Myocardial macronutrient transporter adaptations in the adult pregestational female intrauterine and postnatal growth-restricted offspring

Abstract

Associations between exponential childhood growth superimposed on low birth weight and adult onset cardiovascular disease with glucose intolerance/type 2 diabetes mellitus exist in epidemiological investigations. To determine the metabolic adaptations that guard against myocardial failure on subsequent exposure to hypoxia, we compared with controls (CON), the effect of intrauterine (IUGR), postnatal (PNGR), and intrauterine and postnatal (IPGR) calorie and growth restriction (n = 6/group) on myocardial macronutrient transporter (fatty acid and glucose) -mediated uptake in pregestational young female adult rat offspring. A higher myocardial FAT/CD36 protein expression in IUGR, PNGR, and IPGR, with higher FATP1 in IUGR, FATP6 in PNGR, FABP-c in PNGR and IPGR, and no change in GLUT4 of all groups was observed. These adaptive macronutrient transporter protein changes were associated with no change in myocardial [(3)H]bromopalmitate accumulation but a diminution in 2-deoxy-[(14)C]glucose uptake. Examination of the sarcolemmal subfraction revealed higher basal concentrations of FAT/CD36 in PNGR and FATP1 and GLUT4 in IUGR, PNGR, and IPGR vs. CON. Exogenous insulin uniformly further enhanced sarcolemmal association of these macronutrient transporter proteins above that of basal, with the exception of insulin resistance of FATP1 and GLUT4 in IUGR and FAT/CD36 in PNGR. The basal sarcolemmal macronutrient transporter adaptations proved protective against subsequent chronic hypoxic exposure (7 days) only in IUGR and PNGR, with notable deterioration in IPGR and CON of the echocardiographic ejection fraction. We conclude that the IUGR and PNGR pregestational adult female offspring displayed a resistance to insulin-induced translocation of FATP1, GLUT4, or FAT/CD36 to the myocardial sarcolemma due to preexistent higher basal concentrations. This basal adaptation of myocardial macronutrient transporters ensured adequate fatty acid uptake, thereby proving protective against chronic hypoxia-induced myocardial compromise.

Early life nutrient restriction impairs blood–brain metabolic profile and neurobehavior predisposing to Alzheimer’s disease with aging

“…However at PN50 while the PNGR/IPGR males continued to demonstrate protection by elevated CSF ketones, this protection was absent in age-matched females. While we did not measure insulin or IGF-I at these early stages in this study, we have previously assessed them and noted insulin and IGF-I to be lower in PNGR and IPGR groups versus CON (Abbasi et al, 2011; Shin et al, 2012; Thamotharan et al, 2005). These hormonal changes are congenial for the use of alternate substrates to fuel brain energy metabolism.…”

Intrauterine Growth Restriction: Hungry for an Answer

“…While this effect was also seen in non-IUGR rats, the effect was greatest in the IUGR diabetes-induced group (79). As measured by protein expression of glucose and fatty acid transporters, female IUGR offspring demonstrate resistance to insulin-induced translocation of several macronutrient transporters in the heart but overall increased expression of these proteins in the basal state (1). We have also previously demonstrated enhanced atherosclerotic patches in IUGR adult male mouse offspring associated with higher circulating cholesterol concentrations (7).…”

Umbilical artery systolic to diastolic ratio is associated with growth and myocardial performance in infants with hypoplastic left heart syndrome

“…The pattern of decreased myocardial performance following Norwood palliation in males with higher SD ratios that mimics the pattern in SGA males parallels the findings of myocardial recovery in animal models of UPI and ischemia-reperfusion injury. [24][25][26] The long bypass and cross-clamp times needed to perform Norwood palliation represent a form of ischemiareperfusion injury. We found that males with UPI (as defined by the SD ratio) had impaired tolerance of this insult.…”