Abstract 12756: Peripheral Organ nd Systemic Metabolism Respond Early to Cardiac Overload in the Absence of Underlying Metabolic Syndrome and Present in Multiaphasic Fashion During the Transition Toward Cardiac Decompensation

Abstract

Reduced long chain fatty acid (LCFA) oxidation in pressure overloaded, hypertrophied hearts coincides with an isoform shift of carnitine palmitoyl transferase I from muscle (mCPT1) to liver (LCPT1). Normal rodent hearts expressing exogenous gene for LCPT1 were recently found to recapitulate the reduced LCFA oxidation of hypertrophied hearts, with surprising elevations of atrial natriuretic peptide (ANP) message consistent with hypertrophic signaling and potentially, peripheral fat mobilization. We therefore studied peripheral and systemic metabolism in male C57BL/6 mice subjected to transverse aortic constriction (TAC). At 2 wks, echocardiography showed LV hypertrophy in TAC and increased heart mass to tibia length (52%) at 6 wks compared to hearts of sham-operated mice (SHAM). Functional decline occurred by 16 wks TAC, with reduced ejection fraction (45.6%) and fractional shortening (22.6%) vs SHAM, weeks after changes in peripheral and systemic metabolism. Surprisingly, glucose tolerance (GT) and insulin sensitivity (IS) initially improved with TAC (2 wks) vs SHAM, linked to enhanced insulin signaling in liver and visceral adipose tissue (VAT), a 48% increase in plasma adiponectin, upregulation of oxidative/thermogenic gene expression in subcutaneous adipose (SAT), and downregulated gene expression for lipolysis and lipogenesis in VAT. However, by 6 wks TAC both IS and GT were impaired with reduced insulin signaling in liver and VAT, downregulation of PGC1a and oxidative enzymes in brown adipose tissue and complete reversal of oxidative and lipogenic gene expression in SAT. Metabolic mediators post-TAC included: 1) elevated plasma ANP (TAC=140±16 pg/ml; SHAM=74±7),and brain NP (TAC=850±36 vs SHAM=771±12); 2) elevated blood adiponectin at 2 wks TAC but a reduction at 6 wks persisting to wk 17 that is consistent with IS and GT shifts. These findings demonstrate multiphasic changes in extra-cardiac metabolic responses to pathogenic stress on the heart with changes in insulin signaling, circulating natriuretic peptides and adipokines, and varied gene expression in adipose tissue that are associated with altered insulin response/glucose handling and thermogenesis in mice prior to any functional decline due to cardiac decompensation.