Influences of pre- and postnatal nutritional exposures on vascular/endocrine systems in animals.

Human epidemiological and animal studies have revealed the long-term effects of malnutrition during gestation and early life on the health of the offspring. The aim of the current review is to survey the different means of achieving fetal malnutrition and its consequences, mainly in animals, and to identify key areas in which to direct future research. We address the impact of various models of a maternal protein-restricted diet and global maternal caloric restriction (either through the reduction of nutrient supply or through mechanic devices), the influence of maternal diabetes, and other maternal causes of fetal damage (maternal infections and toxic food components). More specifically, we enumerate data on how the different insults at different prenatal and early postnatal periods affect and program the development and the function of organs involved in diabetes, hypertension, and cardiovascular disease. Particular emphasis is given to the endocrine pancreas, but insulin-sensitive tissues, kidneys, and vasculature are also analyzed. Where available, the protective effects of maternal food supplementation for fetal organ development and function are discussed. Specific attention is paid to the amino acids profile, and the preventive role of taurine is discussed. Tentative indications about critical time windows for fetal development under different deleterious conditions are presented whenever possible. We also discuss future research and intervention

A mouse model of gestational diabetes shows dysregulated lipid metabolism post-weaning, after return to euglycaemia

Background: Gestational diabetes is associated with increased risk of type 2 diabetes mellitus and cardiovascular disease for the mother in the decade after delivery. However, the molecular mechanisms that drive these effects are unknown. Recent studies in humans have shown that lipid metabolism is dysregulated before diagnosis of and during gestational diabetes and we have shown previously that lipid metabolism is also altered in obese female mice before, during and after pregnancy. These observations led us to the hypothesis that this persistent dysregulation reflects an altered control of lipid distribution throughout the organism.Methods: We tested this in post-weaning (PW) dams using our established mouse model of obese GDM (high fat, high sugar, obesogenic diet) and an updated purpose-built computational tool for plotting the distribution of lipid variables throughout the maternal system (Lipid Traffic Analysis v2.3).Results: This network analysis showed that unlike hyperglycaemia, lipid distribution and traffic do not return to normal after pregnancy in obese mouse dams. A greater range of phosphatidylcholines was found throughout the lean compared to obese post-weaning dams. A range of triglycerides that were found in the hearts of lean post-weaning dams were only found in the livers of obese post-weaning dams and the abundance of odd-chain FA-containing lipids differed locally in the two groups. We have therefore shown that the control of lipid distribution changed for several metabolic pathways, with evidence for changes to the regulation of phospholipid biosynthesis and FA distribution, in a number of tissues.Conclusions: We conclude that the control of lipid metabolism is altered following an obese pregnancy. These results support the hypothesis that obese dams that developed GDM maintain dysregulated lipid metabolism after pregnancy even when glycaemia returned to normal, and that these alterations could contribute to the increased risk of later type 2 diabetes and cardiovascular disease

Early nutrition and ageing: can we intervene?

Ageing, a complex process that results in progressive decline in intrinsic physiological function leading to an increase in mortality rate, has been shown to be affected by early life nutrition. Accumulating data from animal and epidemiological studies indicate that exposure to a suboptimal nutritional environment during fetal life can have long-term effects on adult health. In this paper, we discuss the impact of early life nutrition on the development of age-associated diseases and life span. Special emphasis is given to studies that have investigated the molecular mechanisms underlying these effects. These include permanent structural and cellular changes including epigenetics modifications, oxidative stress, DNA damage and telomere shortening. Potential strategies targeting these mechanisms, in order to prevent or alleviate the detrimental effects of suboptimal early nutrition on lifespan and age-related diseases, are also discussed. Although recent reports have already identified effective therapeutic interventions, such as antioxidant supplementation, further understanding of the extent and nature of how early nutrition influences the ageing process will enable the development of novel and more effective approaches to improve health and extend human lifespan in the future.The British Heart Foundation (PG/14/20/30769), the São Paulo Research Foundation (2014/20380-5) and the Medical Research Council (MC_UU_12012/4) supported this work

Cell-autonomous programming of rat adipose tissue insulin signalling proteins by maternal nutrition.

