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Biomedical subjects

S E Ozanne

Publications and source records attributed to S E Ozanne.

At least 19 recordsLinked to original sources
PubMed2003

For debate: Fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure.

We review the progress in testing the thrifty phenotype hypothesis. Many human epidemiological studies both by ourselves and others have confirmed and extended the original observations on which the hypothesis was based. We are not aware of any contradictory findings and we emphasise the strength of the association between birth weight and the subsequent development of the metabolic syndrome. We have worked extensively experimentally to test the hypothesis in a rat model in which pregnant and/or lactating dams are fed a diet moderately restricted in proteins. The range of programming effects that we have discovered in this example of fetal and early postnatal growth restriction is listed and includes changes in hormone receptors, signalling molecules and regulatory enzymes. We have shown the model to develop diabetes, the metabolic syndrome and signs of premature renal failure. We summarise these and other similarities between the phenotype of this model and human Type 2 diabetes and the metabolic syndrome. The number of insults during early development which can lead to a similar outcome is discussed and the suggestion is made that the early life response to stress is limited in its flexibility with outcomes including ageing and decreased longevity. Our preliminary results indicate that some MODY genes could suggest pathways whereby the changes occur and that epigenetic changes during development are involved. We conclude that the way is now clear to discover early human markers of programming by early life growth restriction and to use these to devise strategies for the prevention of Type 2 diabetes.

Animals↗
PubMed2003

Ageing and telomeres: a study into organ- and gender-specific telomere shortening.

Telomeres, the non-coding sequences at the ends of chromosomes, in the absence of telomerase, progressively shorten with each cell division. Shortening of telomeres can induce cell cycle arrest and apoptosis. The aim of this study was to investigate age- and gender-related changes in telomere length in the rat and to detect possible tissue- specific rates of telomere shortening. Changes with age in telomere lengths were assessed by Southern blotting in the kidney, pancreas, liver, lung and brain of male and female rats. We determined the percentage of telomeres in various molecular size regions rather than measuring the average telomere length. The latter was unable to detect telomere shortening in the tissues. The percentage of short telomeres increased with age in the kidney, liver, pancreas and lung of both males and females, but not in the brain. Males had shorter telomeres than females in all organs analysed except the brain, where the lengths were similar. These findings indicate that telomeres shorten in the rat kidney, liver, pancreas and the lung in an age-dependent manner. These data also provide a novel mechanism for the gender-related differences in lifespan and suggest a tissue-specific regulation of telomere length during development and ageing in the rat.

Aging↗
PubMed2003

Effect of maternal iron restriction during pregnancy on renal morphology in the adult rat offspring.

In rats, maternal anaemia during pregnancy causes hypertension in the adult offspring, although the mechanism is unknown. The present study investigated the renal morphology of adult rats born to mothers who were Fe-deficient during pregnancy. Rats were fed either a control (153 mg Fe/kg diet, n 7) or low-Fe (3 mg/kg diet, n 6) diet from 1 week before mating and throughout gestation. At delivery, the Fe-restricted (IR) mothers were anaemic; the IR pups were also anaemic and growth-retarded at 2 d of age. At 3 and 16 months, systolic blood pressure in the IR offspring (163 (sem 4) and 151 (sem 4) mmHg respectively, n 13) was greater than in control animals (145 (sem 3) and 119 (sem 4) mmHg respectively, n 15, P<0.05). At post mortem at 18 months, there was no difference in kidney weight between treatment groups, although relative kidney weight as a fraction of body weight in the IR offspring was greater than in control animals (P<0.05). Glomerular number was lower in the IR offspring (11.4 (sem 1.1) per 4 mm(2), n 13) compared with control rats (14.8 (sem 0.7), n 15, P<0.05). Maternal treatment had no effect on glomerular size, but overall, female rats had smaller and more numerous glomeruli per unit area than male rats. When all animals were considered, inverse relationships were observed between glomerular number and glomerular size (r-0.73, n 28, P<0.05), and glomerular number and systolic blood pressure at both 3 months (r-0.42, n 28, P<0.05) and 16 months of age (r-0.64, n 28, P<0.05). Therefore, in rats, maternal Fe restriction causes hypertension in the adult offspring that may be due, in part, to a deficit in nephron number.

