Early overnutrition in rats induces premature cardiac alterations independently of blood pressure: leptin-TRH pathway involvement.

MAIA AISICOVICH; ROSATI MACARENA; MARIANO L SCHUMAN; GRACIELA GIARDINA; MARIA S LANDA; SILVIA I GARCÍA

Boston

Congreso; AHA Scientific Sessions 2021; 2021

American Heart Association

Animal models are an interesting tool toevaluate future consequences of early nutritional insults. We described inadult mice that: leptin induces cardiac cTRH, leading to cardiac damageregardless of blood pressure in hyperleptinemic Agouti. Conversely, cTRH in theob/ob lacking leptin is similar to control and even do not have Left VentricularHypertrophy (LVH). Moreover, leptin restitution induces cTRH and later LVH.Also, in C57BL/6 a 3-weeksubanorexigenic leptin dose induced cTRH and sequent LVH. All this suggeststhat 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 dietaryinterventions in childhood, we studied rat litter size reduction, a model witha reported increase in body weight, fat, leptin, insulin and cholesterol levels(Stefanidis A, 2012) We hypothesize that leptin rise increases cTRH leading to cardiacdamage, independently of hypertension. On postnatal day 4, Wistar rat litters of 11pups 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 upto 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. Thereweren?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 increasedcTRH mRNA (p< 0.01 n=6) as protein [WB (p=0.05n=3) IHQ (p<0.04 n=6)] vs C. According to cTRH actions, hypertrophic and fibroticmarkers TGF-B and Collagens 1 and 3 mRNA increased (p<0.01, n=6) confirmedby IHQ and Sirius red staining (p< 0.01 n=6)Also, echocardiogram showed increases in LVend-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 cardiacinfarct model (Schuman ML, 2021)Our results point out that early overnutrition induces evident cardiacdamage already at 7 weeks, independently of blood pressure and mostly driven bythe leptin-TRH pathway.