Changes in the maternal nutritional environment during fetal development can influence offspring's metabolic risk in later life. Animal models have demonstrated that offspring of diet-induced obese ...dams develop metabolic complications, including nonalcoholic fatty liver disease. In this study we investigated the mechanisms in young offspring that lead to the development of nonalcoholic fatty liver disease (NAFLD). Female offspring of C57BL/6J dams fed either a control or obesogenic diet were studied at 8 wk of age. We investigated the roles of oxidative stress and lipid metabolism in contributing to fatty liver in offspring. There were no differences in body weight or adiposity at 8 wk of age; however, offspring of obese dams were hyperinsulinemic. Oxidative damage markers were significantly increased in their livers, with reduced levels of the antioxidant enzyme glutathione peroxidase-1. Mitochondrial complex I and II activities were elevated, while levels of mitochondrial cytochrome c were significantly reduced and glutamate dehydrogenase was significantly increased, suggesting mitochondrial dysfunction. Offspring of obese dams also had significantly greater hepatic lipid content, associated with increased levels of PPARγ and reduced triglyceride lipase. Liver glycogen and protein content were concomitantly reduced in offspring of obese dams. In conclusion, offspring of diet-induced obese dams have disrupted liver metabolism and develop NAFLD prior to any differences in body weight or body composition. Oxidative stress may play a mechanistic role in the progression of fatty liver in these offspring.
Low birth weight and accelerated postnatal growth lead to increased risk of cardiovascular disease. We reported previously that rats exposed to a low‐protein diet in utero and postnatal catch‐up ...growth (recuperated) develop metabolic dysfunction and have reduced life span. Here we explored the hypothesis that cardiac oxidative and nitrosative stress leading to DNA damage and accelerated cellular aging could contribute to these phenotypes. Recuperated animals had a low birth weight (P<0.001) but caught up in weight to controls during lactation. At weaning, recuperated cardiac tissue had increased (P<0.05) protein nitrotyrosination and DNA single‐stranded breaks. This condition was preceded by increased expression of DNA damage repair molecules 8‐oxoguanine‐DNA‐glycosylase‐1, nei‐endonuclease‐VIII‐like, X‐ray‐repair‐complementing‐defective‐repair‐1, and Nthl endonuclease III‐like‐1 on d 3. These differences were maintained on d 22 and became more pronounced in the case of 8‐oxoguanine‐DNA‐glycosylase‐1 and neiendonuclease‐VIII‐like. This was accompanied by increases in xanthine oxidase (P<0.001) and NADPH oxidase (P<0.05), major sources of reactive oxygen species (ROS). The detrimental effects of increased ROS in recuperated offspring may be exaggerated at 22 d by reductions (P<0.001) in the antioxidant enzymes perox‐iredoxin‐3 and CuZn‐superoxide‐dismutase. We conclude that poor fetal nutrition followed by accelerated postnatal growth results in increased cardiac nitrosative and oxidative‐stress and DNA damage, which could contribute to age‐associated disease risk.—TarryAdkins, J. L., Martin‐Gronert, M. S., Fernandez‐Twinn, D. S., Hargreaves, I., Alfaradhi, M. Z., Land, J. M., Aiken, C. E., Ozanne, S. E. Poor maternal nutrition followed by accelerated postnatal growth leads to alterations in DNA damage and repair, oxidative and nitrosative stress and oxidative defense capacity in rat heart. FASEB J. 27, 379–390 (2013). www.fasebj.org
Background & Aims Obesity induced, non-alcoholic fatty liver disease (NAFLD), is now the major cause in affluent countries, of the spectrum of steatosis-to-cirrhosis. Obesity and NAFLD rates in ...reproductive age women, and adolescents, are rising worldwide. Our hypothesis was that maternal obesity and lactation transmit to the offspring a pre-disposition to dysmetabolism, obesity and NAFLD. Methods Female mice were fed standard or obesogenic chow, before, throughout pregnancy, and during lactation. The critical developmental period was studied by cross-fostering offspring of lean and obese dams. Offspring were then weaned onto standard chow and studied at 3 months. Read-outs included markers of metabolic dysfunction, biochemical and histological indicators of NAFLD, induction of liver fibrogenesis, and activation of pro-fibrotic pathways. Mechanisms involved in programming a dysmetabolic and NAFLD phenotype were investigated by assaying breast milk components. Results Offspring of obese dams had a dysmetabolic, insulin resistant and NAFLD phenotype compared to offspring of lean dams. Offspring of lean dams that were suckled by obese dams showed an exaggerated dysmetabolic and NAFLD phenotype, with increased body weight, as well as increased levels of insulin, leptin, aspartate transaminase, interleukin-6, tumour necrosis factor-α, liver triglycerides, steatosis, hepatic fibrogenesis, renal norepinephrine, and liver α1-D plus β1-adrenoceptors, indicative of sympathetic nervous system activation. Obese dams also had raised breast milk leptin levels compared to lean dams. Conclusions Maternal obesity programs development of a dysmetabolic and NAFLD phenotype, which is critically dependent on the early postnatal period and possibly involving alteration of hypothalamic appetite nuclei signalling by maternal breast milk and neonatal adipose tissue derived, leptin.
