Novel leptin-cardiacTRH pathway responsible of the cardiac alterations in the hyperleptinemic obesity

PERES DIAZ, LUDMILA SOLEDAD; AISICOVICH, MAIA; SCHUMAN, MARIANO LUIS; ROSATI MACARENA; TOBLLI, JORGE EDUARDO; ANA UCEDA; GRACIELA GIARDINA; LANDA, MARIA SILVINA; GARCÍA, SILVIA INÉS

MOLECULAR AND CELLULAR BIOCHEMISTRY

SPRINGER

Lugar: Berlin; Año: 2024

0300-8177

Association between hypertensionand obesity-induced cardiac damage is usuallyaccepted. However,  no studies have been  focused on cardiac alterations in obesity,independently of blood pressure increase.It´s well known that cardiac TRH induces leftventricular hypertrophy (LVH)  andfibrosis, and its inhibition prevents the developmentof  hypertrophy. Also, it has beendescribed that the adiponectin leptin induces TRH expression. Thus, wehypothesized that in obesity, the increase in  TRH induced by hyperleptinemia is responsible for the LVH,until now mostly attributed to pressure load.We studied obese Agouti mice suffering hypertension with hyperleptinemia andfound a significant LVH development with increased in the TRH gene expression. Consequently, we found higherfibrotic (collagens and TGFβ) and hypertrophic markers (BNP and βMHC)expression vs lean black controls. As pressurecould explain these results, we treated obese mice with diuretic(hydrochlorothiazide 20 mg/kg/day) sinceweaning. Diuretic treatment was successful as the diuretic group wasnormotensive in contrast to control obese mice. Nevertheless, both groupsshowed LVH development, higher cardiac precursor TRH gene and peptideexpressions and elevated fibrotic and hypertrophic markers expression, pointing out that obesity-induced LVH is not due tohypertension.In addition, we performed cardiac TRH inhibition by specific siRNA injectioncompared to control siRNA treatment and evaluated cardiac damage. As expected,expression and protein increases in hypertrophicand fibrotic markers observed in the AG mouse with the native cTRH system werenot seen in the AG mouse with the cTRH silencing. Indeed, the AG + TRH-siRNAgroup showed hypertrophic markers expression and fibrosis measurements similarto the lean BL mice.In a whole, these results point out that the novel Leptin-cardiac TRH pathwayis responsible for the cardiac alterations present in hyperleptinemic obesity,independent of blood pressure and cTRH long-term silencing since early stagestotally prevent the development of LVH and cardiac fibrosis.