Abstract 091: Leptin-Thyroliberin Pathway in Left Ventricle Hypertrophy

Abstract

Cardiac TRH (cTRH) induces LVH and fibrosis. The adiponectin Leptin induces TRH in CNS. We hypothesized that in obesity, the increase of cTRH induced by hyperleptinemia is responsible for the LVH, mostly attributed to pressure load. We studied obese hyperleptinemic with mild hypertension Agouti mice, and found LVH with higher (p<0.05) cTRH, fibrotic (I/III col,TGFβ) and hypertrophic (BNP,βMHC) marker genes vs lean (BL/6J). We normalized pressure in Agouti mice with hydroclorothiazide (20 mg/kg/day) since weaning (n=9) vs non treated mice. Still both developed (p<0.05) LVH, higher cTRH, fibrotic and hypertrophic marker genes expression, suggesting that LVH would not be due to hypertension. Opposite to Agouti model, we used obese normotensive ob/ob mice, lacking Leptin expression, and without LVH despite their obesity. We treated them with Leptin (80 ug/kg/day) or saline since weaning for 15 days. Only the treated group developed LVH (p< 0.05, n=7) demonstrating that it is Leptin dependant. Also we found increase (p<0.05) in cTRH, col III, TGFβ and BNP suggesting that leptin-TRH interaction is required in obesity-induced LVH. Finally, we evaluated whether Leptin administration, (n=6, 10 ug/kg/day) could induce hypertrophy in lean C57 mice with and withouth native cTRH system, by previous siRNA injection (5ug). Diuretic was given to Leptin groups, to avoid its hypertensive effect. Leptin induced cTRH expression, not observed in the groups with siRNA-TRH (p<0.05).This probably induce fibrotic and hypertrophic markers, demonstrating that the novel interaction is functional also in mildy hyperleptinemia at normal weight status. To confirm TRH's Leptin induction we used cardiomyocytes cell line H9C2 (n=6) stimulated with Leptin (10 and 100 ng/ml). TRH expression and precursor content increased (p<0.05) post Leptin treatment with both concentrations. Moreover in primary cardiomyocytes culture from neonate rats, Leptin stimulus (80 ng/ml, 24 hs) increased (p<0.05) TRH content vs controls, confirming the direct TRH-Leptin induction in heart cells. We described a novel Leptin-cTRH pathway which explains Leptin-induced LVH, highly likely since early stages.