Our aim was to determine the effect of exposure to maternal obesity or to maternal weight loss around conception on the programming of hepatic insulin signaling in the offspring. We used an embryo ...transfer model in sheep to investigate the effects of exposure to either maternal obesity or to weight loss in normal and obese mothers preceding and for 1 wk after conception on the expression of hepatic insulin‐signaling and gluconeogenic factors and key miRNAs involved in insulin signaling in the offspring. We found that exposure to maternal obesity resulted in increased hepatic miR‐29b (P<0.05), miR‐103 (P<0.01), and miR‐107 (P<0.05) expression, a decrease in IR (P<0.05), phopsho‐Akt (P<0.01), and phospho‐FoxO1 (P<0.01) abundance, and a paradoxical decrease in 11βHSD1 (P<0.05), PEPCK‐C (P<0.01), and PEPCK‐M (P<0.05) expression in lambs. These changes were ablated by a period of moderate dietary restriction imposed during the periconceptional period. Maternal dietary restriction alone also resulted in decreased abundance of a separate subset of hepatic insulin‐signaling molecules, namely, IRS1 (P<0.05), PDK1 (P<0.01), phospho‐PDK1 (P<0.05), and aPKCξ (P<0.05) and in decreased PEPCK‐C (P<0.01) and G6Pase (P<0.01) expression in the lamb. Our findings highlight the sensitivity of the epigenome to maternal nutrition around conception and the need for dietary interventions that maximize metabolic benefits and minimize metabolic costs for the next generation.—Nicholas, L. M., Rattanatray, L., MacLaughlin, S. M., Ozanne, S. E., Kleemann, D. O., Walker, S. K., Morrison, J. L., Zhang, S., Muhlhausler, B. S., Martin‐Gronert, M. S., McMillen, I. C., Differential effects of maternal obesity and weight loss in the periconceptional period on the epigenetic regulation of hepatic insulin‐signaling pathways in the offspring. FASEB J. 27, 3786–3796 (2013). www.fasebj.org
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 p85α (P = 0.018), p110β (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.
It is well established that low birth weight and accelerated postnatal growth increase the risk of liver dysfunction in later life. However, molecular mechanisms underlying such developmental ...programming are not well characterized, and potential intervention strategies are poorly defined.
We tested the hypotheses that poor maternal nutrition and accelerated postnatal growth would lead to increased hepatic fibrosis (a pathological marker of liver dysfunction) and that postnatal supplementation with the antioxidant coenzyme Q10 (CoQ10) would prevent this programmed phenotype.
A rat model of maternal protein restriction was used to generate low-birth-weight offspring that underwent accelerated postnatal growth (termed "recuperated"). These were compared with control rats. Offspring were weaned onto standard feed pellets with or without dietary CoQ10 (1 mg/kg body weight per day) supplementation. At 12 mo, hepatic fibrosis, indexes of inflammation, oxidative stress, and insulin signaling were measured by histology, Western blot, ELISA, and reverse transcriptase-polymerase chain reaction.
Hepatic collagen deposition (diameter of deposit) was greater in recuperated offspring (mean ± SEM: 12 ± 2 μm) than in controls (5 ± 0.5 μm) (P < 0.001). This was associated with greater inflammation (interleukin 6: 38% ± 24% increase; P < 0.05; tumor necrosis factor α: 64% ± 24% increase; P < 0.05), lipid peroxidation (4-hydroxynonenal, measured by ELISA: 0.30 ± 0.02 compared with 0.19 ± 0.05 μg/mL per μg protein; P < 0.05), and hyperinsulinemia (P < 0.05). CoQ10 supplementation increased (P < 0.01) hepatic CoQ10 concentrations and ameliorated liver fibrosis (P < 0.001), inflammation (P < 0.001), some measures of oxidative stress (P < 0.001), and hyperinsulinemia (P < 0.01).