Anemia, Iron-Deficiency↗
PubMed2003

The maternal endocrine environment in the low-protein model of intra-uterine growth restriction.

Many adult diseases, including type 2 diabetes, hypertension and cardiovascular disease, are related to low birth weight. The mechanistic basis of this relationship is not known. To investigate the role of fetal undernutrition, we used a rat model of maternal protein restriction in which dams were fed a diet containing 80 g protein/kg (v. 200 g/kg in the control group) throughout gestation and lactation. Offspring were born smaller than controls and in adulthood developed diabetes, hyperinsulinaemia and tissue insulin resistance. To determine possible mechanisms of fetal programming, circulating levels of several hormones were measured in maternal plasma at gestational days 14, 17 and 21 and fetal plasma at gestational day 21. Several differences were noted at day 14, when glucose concentrations in maternal and feto-placental blood were raised significantly (P=0.04 and P=0.0001 respectively); insulin levels in the low-protein (LP) dams were raised (P=0.04), prolactin levels were raised (P=0.047) and progesterone levels were reduced (P=0.02). Circulating 17beta-oestradiol in the LP dams was raised by 35 % over those of the controls from day 17 to day 21 (P=0.008). A significant decrease in maternal leptin levels (P=0.004) was observed at gestation on day 21. Neither oestradiol nor leptin levels were altered in the fetal circulation at day 21. Maternal and fetal corticosterone levels were comparable with control levels, suggesting that they do not initiate the programming effects in this model. Our present results suggest that maternal protein restriction imposes changes in maternal levels of glucose, insulin, prolactin, progesterone, oestradiol and leptin; these changes could influence the programming of eventual adult disease in the developing fetus.

Animals↗
PubMed2003

Early growth restriction leads to down regulation of protein kinase C zeta and insulin resistance in skeletal muscle.

Epidemiological studies have revealed a relationship between early growth restriction and the subsequent development of type 2 diabetes. A rat model of maternal protein restriction has been used to investigate the mechanistic basis of this relationship. This model causes insulin resistance and diabetes in adult male offspring. The aim of the present study was to determine the effect of early growth restriction on muscle insulin action in late adult life. Rats were fed either a 20% or an isocaloric 8% protein diet during pregnancy and lactation. Offspring were weaned onto a 20% protein diet and studied at 15 Months of age. Soleus muscle from growth restricted offspring (LP) (of dams fed 8% protein diet) had similar basal glucose uptakes compared with the control group (mothers fed 20% protein diet). Insulin stimulated glucose uptake into control muscle but had no effect on LP muscle. This impaired insulin action was not related to changes in expression of either the insulin receptor or glucose transporter 4 (GLUT 4). However, LP muscle expressed significantly less (P<0.001) of the zeta isoform of protein kinase C (PKC zeta) compared with controls. This PKC isoform has been shown to be positively involved in GLUT 4-mediated glucose transport. Expression levels of other isoforms (betaI, betaII, epsilon, theta) of PKC were similar in both groups. These results suggest that maternal protein restriction leads to muscle insulin resistance. Reduced expression of PKC zeta may contribute to the mechanistic basis of this resistance.

Animals↗
PubMed2002

The dangerous road of catch-up growth.

Many epidemiological studies have now shown a strongly increased risk of developing type 2 diabetes and the metabolic syndrome in adults who as neonates showed signs of poor early (fetal and early postnatal) growth. The thrifty phenotype hypothesis was proposed to provide a conceptual and experimentally testable basis of these relationships. We have used protein restriction of rat dams, as a means to test this hypothesis. In vivo and in vitro studies of the growth-restricted offspring of such pregnancies have provided findings showing remarkable parallels with the human conditions. Permanent changes in the expression of regulatory proteins in liver, muscle and adipose tissue provide at least part of the explanation of the changes observed and offer potential markers for testing in the human context. These studies have also raised the question as to whether 'catch up' growth following early growth retardation may add to the risks posed by this early handicap. Male rats growth-retarded during fetal life and cross-fostered shortly after birth to normal lactating dams reach normal body and organ weights by weaning but have a reduced longevity. This finding raises the possibility that catch up growth, whilst potentially beneficial in the short term, may be detrimental to long-term survival. Human epidemiological studies may point in the same direction. Work by others on other models of early growth restriction have produced similar, although more limited, data. These findings raise the interesting possibility that the response to fetal stress, be it nutritional or other, may evoke a somewhat restricted and uniform pattern of adaptive response.

