Extensive epidemiological and experimental evidence indicates that a sub-optimal environment during fetal and neonatal development in both humans and animals may programme offspring susceptibility to later development of chronic diseases including obesity and diabetes that are the result of altered carbohydrate metabolism. We determined the effects of protein restriction during pregnancy and/or lactation on growth, serum leptin, and glucose and insulin responses to a glucose tolerance test in male and female offspring at 110 days postnatal life. We fed Wistar rats a normal control 20% casein diet (C) or a restricted diet (R) of 10% casein during pregnancy. Female but not male R pups weighed less than C at birth. After delivery, mothers received the C or R diet during lactation to provide four offspring groups: CC (first letter maternal pregnancy diet and second maternal lactation diet), RR, CR and RC. All offspring were fed ad libitum with C diet after weaning. Relative food intake correlated inversely with weight. Offspring serum leptin correlated with body weight and relative, but not absolute, food intake in both male and female pups. Serum leptin was reduced in RR female pups compared with CC and increased in RC males compared with CC at 110 days of age. Offspring underwent a glucose tolerance test (GTT) at 110 days postnatal life. Female RR and CR offspring showed a lower insulin to glucose ratio than CC. At 110 days of age male RR and CR also showed some evidence of increased insulin sensitivity. Male but not female RC offspring showed evidence of insulin resistance compared with CC. Cholesterol was similar and triglycerides (TG) higher in male compared with female CC. Cholesterol and TG were higher in males than females in RR, CR and RC (P < 0.05). Cholesterol and TG did not differ between groups in females. Cholesterol and TG were elevated in RC compared with CC males. Nutrient restriction in lactation increased relative whole protein and decreased whole lipid in both males and females. RC females showed decreased relative levels of protein and increased fat. We conclude that maternal protein restriction during either pregnancy and/or lactation alters postnatal growth, appetitive behaviour, leptin physiology, TG and cholesterol concentrations and modifies glucose metabolism and insulin resistance in a sexand time window of exposure-specific manner.

Compelling epidemiological and experimental evidence indicates that a suboptimal environment during fetal and neonatal development in both humans and animals may programme offspring susceptibility to later development of several chronic diseases including obesity and diabetes in which altered carbohydrate metabolism plays a central role. One of the most interesting and significant features of developmental programming is the evidence from several studies that the adverse consequences of altered intrauterine environments can be passed transgenerationally from mother (F 0 ) to daughter (F 1 ) to second generation offspring (F 2 ). We determined whether when F 0 female rats are exposed to protein restriction during pregnancy and/or lactation their F 1 female pups deliver F 2 offspring with in vivo evidence of altered glucose and insulin metabolism. We fed F 0 virgin Wistar rats a normal control 20% casein diet (C) or a protein restricted isocaloric diet (R) containing 10% casein during pregnancy. F 1 female R pups weighed less than C at birth. After delivery, mothers received C or R diet during lactation to provide four F 1 offspring groups CC (first letter pregnancy diet and second lactation diet), RR, CR and RC. All F 1 female offspring were fed ad libitum with C diet after weaning and during their first pregnancy and lactation. As they grew female offspring (F 1 ) of RR and CR mothers exhibited low body weight and food intake with increased sensitivity to insulin during a glucose tolerance test at 110 days of postnatal life. Male F 2 CR offspring showed evidence of insulin resistance. In contrast RC F 2 females showed evidence of insulin resistance. Sex differences were also observed in F 2 offspring in resting glucose and insulin and insulin : glucose ratios. These sex differences also showed differences specific to stage of development time window. We conclude that maternal protein restriction adversely affects glucose and insulin metabolism of male and female F 2 offspring in a manner specific to sex and developmental time window during their mother's (the F 1 ) fetal and neonatal development.

