Maternal Metabolic Environment Research Articles

Different effects of maternal parity, cold exposure and nutrient restriction in late pregnancy on the abundance of mitochondrial proteins in the kidney, liver and lung of postnatal sheep

Adaptation to the extrauterine environment at birth relies upon the onset of postnatal function and increased metabolism in the lungs, liver and kidney, mediated partly by activation of mitochondrial proteins such as the voltage-dependent anion channel (VDAC), cytochrome c and, in the lung only, uncoupling protein (UCP)2. The magnitude of adaptation is dependent on the maternal metabolic and endocrine environment. We, therefore, examined the influence of maternal cold exposure (MCE) induced by winter shearing of pregnant sheep in conjunction with nutrient restriction (NR; 50% reduction in maternal food intake from 110 days gestation up to term). The effect of parity was also examined, as the offspring of nulliparous mothers are growth restricted compared with multiparous offspring. All sheep were twin bearing. One twin was sampled after birth and its sibling at 30 days. In the lung, both MCE and maternal nulliparity enhanced UCP2 abundance. However, whilst VDAC abundance was decreased in both the offspring of nulliparous mothers and by NR, it was transiently raised by MCE. Kidney VDAC abundance was reduced by MCE and nulliparity, adaptations only influenced by NR in multiparous mothers. Cytochrome c abundance was raised by MCE and by NR in multiparous controls and raised in offspring of nulliparous mothers. Liver VDAC and cytochrome c abundance were transiently reduced by MCE and persistently lower in offspring of nulliparous mothers. In conclusion, changes in the maternal metabolic environment have marked tissue-specific effects on mitochondrial protein abundance in the lungs, liver and kidney that may be important in enabling the newborn to effectively adapt to the extrauterine environment.

Long-term effects of nutritional programming of the embryo and fetus: mechanisms and critical windows

The maternal nutritional and metabolic environment is critical in determining not only reproduction, but also long-term health and viability. In the present review, the effects of maternal nutritional manipulation at defined stages of gestation coinciding with embryogenesis, maximal placental or fetal growth will be discussed. Long-term outcomes from these three developmental windows appear to be very different, with brain and cardiovascular function being most sensitive to influences in the embryonic period, the kidney during placental development and adipose tissue in the fetal phase. In view of the similarities in fetal development, number and maturity at birth, there are close similarities in these outcomes between findings from epidemiological studies in historical human cohorts and nutritional manipulation of large animals, such as sheep. One key nutrient that may modulate the long-term metabolic effects is the supply of glucose from the mother to the fetus, because this is sensitive to both global changes in food intake, maternal glucocorticoid status and an increase in the carbohydrate content of the diet. The extent to which these dietary-induced changes may reflect epigenetic changes remains to be established, especially when considering the very artificial diets used to induce these types of effects. In summary, the maintenance of a balanced and appropriate supply of glucose from the mother to the fetus may be pivotal in ensuring optimal embryonic, placental and fetal growth. Increased or decreased maternal plasma glucose alone, or in conjunction with other macro- or micronutrients, may result in offspring at increased risk of adult diseases.

Fetal programming: prenatal testosterone excess leads to fetal growth retardation and postnatal catch-up growth in sheep.

Alterations in the maternal endocrine, nutritional, and metabolic environment disrupt the developmental trajectory of the fetus, leading to adult diseases. Female offspring of rats, subhuman primates, and sheep treated prenatally with testosterone (T) develop reproductive/metabolic defects during adult life similar to those that occur after intrauterine growth retardation. In the present study we determined whether prenatal T treatment produces growth-retarded offspring. Cottonseed oil or T propionate (100 mg, im) was administered twice weekly to pregnant sheep between 30-90 d gestation (term = 147 d; cottonseed oil, n = 16; prenatal T, n = 32). Newborn weight and body dimensions were measured the day after birth, and postnatal weight gain was monitored for 4 months in all females and in a subset of males. Consistent with its action, prenatal T treatment produced females and males with greater anogenital distances relative to controls. Prenatal T treatment reduced body weights and heights of newborns from both sexes and chest circumference of females. Prenatally T-treated females, but not males, exhibited catch-up growth during 2-4 months of postnatal life. Plasma IGF-binding protein-1 and IGF-binding protein-2, but not IGF-I, levels of prenatally T-treated females were elevated in the first month of life, a period when the prenatally T-treated females were not exhibiting catch-up growth. This is suggestive of reduced IGF availability and potential contribution to growth retardation. These findings support the concept that fetal growth retardation and postnatal catch-up growth, early markers of future adult diseases, can also be programmed by prenatal exposure to excess sex steroids.