Animals↗
PubMed2001

Programming of intermediary metabolism.

Studies of animal models were carried out to explore mechanisms that might underlie epidemiological findings linking indices of poor early (fetal and early postnatal) growth to an increased risk of developing poor glucose tolerance, including the metabolic syndrome, in adult life. Adult obesity was also seen to play an important role in adding to these risks. We proposed the 'thrifty phenotype' hypothesis to provide a conceptual and mechanistic framework that could be tested by experimentation in animal models. Our main approach has been to feed a reduced protein diet to pregnant and/or lactating rat dams as a means of reducing growth in the fetal and/or preweaning stages of pup growth. Animals were weaned onto either a normal diet or an obesity-inducing highly palatable, cafeteria-style diet. Alterations in intermediary metabolism were noted in the rats with early growth restriction, which provide support for our hypothesis and clues to the mechanism.

Animals↗
PubMed2001

Effects of maternal iron restriction in the rat on blood pressure, glucose tolerance, and serum lipids in the 3-month-old offspring.

Epidemiologic studies have demonstrated associations between low birth weight and increased rates of adult diseases such as hypertension and diabetes. Maternal iron restriction in the rat has been reported to both reduce birth weight and to elevate blood pressure at 40 days of age. The aim of the present study was to extend these findings to investigate the effects of maternal iron restriction on glucose tolerance and serum lipids, 2 important components of the metabolic syndrome, in adult offspring. Blood pressure, glucose tolerance, and serum lipids were measured in the 3-month-old offspring of iron-restricted dams. Rats were placed on control or iron-restricted diets 1 week before mating. At term, dams on the iron-restricted diet were anemic with decreased haemoglobin, red blood cell (RBC) count, hematocrit, and mean RBC volume compared with controls. Neonates from iron-restricted litters were more severely anemic than the dams. At birth, body weight was lower in the offspring of iron-restricted dams than in controls and was still decreased at 3 months of age. At this same age, systolic blood pressure was significantly elevated in the offspring of iron-restricted dams. Glucose tolerance was improved in the maternal iron-restricted group. Fasting serum insulin levels were not different between the control and maternal iron-restricted groups. Fasting serum triglyceride was decreased in the offspring of iron-restricted dams compared with controls. Fasting serum cholesterol and free fatty acid concentrations were similar in both groups. These results suggest that maternal iron restriction has long-term effects on physiology and metabolism in the offspring. Some of these findings are comparable to those reported for the maternal protein-restriction model. It is thus speculated that the long-term effects of maternal dietary restriction may result from common fetal metabolic responses to this restriction.

Animals↗
PubMed2001

Early growth restriction, membrane phospholipid fatty acid composition, and insulin sensitivity.

An animal model of protein restriction during pregnancy and lactation with subsequent dietary fatty acid manipulation was used to investigate the association between poor early growth, defective unsaturated fatty acid handling, and later disease. Both control and early growth-restricted animals fed a diet rich in saturated fatty acids showed a doubling of the plasma insulin levels as well as a reduced degree of unsaturation in liver and skeletal muscle membrane phospholipids compared with animals fed diets rich in unsaturated fatty acids. The skeletal muscle of early growth-restricted animals weaned onto a saturated fat diet had reduced proportions of 22:6n-3 and increased proportions of 18:1n-9. This reduction in 22:6n-3 is similar to that observed in Pima Indians, a population with a high prevalence of type 2 diabetes.

Animals↗
PubMed2001

Metabolic programming in animals.

