Imran Y. Khan

Developmental programming of the metabolic syndrome by maternal nutritional imbalance: how strong is the evidence from experimental models in mammals?

The incidence of the metabolic syndrome, a cluster of abnormalities focusing on insulin resistance and associated with high risk for cardiovascular disease and diabetes, is reaching epidemic proportions. Prevalent in both developed and developing countries, the metabolic syndrome has largely been attributed to altered dietary and lifestyle factors that favour the development of central obesity. However, population‐based studies have suggested that predisposition to the metabolic syndrome may be acquired very early in development through inappropriate fetal or neonatal nutrition. Further evidence for developmental programming of the metabolic syndrome has now been suggested by animal studies in which the fetal environment has been manipulated through altered maternal dietary intake or modification of uterine artery blood flow. This review examines these studies and assesses whether the metabolic syndrome can be reliably induced by the interventions made. The validity of the different species, diets, feeding regimes and end‐point measures used is also discussed.

Gender-Linked Hypertension in Offspring of Lard-Fed Pregnant Rats

Abstract—Epidemiological studies suggest an association between maternal nutrition and offspring cardiovascular disease. We previously demonstrated endothelial dysfunction and abnormal aortic fatty acid composition in adult female offspring of rats fed animal lard during pregnancy. We have now further investigated this model. Female Sprague-Dawley rats were fed a control breeding diet (5.3% fat) or a diet rich in lard (25.7% fat) 10 days before and throughout pregnancy and lactation. Male and female offspring were implanted with radiotelemeters for recording of blood pressure, heart rate, and activity at 80, 180, and 360 days of age. Reactivity to acetylcholine and to nitric oxide were assessed in isolated small mesenteric arteries from 80- and 180-day-old littermates. Systolic blood pressure (awake phase) was raised in female offspring (180 days: offspring of control, 130.7±1.6 mm Hg, n=5, versus offspring of lard-fed, 138.1±2.9, n=5, P =0.029; 360 days: offspring of control, 129.7±3.7 mm Hg, n=6, versus offspring of lard-fed, 142.1±3.2, n=6, P =0.005). Diastolic blood pressure was also raised at 180 days (offspring of control, 87.6±1.0 mm Hg, n=5, versus offspring of lard-fed, 94.7±2.6, n=5, P =0.011). Blood pressure was not raised in male offspring. Endothelium-dependent relaxation to acetylcholine was blunted in male and female offspring of lard-fed dams (80 and 180 days). Feeding a diet rich in lard to pregnant rats leads to gender-related cardiovascular dysfunction in normally fed offspring.

Predictive Adaptive Responses to Maternal High-Fat Diet Prevent Endothelial Dysfunction but Not Hypertension in Adult Rat Offspring

Background—Population-based studies suggest that fetal adaptive responses to maternal dietary imbalance confer survival benefit when the postnatal diet remains suboptimal but increase susceptibility to cardiovascular disease when postnatal nutrition is improved. We have investigated “predictive adaptive” responses in a rodent model in which adult offspring of fat-fed dams develop characteristics of the metabolic syndrome. Methods and Results—Sprague-Dawley rats were fed a fat-rich diet or normal chow throughout pregnancy and weaning. Vascular endothelial function and blood pressure were determined in 180-day-old offspring of fat-fed dams raised on standard chow (FC) or on the fat-rich diet (FF) and in offspring of chow-fed dams raised on chow (CON). Small mesenteric artery endothelium-dependent dilation to acetylcholine was impaired in male and female FC (by ANOVA, P<0.001 versus CON) but similar to CON in FF (P=NS). Blood glucose was lower in FF versus FC. Heart rate was reduced in male FC versus CON (P<0.05) but not in FF. Plasma triglyceride concentrations were reduced in male FF compared with CON (P<0.05). Blood pressure was raised in female FC (systolic, 132.5±3.0 mm Hg versus CON, 119.0±3.8 mm Hg, P<0.05; diastolic, 91.2±1.7 mm Hg versus CON, 81.1±1.4 mm Hg, P<0.05) and in female FF (systolic, 132.5±4.2 mm Hg versus CON, P<0.05; diastolic, 91.0±1.9 mm Hg versus CON, P<0.05). Blood pressure was similar to CON in male FC and FF. Conclusions—Predictive adaptive responses prevent endothelial dysfunction and reduced heart rate in offspring of fat-fed dams if offspring are raised on the same diet but do not prevent development of raised blood pressure.

