Susana Astiz

Diet-Induced Swine Model with Obesity/Leptin Resistance for the Study of Metabolic Syndrome and Type 2 Diabetes

The objective of the present study was to determine the suitability of a swine breed with leptin resistance and predisposition to obesity (the Iberian pig) as model for studies on metabolic syndrome and type 2 diabetes. Thus, six Iberian sows had ad libitum access to food enriched with saturated fat (SFAD group; food consumption was estimated to be 4.5 kg/animal/day) whilst four females acted as controls and were fed with 2 kg/animal/day of a commercial maintenance diet. After three months of differential feeding, SFAD animals developed central obesity, dyslipidemia, insulin resistance and impaired glucose tolerance, and elevated blood pressure; the five parameters associated with the metabolic syndrome. Thus, the current study characterizes the Iberian pig as a robust, amenable, and reliable translational model for studies on nutrition-associated diseases.

Gender-specific early postnatal catch-up growth after intrauterine growth retardation by food restriction in swine with obesity/leptin resistance

The effects of undernutrition during pregnancy on prenatal and postnatal development of the offspring were evaluated in sows with obesity/leptin resistance. Females were fed, from day 35 of pregnancy onwards, a diet fulfilling either 100% (group control, n=10) or 50% of the nutritional requirements (group underfed, n=10). In the control group, maternal body weight increased during pregnancy (P<0.05) while it decreased or remained steady in the underfed group. At days 75 and 100 of gestation, plasma triglycerides were lower but urea levels were higher in restricted than in control sows (P<0.05 for both). Assessment of the offspring indicated that the trunk diameter was always smaller in the restricted group (P<0.01 at day 50, P<0.005 at days 75 and 100 and P<0.0001 at birth) while head measurements were similar through pregnancy, although smaller in the restricted than in the control group at birth (P<0.05). Newborns from restricted sows were also lighter than offspring from control females (P<0.01) and had higher incidence of growth retardation (P<0.01). Afterwards, during lactation, early postnatal growth in restricted piglets was modulated by gender. At weaning, males from restricted sows were still lighter than their control counterparts (P<0.05), while females from control and underfed sows were similar. Thus, the current study indicates a gender-related differential effect in the growth patterns of the piglets, with females from restricted sows evidencing catch-up growth to neutralise prenatal retardation and reaching similar development than control counterparts.

Reproductive, endocrine and metabolic feto-maternal features and placental gene expression in a swine breed with obesity/leptin resistance

The current study was conducted in a swine breed (Iberian pig) with a genotype that predisposed the pig to obesity. The aim of the study was to determine the morphological, metabolomic and endocrine features of early conceptuses and to elucidate how placental gene expression (related to placentation, angiogenesis and fetal nutrition), maternal hormones and the metabolome affect the fetal environment and fetal growth. Conceptus viability and growth were found to be related to maternal endocrine (plasma progesterone levels) and metabolic features (plasma levels of leptin, cholesterol, HDL-c, LDL-c and triglycerides). These features were related to the placental expression of the vascular endothelial growth factor A (VEGFA) and leptin (LEP) genes, the placental efficiency and, thus, the nutrition and the metabolism of the fetus (availability of glucose, triglycerides and cholesterol, as HDL-c). Viability of conceptuses in females with evidence of dyslipidemia (low plasma levels of total cholesterol due to low HDL-c concentration but high levels of triglycerides) was diminished. The availability of nutrients and metabolic substrates to the conceptus was also affected in females with higher fat deposition and evidence of dyslipidemia. In conclusion, the conceptus viability and growth appear to be strongly related to maternal metabolic features and, thus, affected in females with alterations in lipid metabolism.

Prenatal programming in an obese swine model: sex-related effects of maternal energy restriction on morphology, metabolism and hypothalamic gene expression.

Maternal energy restriction during pregnancy predisposes to metabolic alterations in the offspring. The present study was designed to evaluate phenotypic and metabolic consequences following maternal undernutrition in an obese pig model and to define the potential role of hypothalamic gene expression in programming effects. Iberian sows were fed a control or a 50 % restricted diet for the last two-thirds of gestation. Newborns were assessed for body and organ weights, hormonal and metabolic status, and hypothalamic expression of genes implicated in energy homeostasis, glucocorticoid function and methylation. Weight and adiposity were measured in adult littermates. Newborns of the restricted sows were lighter (P <0·01), but brain growth was spared. The plasma concentration of TAG was lower in the restricted newborns than in the control newborns of both the sexes (P <0·01), while the concentration of cortisol was higher in females born to the restricted sows (P <0·04), reflecting a situation of metabolic stress by nutrient insufficiency. A lower hypothalamic expression of anorexigenic peptides (LEPR and POMC, P <0·01 and P <0·04, respectively) was observed in females born to the restricted sows, but no effect was observed in the males. The expression of HSD11B1 gene was down-regulated in the restricted animals (P <0·05), suggesting an adaptive mechanism for reducing the harmful effects of elevated concentrations of cortisol. At 4 and 7 months of age, the restricted females were heavier and fatter than the controls (P< 0·01). Maternal feed restriction induces asymmetrical growth retardation and metabolic alterations in the offspring. Differences in gene expression at birth and higher growth and adiposity in adulthood suggest a female-specific programming effect for a positive energy balance, possibly due to overexposure to endogenous stress-induced glucocorticoids.