Gestational Diabetes and Insulin Resistance: Role in Short- and Long-Term Implications for Mother and Fetus

Gestational diabetes and obesity are the common metabolic abnormalities occurring during pregnancy. Decreased maternal pregravid insulin sensitivity (insulin resistance) coupled with an inadequate insulin response are the pathophysiological mechanisms underlying the development of gestational diabetes. Insulin-regulated carbohydrate, lipid and protein metabolism are all affected to a variable degree. Decreased maternal insulin sensitivity in women with gestational diabetes may increase nutrient availability to the fetus, possibly accounting for an increased risk of fetal overgrowth and adiposity. Epidemiological studies from Europe show an increased risk of the insulin resistance syndrome in adults who were low birth weight at delivery. However, in the United States over the past 20 y there has been a significant 33% increase in the incidence of type 2 diabetes, which has been associated with a parallel increase in obesity. All age groups have been affected but the most dramatic increases have occurred in adolescents. The relationship between decreased maternal insulin sensitivity and fetal overgrowth particularly in obese women and women with gestational diabetes may help explain the increased incidence of adolescent obesity and related glucose intolerance in the offspring of these women. In this review, we address 1) the pathophysiology of gestational diabetes, 2) the changes in maternal insulin sensitivity during pregnancy that effect maternal accretion of adipose tissue and energy expenditure, 3) the influence of maternal metabolic environment on fetal growth, 4) the life-long effect of being born at either extreme of the birth weight continuum and 5) micronutrients and decreased insulin sensitivity during pregnancy.

Brown adipose tissue development in the ovine foetus during the final month of gestation

In the ovine foetus brown adipose tissue (BAT) is mainly found in the perirenal region and grows rapidly relative to body weight between 70 to 120 days of gestation (Alexander, 1978). After this stage only a small amount of BAT growth occurs in comparison with that of the whole foetus, and in the case of undernutrition may decline (Alexander, 1978). Maternal cold stress, induced by winter shearing twin-bearing pregnant ewes 8 weeks before parturition improves lamb birth weight and lamb growth rate independently of effects on maternal food intake (Symonds, Bryant and Lomax, 1986 and 1990). At the same time this can stimulate the in vivo capacity for non-shivering thermogenesis in newborn lambs (Stott and Slee, 1985). The following study extends these findings by investigating the extent to which changing the maternal metabolic environment influences BAT development over the final month of gestation.Thirty-two Bluefaced Leicester × Swaledale ewes were housed individually at ambient temperature (−6 to 19°C) 6 weeks prior to lambing and 2 weeks later 15 ewes were shorn. Ewes were offered daily a diet comprising 200 g barley concentrate and 1 kg chopped hay. Between 116 and 145 days of gestation and within 2 h of birth ewes were humanely slaughtered with an overdose of barbiturate and foetal or neonatal perirenal BAT sampled, born from shorn or unshorn ewes. The thermogenic capacity of BAT was assessed by guanosine-5′-diphosphate (GDP) binding to uncoupling protein in mitochondrial preparations (Cooper, Dascombe, Rothwell and Vale, 1989) and the amount of mitochondrial protein measured from cytochrome Coxidase activity.

Glucose utilization by the placenta of anesthetized rats: effect of insulin, glucose, and ketone bodies.

Placental glucose metabolism and its regulation have been investigated in vivo in the rat using the radioactive 2-deoxyglucose technique. In the basal state, placental glucose utilization rates were similar on days 19 and 21 of gestation: 139 +/- 5 and 155 +/- 22 nmol/min/g at maternal blood glucose concentrations of 4.3 +/- 0.1 and 4.2 +/- 0.1 mmol/1. During hyperglycemic clamps, maternal glycemia was raised to 5.5 mmol/liter, a value similar to that during a meal in the rat. In this condition, the rate of placental glucose utilization at 19 days of gestation was increased by 85%. This was due not only to hyperglycemia but also to glucose-induced hyperinsulinemia. Indeed during hyperinsulinemic euglycemic clamps, placental glucose utilization showed a dose-response relationship to insulin (400 and 5000 microU/ml). At 21 days of gestation, placental glucose utilization was not affected by hyperglycemia or by hyperinsulinemia suggesting that in term placenta, glucose metabolism is no longer regulated. When 19-day pregnant rats were fasted for 48 and 96 h, the resulting low blood glucose and plasma insulin concentrations and the high ketone body concentrations induced, respectively, a 40 and 47% reduction of placental glucose utilization. The decrease in placental glucose utilization probably was due to both maternal hypoglycemia and long term adaptation to hyperketonemia. Indeed, the acute hyperketonemia in fed rats did not alter glucose utilization rate in placenta at 19 days of gestation. These data suggest that glucose metabolism in the preterm rat placenta is modulated in vivo by the maternal metabolic environment, particularly by maternal blood glucose and insulin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)