BACKGROUNDMaternal obesity (MO) impairs maternal and offspring health. Mechanisms and interventions to prevent adverse maternal and offspring outcomes need to be determined. Human studies are confounded by socio-economic status providing the rationale for controlled animal data on effects of maternal exercise (MEx) intervention on maternal (F0) and offspring (F1) outcomes in MO.HYPOTHESISMO produces metabolic and endocrine dysfunction, increases maternal and offspring glucocorticoid exposure, oxidative stress and adverse offspring outcomes by postnatal day (PND) 36. MEx prevents these outcomes.METHODSF0 female rats ate either control or obesogenic diet from weaning through lactation. Half of each group wheel ran (from day ninety of life through pregnancy beginning day 120) providing four groups (n=8/group) – i) controls, ii) obese, iii) exercised controls and iv) exercised obese. After weaning, PND 21, F1 offspring ate a control diet. Metabolic parameters of F0 prepregnancy and end of lactation and F1 offspring at PND 36 were analyzed.RESULTSExercise did not change maternal weight. Before breeding, MO elevated F0 glucose, insulin, triglycerides, cholesterol, leptin, fat and oxidative stress. Exercise completely prevented the triglyceride rise and partially glucose, insulin, cholesterol and oxidative stress increases. MO decreased fertility, recovered by exercise. At the end of lactation, exercise returned all metabolic variables except leptin to control levels. Exercise partially prevented MO elevated corticosterone. F1 Offspring weights were similar at birth. At PND 36 MO increased F1 male but not female offspring leptin, triglycerides and fat mass. In controls exercise reduced male and female offspring glucose, prevented the offspring leptin increase and partially the triglyceride rise.CONCLUSIONSMEx before and during pregnancy has beneficial effects on maternal and offspring metabolism and endocrine function occurring with no weight change in mothers and offspring indicating the importance of body composition rather than weight in evaluations of metabolic status.

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The first human use of endovenous cyanoacrylate for closure of insufficient great saphenous veins proved to be feasible, safe and effective. Clinical efficacy was maintained over a period of 24 months.

Maternal obesity (MO) predisposes offspring (F1) to obesity, insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). MO's effects on the F1 liver transcriptome are poorly understood. We used RNA-seq to determine the liver transcriptome of male and female F1 of MO and control-fed mothers. We hypothesized that MO-F1 are predisposed to sex-dependent adult liver dysfunction. Female Wistar rat mothers ate a control (C) or obesogenic (MO) diet from the time they were weaned through breeding at postnatal day (PND) 120, delivery and lactation. After weaning, all male and female F1 ate a control diet. At PND 110, F1 serum, liver and fat were collected to analyse metabolites, histology and liver differentially expressed genes. Male and female MO-F1 showed increased adiposity index, triglycerides, insulin and homeostatic model assessment vs. C-F1 with similar body weight and glucose serum concentrations. MO-F1 males presented greater physiological and histological NAFLD characteristics than MO-F1 females. RNA-seq revealed 1365 genes significantly changed in male MO-F1 liver and only 70 genes in female MO-F1 compared with controls. GO and KEGG analysis identified differentially expressed genes related to metabolic processes. Male MO-F1 liver showed the following altered pathways: insulin signalling (22 genes), phospholipase D signalling (14 genes), NAFLD (13 genes) and glycolysis/gluconeogenesis (7 genes). In contrast, few genes were altered in these pathways in MO-F1 females. In summary, MO programs sex-dependent F1 changes in insulin, glucose and lipid signalling pathways, leading to liver dysfunction and insulin resistance.

