Hypertension in Prenatally Undernourished Young-Adult Rats Is Maintained by Tonic Reciprocal Paraventricular–Coerulear Excitatory Interactions

Prenatally malnourished rats develop hypertension in adulthood, in part through increased α1-adrenoceptor-mediated outflow from the paraventricular nucleus (PVN) to the sympathetic system. We studied whether both α1-adrenoceptor-mediated noradrenergic excitatory pathways from the locus coeruleus (LC) to the PVN and their reciprocal excitatory CRFergic connections contribute to prenatal undernutrition-induced hypertension. For that purpose, we microinjected either α1-adrenoceptor or CRH receptor agonists and/or antagonists in the PVN or the LC, respectively. We also determined the α1-adrenoceptor density in whole hypothalamus and the expression levels of α1A-adrenoceptor mRNA in the PVN. The results showed that: (i) agonists microinjection increased systolic blood pressure and heart rate in normotensive eutrophic rats, but not in prenatally malnourished subjects; (ii) antagonists microinjection reduced hypertension and tachycardia in undernourished rats, but not in eutrophic controls; (iii) in undernourished animals, antagonist administration to one nuclei allowed the agonists recover full efficacy in the complementary nucleus, inducing hypertension and tachycardia; (iv) early undernutrition did not modify the number of α1-adrenoceptor binding sites in hypothalamus, but reduced the number of cells expressing α1A-adrenoceptor mRNA in the PVN. These results support the hypothesis that systolic pressure and heart rate are increased by tonic reciprocal paraventricular–coerulear excitatory interactions in prenatally undernourished young-adult rats.

Epidemiological evidence for the developmental origins of health and disease: effects of prenatal undernutrition in humans

This paper describes the findings of studies among men and women who were born around the time of the Dutch famine of 1944–1945, investigating the effects of undernutrition during critical periods of development on later health and disease. The Dutch famine was remarkable in several ways and its unique features have allowed scientists to investigate the long-term consequences of prenatal undernutrition in humans. The effects of undernutrition depended on its timing during gestation, and the organs and tissues undergoing critical periods of development at that time. Early gestation appeared to be the most vulnerable. The effects of famine were widespread and affected the structure and function of many organs and tissues, resulted in altered behaviour and increased risks of chronic degenerative diseases, which in turn led to reduced participation in the labour market and increased mortality. Also, the effects of famine were independent of size at birth, which suggests that programming may occur without altering size at birth. Studies in other settings show that those faced with undernutrition during the critical earliest stages of development have increased rates of chronic generative disease in adult life. This suggests that these findings reflect biologically fundamental processes that describe human plasticity. These findings teach us the fundamental importance of a good start in life. Adequately feeding women before and during pregnancy will allow future generations to reach their full potential and lead healthier and more productive lives, ultimately leading to healthier and more equal future.

Prenatal undernutrition affects the phenotypes of PCOS model rats

Although polycystic ovary syndrome (PCOS) is among the most common endocrine disorders in women of reproductive age, its etiology remains poorly understood. From the perspective of developmental origins of health and disease, some studies have investigated the relationship between low birth weight and the prevalence of PCOS and/or PCOS phenotypes in humans; however, the results of these studies were inconclusive. Here, we evaluated the effects of prenatal undernutrition on the metabolic and reproductive phenotypes of dihydrotestosterone-induced PCOS model rats. The PCOS model rats showed increased body weight, food intake, fat weight, adipocyte size and upregulation of inflammatory cytokines in adipose tissue; prenatal undernutrition exacerbated these metabolic changes. Prenatal undernutrition also increased the gene expression of hypothalamic orexigenic factor and decreased the gene expression of anorexigenic factor in the PCOS model rats. In addition, the PCOS model rats exhibited irregular cyclicity, polycystic ovaries and disrupted gene expression of ovarian steroidogenic enzymes. Interestingly, prenatal undernutrition attenuated these reproductive changes in the PCOS model rats. Our results suggest that in dihydrotestosterone-induced PCOS model rats, prenatal undernutrition exacerbates the metabolic phenotypes, whereas it improves the reproductive phenotypes and that such phenotypic changes may be induced by the alteration of some peripheral and central factors.

Impacts of pre- and postnatal nutrition on glucagon regulation and hepatic signalling in sheep

To evaluate the long-term impacts of early-life nutritional manipulations on glucagon secretion and hepatic signalling, thirty-six twin-pregnant ewes during their last trimester were exposed to NORM (fulfilling 100% of daily energy/protein requirements), HIGH (fulfilling 150/110% of daily energy/protein requirements) or LOW (50% of NORM) diets. Twin lambs were assigned after birth to a moderate (CONV) or high-carbohydrate high-fat (HCHF) diet until 6 months. Then, responses in plasma glucagon concentrations and glucagon ratios relative to previously reported values for insulin, glucose and lactate were determined after intravenous bolus injections of glucose or propionate (fed and 2-day fasting state). Hepatic mRNA expressions of glucagon receptor (GCGR), glucose-6-phosphatase (G6PC), phosphoenolpyruvate carboxykinase (PEPCK) and fructose 1,6-biphosphatase (FBP) were also determined in a sub group of autopsied lambs. Expression of GCGR and all three enzymes were supressed by prenatal LOW compared to NORM (except PEPCK) and HIGH (except FBP) nutrition. The postnatal HCHF diet reduced plasma glucagon responses to propionate and hepatic mRNA expression of all genes. In response to propionate, insulin/glucagon ratio was decreased (fasted state), but lactate/glucagon and glucose/glucagon increased in HCHF compared to CONV lambs. In conclusion, prenatal undernutrition and postnatal overnutrition had similar long-term implications and reduced hepatic glucagon signalling. Glucagon secretory responses to propionate were, however, not related to the prenatal nutrition history, but negatively affected by the postnatal obesogenic diet. The pancreatic α-cell compared to β-cells may thus be less sensitive towards late gestation malnutrition, whereas hepatic glucagon signalling appears to be a target of prenatal programming.