Effect of an obesogenic diet during the juvenile period on growth pattern, fatness and metabolic, cardiovascular and reproductive features of Swine with obesity/leptin resistance.

The objective of this study was to determine, in a female swine model of leptin resistance (Iberian pig), the effect of an obesogenic diet, with high saturated fat content, during the juvenile period, on the appearance of early obesity and its possible effects on metabolic syndrome-related parameters and reproductive features (puberty attainment). Thus, from 130 to 245 days-old, seven Iberian gilts had ad libitum access to food enriched with saturated fat whilst six females acted as controls and had ad libitum access to a commercial maintenance diet. Results showed that a high fat intake-level during the juvenile period induces early obesity with lower body weight and size but a higher body fat-content. Such obesity was related with impairments of glucose regulation predisposing for insulin resistance, but also with an earlier onset of puberty. However, there were no signs of hypertriglyceridemia and hypertension; the gilts diminish their intake level and modify their metabolic features by increasing insulin secretion. In conclusion, Iberian gilts freely eating saturated fat diets during the juvenile period have the prodrome of metabolic syndrome but, during their juvenile period, are still able to develop an adaptive response to the diet.

Maternal malnutrition and offspring sex determine juvenile obesity and metabolic disorders in a swine model of leptin resistance.

The present study aimed to determine, in a swine model of leptin resistance, the effects of type and timing of maternal malnutrition on growth patterns, adiposity and metabolic features of the progeny when exposed to an obesogenic diet during their juvenile development and possible concomitant effects of the offspring sex. Thus, four groups were considered. A CONTROL group involved pigs born from sows fed with a diet fulfilling their daily maintenance requirements for pregnancy. The treated groups involved the progeny of females fed with the same diet but fulfilling either 160% or 50% of pregnancy requirements during the entire gestation (OVERFED and UNDERFED, respectively) or 100% of requirements until Day 35 of pregnancy and 50% of such amount from Day 36 onwards (LATE-UNDERFED). OVERFED and UNDERFED offspring were more prone to higher corpulence and fat deposition from early postnatal stages, during breast-feeding; adiposity increased significantly when exposed to obesogenic diets, especially in females. The effects of sex were even more remarkable in LATE-UNDERFED offspring, which had similar corpulence to CONTROL piglets; however, females showed a clear predisposition to obesity. Furthermore, the three groups of pigs with maternal malnutrition showed evidences of metabolic syndrome and, in the case of individuals born from OVERFED sows, even of insulin resistance and the prodrome of type-2 diabetes. These findings support the main role of early nutritional programming in the current rise of obesity and associated diseases in ethnics with leptin resistance.

Developmental Origins of Health and Disease in swine: implications for animal production and biomedical research

The concept of Developmental Origins of Health and Disease (DOHaD) addresses, from a large set of epidemiological evidences in human beings and translational studies in animal models, both the importance of genetic predisposition and the determinant role of maternal nutrition during pregnancy on adult morphomics and homeostasis. Compelling evidences suggest that both overnutrition and undernutrition may modify the intrauterine environment of the conceptus and may alter the expression of its genome and therefore its phenotype during prenatal and postnatal life. In fact, the DOHaD concept is an extreme shift in the vision of the factors conditioning adult phenotype and supposes a drastic change from a gene-centric perspective, only modified by lifestyle and nutritional strategies during juvenile development and adulthood, to a more holistic approach in which environmental, parental, and prenatal conditions are strongly determining postnatal development and homeostasis. The implications of DOHaD are profound in all the mammalian species and the present review summarizes current knowledge on causes and consequences of DOHaD in pigs, both for meat production and as a well-recognized model for biomedicine research.