Dietary soy isoflavone-induced increases in antioxidant and eNOS gene expression lead to improved endothelial function and reduced blood pressure in vivo

Epidemiological evidence suggests that populations consuming large amounts of soy protein have a reduced incidence of coronary heart disease (1–5). The cardiovascular risks associated with conventional hormone replacement therapy in postmenopausal women (5–7) have precipitated a search for alternative estrogen receptor modulators. Here we report that long‐term feeding of rats with a soy protein‐rich (SP) diet during gestation and adult life results in decreased oxidative stress, improved endothelial function, and reduced blood pressure in vivo measured by radiotelemetry in aged male offspring. Improved vascular reactivity in animals fed an SP diet was paralleled by increased mitochondrial glutathione and mRNA levels for endothelial nitric oxide synthase (eNOS) and the antioxidant enzymes manganese superoxide dismutase and cytochrome c oxidase. Reduced eNOS and antioxidant gene expression, impaired endothelial function, and elevated blood pressure in animals fed a soy‐deficient diet was reversed after refeeding them an SP diet for 6 months. Our findings suggest that an SP diet increases eNOS and antioxidant gene expression in the vasculature and other tissues, resulting in reduced oxidative stress and increased NO bioavailability. The improvement in endothelial function, increased gene expression, and reduced blood pressure by soy isoflavones have implications for alternative therapy for postmenopausal women and patients at risk of coronary heart disease.

Uterine Artery Function in Pregnant Rats Fed a Diet Supplemented with Animal Lard

We hypothesised that maternal uterine artery vascular dysfunction could contribute to cardiovascular dysfunction in offspring of rats fed a diet rich in fat. Sprague‐Dawley rats were fed for 10 days prior to pregnancy and throughout gestation either: (a) a control breeding diet, or (b) the same diet supplemented with 20% w/w lard, vitamins, essential micronutrients and protein to control values. At 20 days gestation vascular function was assessed in uterine arteries and third‐order mesenteric arteries. Vascular reactivity in response to application of potassium, noradrenaline, the thromboxane analogue U46619, acetylcholine and nitric oxide was assessed. Maternal plasma concentrations of factors likely to contribute to endothelial dysfunction were measured. Maximum acetylcholine‐induced relaxation was impaired in the mesenteric arteries of the lard‐fed dams (max% relaxation: lard‐fed, 69.7 ± 6.48; control, 85.37 ± 2.69, P = 0.03). Uterine artery vascular function was similar in the two groups (max% acetylcholine‐induced relaxation: lard‐fed, 73.7 ± 4.01; control, 77.5 ± 4.72, P = 0.98). Concentrations of plasma lipids, 8‐epi‐PGF2α and leptin were normal, whereas insulin and corticosterone concentrations were raised in the lard‐fed group (insulin (ng ml−1): lard‐fed, 8.04 ± 0.47; control, 1.35 ± 0.37, P < 0.0001; corticosterone (ng ml−1): lard‐fed, 1164.0 ± 170.9; control, 541.9 ± 96.3, P = 0.005). Fetal and placental weights were reduced in lard‐fed dams (fetus (g): lard‐fed, 4.27 ± 0.38; control, 2.96 ± 0.40, P = 0.025; placenta (g): lard‐fed, 0.72 ± 0.06; control, 0.57 ± 0.04, P = 0.05). Cardiovascular dysfunction in offspring is not associated with reduced uterine artery endothelial function but is associated with activation of the hypothalamic‐pituitary‐adrenal axis, hyperinsulinaemia and fetoplacental growth retardation.

Generation of Maternal Obesity Models in Studies of Developmental Programming in Rodents

Mother-child cohort studies have established that both pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) are independently associated with cardio-metabolic risk factors in juvenile and adult offspring, including systolic and diastolic blood pressure. In rodent studies maternal obesity confers many facets of the metabolic syndrome including a persistent sympathy-excitatory hyperresponsiveness and hypertension acquired in the early stages of development. Insight from these animal models raises the possibility that early life exposure to the nutritional and hormonal environment of obesity in pregnancy in humans may lead to early onset of metabolic syndrome and/or essential hypertension. This chapter will address the development of rodent models of maternal overnutrition and obesity, which have proved invaluable in generating testable hypotheses for clinical translation and the development of intervention strategies to stem the swelling tide of obesity and its comorbidities predicted for future generations.