A large number of epidemiological studies have revealed that there is a relationship between early growth restriction and the subsequent development of type 2 diabetes or the metabolic syndrome. The mechanistic basis of this relationship and the relative roles played by genes and the environment remains the subject of much current debate. Animal models of early growth restriction have been developed in an attempt to understand its relationship with adult disease and to provide insight into the underlying molecular mechanisms. These models show many features of the metabolic syndrome. In the maternal protein restriction model, insulin resistance and hypertension is observed. The uterine artery ligation model shows obesity in adulthood. This provides strong evidence that alterations in the fetal environment can lead to diabetes in adult life.

Animals↗
PubMed2001

Impaired PI 3-kinase activation in adipocytes from early growth-restricted male rats.

Epidemiological studies have established a relationship between early growth restriction and subsequent development of type 2 diabetes. Animal studies have shown that offspring of protein-restricted rats undergo a greater age-related loss of glucose tolerance than controls. The aim of this study was to investigate the possibility that this deterioration of glucose tolerance is associated with changes in adipocyte insulin action. Adipocytes from low-protein offspring had higher basal levels of glucose uptake than controls. Insulin stimulated glucose uptake into control adipocytes but had little effect on low-protein adipocytes. Both groups had similar levels of basal and isoproterenol-stimulated lipolysis. Insulin inhibited lipolysis in control adipocytes but had a reduced effect on low-protein adipocytes. These changes in insulin action were not related to altered expression of insulin receptors or insulin receptor tyrosine phosphorylation; however, they were associated with reduced phosphatidylinositol 3-kinase and protein kinase B activation. These results demonstrate that reduced glucose tolerance observed in late adult life after early growth restriction is associated with adipocyte insulin resistance.

Adipocytes↗
PubMed2001

Diabetes in old male offspring of rat dams fed a reduced protein diet.

Restricted fetal growth is associated with increased risk for the future development of Type 2 diabetes in humans. The study aim was to assess the glucose tolerance of old (seventeen months) male rats, which were growth restricted in early life due to maternal protein restriction during gestation and lactation. Rat mothers were fed diets containing either 20% or 8% protein and all offspring weaned onto a standard rat diet. In old-age fasting plasma glucose concentrations were significantly higher in the low protein offspring: 8.4 (1.3) mmol/l v. 5.3 (1.3) mmol/l (p = 0.005). Areas under the curves were increased by 67% for glucose (p = 0.01) and 81% for insulin (p = 0.01) in these rats in intravenous glucose tolerance tests, suggesting (a degree of) insulin resistance. These results show that early growth retardation due to maternal protein restriction leads to the development of diabetes in old male rat offspring. The diabetes is predominantly associated with insulin resistance.

Animals↗
PubMed2000

Catecholamine levels and receptor expression in low protein rat offspring.

AIMS: Low birthweight in humans has been shown to lead to increased resting pulse rate in adult life, suggesting possible increased sympathoadrenal activity. The hypothesis that early growth restriction is associated with permanent alterations in catecholamine metabolism was tested. METHODS: Circulating catecholamine concentrations (by radioimmunoassay) and adipocyte adrenoceptor expression from different fat depots (by Western blot) were estimated in 12-week-old male offspring of rat dams fed a reduced protein diet during pregnancy and lactation. RESULTS: In the fed state, median (interquartile range) plasma adrenaline concentrations for male control and low protein offspring rats were: 0.65 (0.48-0.86) vs. 1.42 (0.89-1.87) nmol/l (P < 0.005), respectively. Equivalent noradrenaline concentrations were: 2.71 (2.16-3.46) vs. 3.45 (3.00-4.28) nmol/l (P < 0.05). After 24 h starvation, plasma adrenaline concentrations of controls rose to become similar to those of low protein offspring: 1.03 (0.95-1.31) vs. 1.41 (0.69-1.62) nmol/l (P = 0.3), respectively. Noradrenaline concentrations rose in both groups to become similar: 3.84 (3.33-4.54) vs. 4.32 (3.70-6.54) nmol/l (P = 0.3). In epididymal adipocytes adrenoceptor expression (relative to that of controls) was: alpha2A 0.79 (0.66-0.94) (P = 0.08), beta1 2.60 (2.27-3.07) (P = 0.04), beta3 1.37 (1.27-1.46) (P = 0.02). Similar-pattern differences in adrenoceptor expression were observed in subcutaneous and intra-abdominal adipocytes. CONCLUSIONS: These results are consistent with the suggestion that long-term alterations in catecholamine metabolism are present in adult offspring of rats fed a reduced protein diet during pregnancy and lactation.