Key pointsr Maternal protein restriction during pregnancy increases both maternal and offspring oxidative stress and leads to metabolic dysfunction.r Maternal low protein diet during pregnancy increases maternal and offspring corticosterone. r Resveratrol administration partially prevents both maternal and offspring adverse outcomes induced by maternal protein restriction during pregnancy.Abstract Protein restriction in pregnancy produces maternal and offspring metabolic dysfunction potentially as a result of oxidative stress. Data are lacking on the effects of inhibition of oxidative stress. We hypothesized that maternal resveratrol administration decreases oxidative stress, preventing, at least partially, maternal low protein-induced maternal and offspring metabolic dysfunction. In the present study, pregnant wistar rats ate control (C) (20% casein) or a protein-restricted (R) (10% casein) isocaloric diet. Half of each group received resveratrol orally, 20 mg kg −1 day −1 , throughout pregnancy. Post-delivery, mothers and offspring ate C. Oxidative stress biomarkers and anti-oxidant enzymes were measured in placenta, maternal and fetal liver, and maternal serum corticosterone at 19 days of gestation (dG). Maternal (19 dG) and offspring (postnatal day 110) glucose, insulin, triglycerides, cholesterol, fat and leptin were determined. R mothers showed metabolic dysfunction, increased corticosterone and oxidative stress and reduced anti-oxidant enzyme activity vs. C. R placental and fetal liver oxidative stress biomarkers and anti-oxidant enzyme activity increased. R offspring showed higher male and female leptin, insulin and corticosterone, male triglycerides and female fat than C. Resveratrol decreased maternal leptin and improved maternal, fetal and placental oxidative stress markers. R induced offspring insulin and leptin increases were prevented and other R changes were offspring sex-dependent. Resveratrol partially prevents low protein diet-induced maternal, placental and sex-specific offspring oxidative stress and metabolic dysfunction. Oxidative stress is one mechanism programming offspring metabolic outcomes. These studies provide mechanistic evidence to guide human pregnancy interventions when fetal nutrition is impaired by poor maternal nutrition or placental function.

Suboptimal developmental environments program offspring to lifelong metabolic problems. We evaluated effects of maternal isocaloric low protein diet during pregnancy and/or lactation on milk quantity and leptin concentration at postnatal day 7, 14, and 21. Control mothers ate 20% casein (C) and restricted mothers (R) 10% casein to provide four groups: CC, RR, CR, and RC (first letter pregnancy and second lactation diet) to enable evaluation of effects influenced by maternal diet during pregnancy and lactation. Milk leptin was not a determinant of pup serum leptin. Pup serum leptin did not inhibit milk appetite at any postnatal age. Pup serum leptin did not correlate with pup adipose tissue. Finally, the normal postnatal leptin rise in pup serum was delayed by prenatal undernutrition. These data suggest that fetal nutrition modifies timing of neonatal leptin surge and may contribute to the development of altered appetite and metabolic disorders in later life. H uman epidemiologic (1) and experimental animal studies (2) have shown that suboptimal environments in the womb and during early neonatal life alter growth and predispose individuals to lifelong health problems. Effects of maternal nutrient restriction during pregnancy and/or lactation have been studied in many different models. A variety of growth, endocrine and cardiovascular phenotypes result from nutrient restriction in different developmental windows. Perinatal malnutrition predisposes to offspring obesity in adulthood by changes during the development of central neural pathways mediated by regulatory mechanisms including leptin (3). Rapid catch-up growth after early growth restriction increases the risk of developing obesity and cardiovascular disease in later life (4,5).One of the most important neonatal factors involved in developmental programming is the adequacy of nutrition during the lactation period. Breast feeding decreases the risk of obesity in later childhood (6). Many factors including maternal milk composition, energy content, and quantity may influence future appetite control. Breast milk contains leptin (7) a hormone produced and secreted in a variety of tissues, predominantly by adipocytes (8) which regulates food intake and energy expenditure at the hypothalamic level in adult animals (8,9). Circulating levels of leptin correlate positively with the amount of fat stores (10). During the first days of postnatal life, leptin levels are higher than those observed later in development (11). Several studies have demonstrated a surge of leptin around postnatal days (PND) 10 -14 in the rat (11). This surge has been correlated with maturation of the central nervous mechanisms that regulate appetite in later life. Leptin also seems to play a key role in programming the structural and functional development of hypothalamic orixigenic and anorexigenic centers in the early postnatal period.We have demonstrated that maternal protein restriction in the rat during either pregnancy or lactation alters postnatal growth, appetitive behavior, ...