AIMS/HYPOTHESIS: Individuals with a low birthweight have an increased risk of developing type 2 diabetes mellitus in adulthood. This is associated with peripheral insulin resistance. Here, we aimed to determine whether changes in insulin signalling proteins in white adipose tissue (WAT) can be detected prior to the onset of impaired glucose tolerance, determine whether these changes are cell-autonomous and identify the underlying mechanisms involved. METHODS: Fourteen-month-old male rat offspring born to dams fed a standard protein (20%) diet or a low (8%) protein diet throughout gestation and lactation were studied. Fat distribution and adipocyte size were determined. Protein content and mRNA expression of key insulin signalling molecules were analysed in epididymal WAT and in pre-adipocytes that had undergone in vitro differentiation. RESULTS: The offspring of low protein fed dams (LP offspring) had reduced visceral WAT mass, altered fat distribution and a higher percentage of small adipocytes in epididymal WAT. This was associated with reduced levels of IRS1, PI3K p110β, Akt1 and PKCζ proteins and of phospho-Akt Ser473. Corresponding mRNA transcript levels were unchanged. Similarly, in vitro differentiated adipocytes from LP offspring showed reduced protein levels of IRβ, IRS1, PI3K p85α and p110β subunits, and Akt1. Levels of Akt Ser473 and IRS1 Tyr612 phosphorylation were reduced, while IRS1 Ser307 phosphorylation was increased. CONCLUSIONS/INTERPRETATION: Maternal protein restriction during gestation and lactation changes the distribution and morphology of WAT and reduces the levels of key insulin signalling proteins in the male offspring. This phenotype is retained in in vitro differentiated adipocytes, suggesting that programming occurs via cell-autonomous mechanism(s).This work was supported by Diabetes UK (MSM-G; no. 12/0004508), the British Heart Foundation (SEO; no. FS/09/029/27902) and the UK Medical Research Council (SEO; no. MC_UU_12012/4)This is the accepted manuscript. It is currently embargoed pending publication

Lipid Metabolism Is Dysregulated before, during and after Pregnancy in a Mouse Model of Gestational Diabetes.

The aim of the current study was to test the hypothesis that maternal lipid metabolism was modulated during normal pregnancy and that these modulations are altered in gestational diabetes mellitus (GDM). We tested this hypothesis using an established mouse model of diet-induced obesity with pregnancy-associated loss of glucose tolerance and a novel lipid analysis tool, Lipid Traffic Analysis, that uses the temporal distribution of lipids to identify differences in the control of lipid metabolism through a time course. Our results suggest that the start of pregnancy is associated with several changes in lipid metabolism, including fewer variables associated with de novo lipogenesis and fewer PUFA-containing lipids in the circulation. Several of the changes in lipid metabolism in healthy pregnancies were less apparent or occurred later in dams who developed GDM. Some changes in maternal lipid metabolism in the obese-GDM group were so late as to only occur as the control dams' systems began to switch back towards the non-pregnant state. These results demonstrate that lipid metabolism is modulated in healthy pregnancy and the timing of these changes is altered in GDM pregnancies. These findings raise important questions about how lipid metabolism contributes to changes in metabolism during healthy pregnancies. Furthermore, as alterations in the lipidome are present before the loss of glucose tolerance, they could contribute to the development of GDM mechanistically

Maternal protein restriction affects postnatal growth and the expression of key proteins involved in lifespan regulation in mice.

We previously reported that maternal protein restriction in rodents influenced the rate of growth in early life and ultimately affected longevity. Low birth weight caused by maternal protein restriction followed by catch-up growth (recuperated animals) was associated with shortened lifespan whereas protein restriction and slow growth during lactation (postnatal low protein: PLP animals) increased lifespan. We aim to explore the mechanistic basis by which these differences arise. Here we investigated effects of maternal diet on organ growth, metabolic parameters and the expression of insulin/IGF1 signalling proteins and Sirt1 in muscle of male mice at weaning. PLP mice which experienced protein restriction during lactation had lower fasting glucose (P = 0.038) and insulin levels (P = 0.046) suggesting improved insulin sensitivity. PLP mice had higher relative weights (adjusted by body weight) of brain (P = 0.0002) and thymus (P = 0.031) compared to controls suggesting that enhanced functional capacity of these two tissues is beneficial to longevity. They also had increased expression of insulin receptor substrate 1 (P = 0.021) and protein kinase C zeta (P = 0.046). Recuperated animals expressed decreased levels of many insulin signalling proteins including PI3 kinase subunits p85alpha (P = 0.018), p110beta (P = 0.048) and protein kinase C zeta (P = 0.006) which may predispose these animals to insulin resistance. Sirt1 protein expression was reduced in recuperated offspring. These observations suggest that maternal protein restriction can affect major metabolic pathways implicated in regulation of lifespan at a young age which may explain the impact of maternal diet on longevity

