10 ANOVA) confirmed the model. There weren’t any blood pressure differences between groups, still LVH index increased (heart weight/tibia length) (p< 0.01 n=6) in ON vs C. As expected, in ON the higher leptin increased cTRH mRNA (p< 0.01 n=6) as protein [WB (p=0.05 n=3) IHQ (p<0.04 n=6)] vs C. According to cTRH actions, hypertrophic and fibrotic markers TGF-B and Collagens 1 and 3 mRNA increased (p<0.01, n=6) confirmed by IHQ and Sirius red staining (p< 0.01 n=6) Also, echocardiogram showed increases in LV end-diastolic (0.26±0.08 vs 0.61±0.07 ml p <0.01) and end-systolic (0.02±0.02 vs 0.11±0.01 ml p <0.01) volumes, and decreases in LV ejection fraction (94.5±2.2 vs 83.3±1.9 % p <0.01) and SF (54.4±2.6 vs 45.0±2.3 % p <0.02) This could be restored by cTRH inhibition as demonstrated in the cardiac infarct model (Schuman ML, 2021) Our results point out that early overnutrition induces evident cardiac damage already at 7 weeks, independently of blood pressure and mostly driven by the leptin-TRH pathway.