Submitted on December 16, 2008
Revised on February 24, 2009
Accepted on February 24, 2009
Effect of maternal nutrient restriction from early-to-mid gestation on cardiac function and metabolism after adolescent-onset obesity
Laureen L.Y. Chan, Sylvain P. Sebert, Melanie A. Hyatt, Terence Stephenson, Helen Budge1, Michael E. Symonds2, and David S. Gardner3*
1 Academic Division of Child Health, University of Nottingham
2 School of Clinical Sciences, Division of Human Development
3 University of Nottingham
* To whom correspondence should be addressed. E-mail: david.gardner{at}nottingham.ac.uk.
Maternal nutrient restriction (NR) from early-mid gestation has marked effects on endocrine sensitivity and organ function of the resulting offspring. We hypothesized that early NR may re-set the expression profile of genes central to myocardial energy metabolism, influencing ectopic lipid deposition and cardiac function in the subsequent adult offspring when obese. NR offspring were exposed to an 'obesogenic' environment and their cardiac function and molecular indices of myocardial energy metabolism assessed to explore the hypothesis that an obese individual's risk of heart disease may be modified after maternal NR. Pregnant sheep were fed either 100% (control) or 50% (NR) energy requirement from 30-80 days gestation and 100% thereafter. At weaning, offspring were either exposed to an obesogenic environment or remained lean. At ~one year of age their haemodynamic response to hypotension was determined, together with left ventricular expression profiles of fatty acid binding protein 3 (FABP3), peroxisome proliferator-activated receptor 
(PPAR) and its co-activator (PGC)1
, acetyl CoA carboxylase (ACC), AMP-activated protein kinase (AMPK)2 and voltage-dependent anion channel 1 (VDAC1). Obesity produced left ventricular hypertrophy in all animals, with increased ectopic (myocardial) lipid in NR offspring. Obesity per se significantly reduced myocardial transcript expression of PGC-1, AMPK2, VDAC1 and ACC and increased expression of PPAR and FABP3. However, despite NR animals being similarly obese their transcript expression of ACC, PPAR and FABP3 was similar to lean animals, indicating altered cardiac energy metabolism. Indeed, blunted tachycardia and an amplified inotrophic response to hypotension characterized cardiac function in obese NR offspring. The results suggest that maternal NR during early organogenesis can precipitate an altered myocardial response to hypotension and increased myocardial lipid deposition in the adult offspring after adolescent-onset obesity, potentially rendering these individuals more at risk of early heart failure as they age.
