Abstract MP237: Multi-omics Profiling Reveals Stearoylcarnitine As A Novel Biomarker Of Cardiometabolic Disease Development In Rat Offspring Exposed To Gestational Diabetes

Abstract

Through unknown mechanisms, fetal exposure to gestational diabetes mellitus (GDM) increases the risk for cardiovascular disease development later in life. We hypothesize that fetal exposure to GDM alters offspring cardiomyocyte metabolism and left ventricular (LV) function with age. To induce GDM, female rats were fed a high fat (45% kcal) and sucrose diet prior to mating, throughout pregnancy and lactation. Lean controls received a low fat (10% kcal) diet. Fetal rat ventricular cardiomyocytes (FRVC) were isolated from e20 offspring for U-13C glucose metabolic flux analysis, mitochondrial respiration and calcium handling. The cardiac transcriptome and metabolome were measured in 3-month old offspring. LV morphology and function was assessed in the offspring from e18 to 12-months of age by transthoracic ultrasound. Offspring exposed to GDM exhibited increased LV posterior wall thickness and impaired LV filling across their life course (fetal to 12-months of age; p<0.05). Consistent with the development of diastolic dysfunction in vivo, alterations in calcium flux and sarcoplasmic reticulum-dependent calcium re-uptake (1.5 and 1.6-fold greater, respectively) were observed in FRVC isolated from GDM offspring (p<0.05). When FRVC were treated with isoproterenol, U-13C glucose metabolic flux through glycolysis and the citric acid cycle was reduced in GDM offspring, compared to Lean controls. In 3-month old GDM offspring serum and cardiac metabolomics revealed an altered acylcarnitine profile, with specific elevation in long chain acylcarnitine species including stearoylcarnitine. Alterations in the metabolome corresponded to changes in gene expression patterns identified by RNA-Seq associated with glucose metabolism and fatty acid transport pathways (e.g. Irs2, Slc2a4, Pfkfb2, Pdk4 and Cpt1a). These alterations corresponded with mitochondrial dysfunction, impaired cardiomyocyte metabolic flux and contractility, in concert with LV hypertrophy and diastolic dysfunction in the rat offspring. Multi-omics profiling reveals stearoylcarnitine as a novel biomarker and implicates mitochondrial oxidative metabolism as a mechanism that links early-life GDM exposure to the development of cardiovascular disease later in life.