Early-postnatal changes in adiposity and lipids profile by transgenerational developmental programming in swine with obesity/leptin resistance

Maternal malnutrition during pregnancy, both deficiency and excess, induces changes in the intrauterine environment and the metabolic status of the offspring, playing a key role in the growth, status of fitness/obesity and appearance of metabolic disorders during postnatal life. There is increasing evidence that these effects may not be only limited to the first generation of descendants, the offspring directly exposed to metabolic challenges, but to subsequent generations. This study evaluated, in a swine model of obesity/leptin resistance, the existence and extent of transgenerational developmental programming effects. Pre- and postnatal development, adiposity and metabolic features were assessed in the second generation of piglets, descendant of sows exposed to either undernutrition or overnutrition during pregnancy. The results indicated that these piglets exhibited early-postnatal increases in adiposity and disturbances in lipid profiles compatible with the early prodrome of metabolic syndrome, with liver tissue also displaying evidence of paediatric liver disease. These features indicative of early-life metabolic disorders were more evident in the males that were descended from overfed grandmothers and during the transition from milk to solid feeding. Thus, this study provides evidence supporting transgenerational developmental programming and supports the necessity for the development of strategies for avoiding the current epidemics of childhood overweight and obesity.

Influence of age at first lambing on reproductive and productive performance of Lacaune dairy sheep under an intensive management system.

The present study investigated the effect of age at first lambing (AFL) on the performance of Lacaune sheep under intensive management conditions. Records from 3088 maiden sheep from one farm, for the period 2005-2010, were classified into four experimental groups: group E (early) ewes with AFL ⩽390 d; group M (middle) with AFL of 391-450 d; group L (late) with AFL of 451-510 d; and group A (aged) with AFL ⩾511 d. The higher the number of lactations, the lower were the yield/lactation and yield/Day in Milk. Ewes from group M up to 450 days old lambed 0.2 times more often and had 0.25 more lactations than the ewes from group L; in addition, the former group lambed 0.5 times more often and had 0.49 more lactations than ewes from group A. Group A had the lowest yield per lifetime; the yield followed the sequence: group E (1032 l) >group M (1051 l) >group L (989 l) > group A (859 l) (P<0.0001). Yield/lactation was affected by AFL during the first three lactations (P<0.05). Group E produced significantly less milk in the first lactation than ewes from groups M, L and A. AFL correlated negatively with the number of lactations in life (r= -0.26; P<0.0001) and with total milk yield (r= -209; P<0.0001). The productive performance between the ewes that reached puberty early (n=404) or late (n=2684) in life were different (P<0.0001) with the early sheep having a lower total milk yield (591 v. 1073 l, P<0.0001). In conclusion, the current study indicates that the optimal AFL for the Lacaune breed under an intensive dairy system is between 390 and 450 d. Ewes with AFL earlier than 390 d or later than 450 d are likely to have a shorter productive life and a lower lifetime milk production.

Fertility in a high-altitude environment is compromised by luteal dysfunction: the relative roles of hypoxia and oxidative stress

BackgroundAt high altitudes, hypoxia, oxidative stress or both compromise sheep fertility. In the present work, we tested the relative effect of short- or long-term exposure to high altitude hypobaric hypoxia and oxidative stress on corpora luteal structure and function.MethodsThe growth dynamics of the corpora lutea during the estrous cycle were studied daily by ultrasonography in cycling sheep that were either native or naïve to high-altitude conditions and that were supplemented or not supplemented with antioxidant vitamins. Arterial and venous blood samples were simultaneously drawn for determination of gases and oxidative stress biomarkers and progesterone measurement. On day five after ovulation in the next cycle, the ovaries were removed for immunodetection of luteal HIF-1alpha and VEGF and IGF-I and to detect IGF-II gene expression.ResultsThe results showed that both short- and long-term exposure to high-altitude conditions decreased luteal growth and IGF-I and IGF-II gene expression but increased HIF-1 alpha and VEGF immunoexpression. The level of plasma progesterone was also increased at a high altitude, although an association with increased corpus luteum vascularization was only found in sheep native to a high-altitude location. Administration of antioxidant vitamins resulted in a limited effect, which was restricted to decreased expression of oxidative stress biomarkers and luteal HIF-1alpha and VEGF immunoexpression.ConclusionsExposure of the sheep to high-altitude hypobaric hypoxia for short or long time periods affects the development and function of the corpus luteum. Moreover, the observed association of oxidative stress with hypoxia and the absence of any significant effect of antioxidant vitamins on most anatomical and functional corpus luteum traits suggests that the effects of high altitude on this ovarian structure are mainly mediated by hypoxia. Thus, these findings may help explain the decrease in sheep fertility at a high altitude.