Effect of maternal nutrient restriction from early to midgestation on cardiac function and metabolism after adolescent-onset obesity

Abstract

Maternal nutrient restriction (NR) from early to midgestation has marked effects on endocrine sensitivity and organ function of the resulting offspring. We hypothesized that early NR may reset the expression profile of genes central to myocardial energy metabolism, influencing ectopic lipid deposition and cardiac function in the obese adult offspring. NR offspring were exposed to an "obesogenic" environment, and their cardiac function and molecular indexes of myocardial energy metabolism were assessed to explore the hypothesis that an obese individual's risk of heart disease may be modified after maternal NR. Pregnant sheep were fed 100% (control) or 50% (NR) energy requirement from days 30 to 80 of gestation and 100% energy requirement thereafter. At weaning, offspring were exposed to an obesogenic environment or remained lean. At approximately 1 yr of age, the hemodynamic response of these offspring to hypotension, together with left ventricular expression profiles of fatty acid-binding protein 3 (FABP3), peroxisome proliferator-activated receptor-gamma (PPARgamma) and its coactivator (PGC)-1alpha, acetyl-CoA carboxylase (ACC), AMP-activated protein kinase (AMPK)-alpha(2), and voltage-dependent anion channel 1 (VDAC1), was determined. 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-1alpha, AMPKalpha(2), VDAC1, and ACC and increased expression of PPARgamma and FABP3. However, although NR animals were similarly obese, their transcript expression of ACC, PPARgamma, and FABP3 was similar to that of lean animals, indicating altered cardiac energy metabolism. Indeed, blunted tachycardia and an amplified inotropic 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.

Fig. 1.

Left ventricular (LV) triglyceride and transcript expression for cardiac energy metabolism. A: triglyceride content in LV. B–D: mRNA abundance of fatty acid-binding protein 3 (FABP3), acetyl-CoA carboxylase (ACC), and peroxisome proliferator-activated receptor-γ (PPARγ). AU, arbitrary units. Values are means ± SE for lean (L, n = 8), obese (O, n = 6), and obese offspring born to nutrient-restricted mothers (NRO, n = 10) at 1 yr of age. ^#P < 0.05 and ^##P < 0.01, L vs. O. *P < 0.05 and **P < 0.01, O vs. NRO.

Fig. 2.

Positive correlation between AMP-activated protein kinase-α₂ (AMPKα₂) and triglyceride content in the heart of obese offspring born to mothers nutrient restricted between early and midgestation.

Fig. 3.

Effects of obesity and maternal nutrient restriction on total plasma catecholamine concentration (A) and cardiac gene expression of β₁- and β₂-adrenergic receptors (β₁- and β₂-AR, B and C). Values are means ± SE of lean (n = 8), obese (n = 6), and obese offspring born to mothers nutrient restricted between early and midgestation (n = 10) sampled at 1 yr of age. ^#P < 0.05, L vs. O. *P < 0.05, O vs. NRO.

Fig. 4.

Cardiovascular response to sodium nitroprusside (SNP) during saline infusion in lean (n = 8), obese (n = 6), and obese offspring born to mothers nutrient restricted between early and midgestation (n = 10) at 1 yr of age. +dP/dt and −dP/dt, 1st derivative of positive and negative change in blood pressure. Values are means ± SE. *P < 0.05, L vs. O.

Fig. 5.

Basal blood pressure response to SNP during atropine infusion in lean (n = 8), obese (n = 6), and obese offspring born to mothers nutrient restricted between early and midgestation (n = 10) at 1 yr of age. Values are means ± SE.

Fig. 6.

Basal blood pressure response to SNP during propranolol infusion in lean (n = 8), obese (n = 6), and obese offspring born to mothers nutrient restricted between early and midgestation (n = 10) at 1 yr of age. Values are means ± SE.