Suboptimal in utero nutrition combined with accelerated postnatal catch-up growth caused more hepatic fibrosis in adulthood, which was associated with higher indexes of oxidative stress and inflammation and hyperinsulinemia. CoQ10 supplementation prevented liver fibrosis accompanied by downregulation of oxidative stress, inflammation, and hyperinsulinemia.
It is well established that there is a relationship between patterns of early growth and subsequent risk of development of metabolic diseases such as type 2 diabetes and cardiovascular disease. ...Studies in both humans and in animal models have provided strong evidence that the early environment plays an important role in mediating these relationships. The concept of the developmental origins of health and disease is therefore widely accepted. The mechanisms by which an event in very early life can have a permanent effect on the long-term health of an individual are still relatively poorly understood. However a growing body of evidence has implicated a number of candidate mechanisms. These include permanent changes in an organ structure, programmed changes in gene expression through epigenetic modifications and persistent effects on regulation of cellular ageing. Understanding the extent and nature of these processes may enable the identification of individuals at risk of metabolic disease as well as providing insight into potential preventative and intervention strategies.
Exposure to maternal obesity before and/or throughout pregnancy may increase the risk of obesity and insulin resistance in the offspring in childhood and adult life, therefore, resulting in its ...transmission into subsequent generations. We have previously shown that exposure to maternal obesity around the time of conception alone resulted in increased adiposity in female lambs. Changes in the abundance of insulin signalling molecules in skeletal muscle and adipose tissue precede the development of insulin resistance and type 2 diabetes. It is not clear, however, whether exposure to maternal obesity results in insulin resistance in her offspring as a consequence of the impact of increased adiposity on skeletal muscle or as a consequence of the programming of specific changes in the abundance of insulin signalling molecules in this tissue. We have used an embryo transfer model in the sheep to investigate the effects of exposure to either maternal obesity or to weight loss in normal and obese mothers preceding and for one week after conception on the expression and abundance of insulin signalling molecules in muscle in the offspring. We found that exposure to maternal obesity resulted in lower muscle GLUT-4 and Ser 9 phospho-GSK3α and higher muscle GSK3α abundance in lambs when compared to lambs conceived in normally nourished ewes. Exposure to maternal weight loss in normal or obese mothers, however, resulted in lower muscle IRS1, PI3K, p110β, aPKCζ, Thr 642 phospho-AS160 and GLUT-4 abundance in the offspring. In conclusion, maternal obesity or weight loss around conception have each programmed specific changes on subsets of molecules in the insulin signalling, glucose transport and glycogen synthesis pathways in offspring. There is a need for a stronger evidence base to ensure that weight loss regimes in obese women seeking to become pregnant minimize the metabolic costs for the next generation.
Low birth weight (LBW) is associated with increased future risk of insulin resistance and type 2 diabetes mellitus. The underlying molecular mechanisms remain poorly understood. We have previously ...shown that young LBW men have reduced skeletal muscle expression of PI3K p85alpha regulatory subunit and p110beta catalytic subunit, PKCzeta and GLUT4 in the fasting state. The aim of this study was to determine whether insulin activation of the PI3K/Akt and MAPK signalling pathways is altered in skeletal muscle of young adult men with LBW.
Vastus lateralis muscle biopsies were obtained from 20 healthy 19-yr old men with BW< or = 10th percentile for gestational age (LBW) and 20 normal birth weight controls (NBW), matched for physical fitness and whole-body glucose disposal, prior to (fasting state) and following a 4-hr hyperinsulinemic euglycemic clamp (insulin stimulated state). Expression and phosphorylation of selected proteins was determined by Western blotting.
Insulin stimulated expression of aPKCzeta (p<0.001) and Akt1 (p<0.001) was decreased in muscle of LBW men when compared to insulin stimulated controls. LBW was associated with increased insulin stimulated levels of IRS1 (p<0.05), PI3K p85alpha (p<0.001) and p110beta (p<0.05) subunits, while there was no significant change in these proteins in insulin stimulated control muscle. In addition LBW had reduced insulin stimulated phospho-Akt (Ser 473) (p<0.01), indicative of reduced Akt signalling. Insulin stimulated expression/phosphorylation of all the MAPK proteins studied p38 MAPK, phospho-p38 MAPK (Thr180/Tyr182), phospho-ERK (Thr 202/Tyr204), JNK1, JNK2 and phospho-JNK (Thr 183/Tyr185) was not different between groups.
We conclude that altered insulin activation of the PI3K/Akt but not the MAPK pathway precedes and may contribute to development of whole-body insulin resistance and type 2 diabetes in men with LBW.
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