Intrauterine programming of obesity and type 2 diabetes

Abstract: The type 2 diabetes epidemic and one of its predisposing factors, obesity, are major influences on global health and economic burden. It is accepted that genetics and the current environment contribute to this epidemic; however, in the last two decades, both human and animal studies have consolidated considerable evidence supporting the ‘developmental programming’ of these conditions, specifically by the intrauterine environment. Here, we review the various in utero exposures that are linked to offspring obesity and diabetes in later life, including epidemiological insights gained from natural historical events, such as the Dutch Hunger Winter, the Chinese famine and the more recent Quebec Ice Storm. We also describe the effects of gestational exposure to endocrine disruptors, maternal infection and smoking to the fetus in relation to metabolic programming. Causal evidence from animal studies, motivated by human observations, is also discussed, as well as some of the proposed underlying molecular mechanisms for developmental programming of obesity and type 2 diabetes, including epigenetics (e.g. DNA methylation and histone modifications) and microRNA interactions. Finally, we examine the effects of non-pharmacological interventions, such as improving maternal dietary habits and/or increasing physical activity, on the offspring epigenome and metabolic outcomes

Exploring Telomere Dynamics in Aging Male Rat Tissues: Can Tissue-Specific Differences Contribute to Age-Associated Pathologies?

INTRODUCTION: Due to increasing lifespan, global aging rates are rising rapidly and age-associated diseases are increasing. To ensure that health span is concomitant with life span, a greater understanding of cellular mechanisms of aging is important. METHODS: Telomere length analysis from a wide range of tissues from weaning, young adult, and middle-aged (3, 12 and 52 week) male Wistar rats were conducted using Southern blotting. Telomere lengths were compared between tissues and ages using regression models based on the ratios of longest-to-shortest telomere fragments. RESULTS: Robust linear age-dependent telomere attrition was observed in the liver; 3 versus 12 weeks, 3 versus 52 weeks (p < 0.01), 12 versus 52 weeks (p < 0.05) and the heart; 3 versus 12 weeks (p < 0.05) and 3 versus 52 weeks (p < 0.001). More subtle shortening was observed in aorta and epididymal fat; 3 and 12 versus 52 weeks (p < 0.001) and in skeletal muscle; 3 versus 52 weeks (p < 0.05), 12 versus 52 weeks (p < 0.01). Young thymus telomeres increased in length (3 vs. 12 weeks) and then shortened between 12 and 52 weeks (p < 0.001). We also reported disparity in telomere shortening within tissues: telomeres in aging brain cortex significantly shortened; 3 versus 52 weeks (p < 0.05), 12 versus 52 weeks (p < 0.01). This was not seen in the hypothalamic region. A robust stepwise shortening was observed in the renal cortex; 3 versus 12 weeks, 12 versus 52 weeks (p < 0.05), and 3 versus 52 weeks (p < 0.001), which was not as apparent in the renal medulla; 3 versus 12 weeks (p < 0.01) and 3 versus 52 weeks (p < 0.01). The vastus lateralis skeletal muscle demonstrated the shortest telomere length at weaning and underwent robust age-associated attrition; 3 versus 52 weeks (p < 0.05), 12 versus 52 weeks (p < 0.01). We demonstrated that specific tissues exhibit unique telomere attrition profiles which may partially explain why certain diseases are more prevalent in aged individuals. DISCUSSION/CONCLUSION: We show wide variations between tissues in vulnerability to the aging process. In the future, this may help target potential interventions to improve health span