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

AISICOVICH, M.; ROSATI, M; SCHUMAN, ML; GIARDINA, G; LANDA, MS; GARCIA, SI

Congreso; AHA Scientific Sessions 2021; 2021

AHA

Animalmodels are an interesting tool to evaluate future consequences of earlynutritional insults. We described in adult mice that: leptin induces cardiaccTRH, leading to cardiac damage regardless of blood pressure in hyperleptinemicAgouti. Conversely, cTRH in the ob/ob lacking leptin is similar to control andeven do not have Left Ventricular Hypertrophy (LVH). Moreover, leptinrestitution 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 furtherinvestigate the impact of early dietary interventions in childhood, we studiedrat litter size reduction, a model with a reported increase in body weight,fat, leptin, insulin and cholesterol levels (Stefanidis A, 2012) We hypothesizethat leptin rise increases cTRH leading to cardiac damage, independently ofhypertension. On postnatal day 4, Wistar rat litters of 11 pups at birth wereadjusted to 4 male pups (overnourished ON) or 11 (control C). At weaning, weindividualized rats with free access to water and standard diet up to 7 weeksold. The rise in body weight, food consumption, and fat in ON vs C (p<0.02n=10 ANOVA) confirmed the model. There weren?t any blood pressure differencesbetween 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 andCollagens 1 and 3 mRNA increased (p<0.01, n=6) confirmed by IHQ and Siriusred 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 LVejection fraction (94.5±2.2 vs 83.3±1.9 % p<0.01) and SF (54.4±2.6 vs45.0±2.3 % p<0.02) This could be restored by cTRH inhibition asdemonstrated in the cardiac infarct model (Schuman ML, 2021) Our resultspoint out that early overnutrition induces evident cardiac damage already at 7weeks, independently of blood pressure and mostly driven by the leptin-TRHpathway.