Adipocytes↗
PubMed2000

Depot-specific effects of early growth retardation on adipocyte insulin action.

Male offspring of rats protein restricted during pregnancy and lactation are growth restricted and have changes in insulin action on epididymal adipocytes. Adipocytes from different anatomical depots are thought to have distinct metabolic functions. The aim of the present study was to determine whether the alterations in metabolism of adipocytes from early growth restricted rats is depot-specific or more generalised. Epididymal, intra-abdominal and subcutaneous adipocytes were studied from three-month-old male offspring of control and protein restricted dams. Basal glucose uptakes were higher in low protein adipocytes (p<0.01) compared to controls. However, insulin stimulation was less in the low protein group in all depots compared to controls (p<0.05). Isoproterenol-stimulated lipolysis was greater in low protein adipocytes (p<0.0001), but the magnitude was greater in epididymal (p<0.0001) and intra-abdominal (p<0.0001) adipocytes than in subcutaneous adipocytes. Epididymal and intra-abdominal adipocytes from low protein offspring were also resistant to the anti-lipolytic action of insulin. These results suggest that certain changes associated with early growth retardation are depot-specific, being enhanced in the more metabolically active intra-abdominal and epididymal tissues.

Adipocytes↗
PubMed2000

Effects of early protein restriction and adult obesity on rat pancreatic hormone content and glucose tolerance.

Rats were fed a diet containing either 20% ("control") or 8% ("reduced-protein") protein throughout pregnancy and lactation. Their female offspring were weaned onto the same respective diets. At 63 days of age one set of control and reduced-protein rats (n = 16 per group) underwent intraperitoneal glucose tolerance tests and one week later were killed and their pancreatic hormones extracted and measured. The reduced protein rats had better glucose tolerance (p < 0.001) and lower pancreatic insulin (p < 0.01) and amylin (p < 0.01) contents. Further sets of control and reduced-protein rats were then fed either chow or a cafeteria-style diet (n = 16 in each of the four groups). These rats underwent intraperitoneal glucose tolerance tests at 133 days of age, which showed the cafeteria-fed animals to have a worse glucose tolerance than the chow-fed animals irrespective of previous diet exposure (p < 0.0001). One week later reduced-protein rats still had lower pancreatic insulin contents (p < 0.05) (and a trend for lower amylin contents), but also had increased pancreatic glucagon contents (p < 0.05). There were no detectable differences in pancreatic somatostatin-like immunoreactivity or pancreatic polypeptide contents. These results are consistent with pancreatic beta- and alpha-cells being selectively susceptible to effects associated with early dietary protein restriction.

Amyloid↗
PubMed2000

Workshop to identify critical windows of exposure for children's health: cardiovascular and endocrine work group summary.

The work group on cardiovascular and endocrine effects was asked to review the current state of knowledge about children's windows of vulnerability to developmental toxicants and to recommend how that information may be used to improve risk assessment and public health. We considered differences between structural defects, where periods of vulnerability are rather well defined, and functional defects, where periods of vulnerability are quite elusive.

Cardiovascular System↗
PubMed1999

Early growth determines longevity in male rats and may be related to telomere shortening in the kidney.

Maternal protein undernutrition can influence the growth and longevity of male offspring in the rat. We tested the hypothesis that these differences in longevity were associated with changes in the rate of telomere shortening. We found age-related shortening of telomeres in the liver and kidney but not in the brain of male rats. Growth retardation in postnatal life was associated with significantly longer kidney telomeres and an increased longevity. Conversely, growth retardation during the foetal life followed by postnatal catch-up growth was associated with a shorter life span and shorter kidney telomeres. These findings may provide a mechanistic basis for epidemiological studies linking early growth retardation to adult degenerative diseases.

Animals↗