Fish oil (FO) supplements are consumed during pregnancy to increase dietary omega-3. However, FO is often oxidized past recommended limits. In rats, a large dose of highly oxidized FO substantially increased newborn mortality, but the... more
Fish oil (FO) supplements are consumed during pregnancy to increase dietary omega-3. However, FO is often oxidized past recommended limits. In rats, a large dose of highly oxidized FO substantially increased newborn mortality, but the effects of human-relevant doses of less oxidized oil are unknown. A dose-response study in rats was conducted to estimate the safe level of oxidation during pregnancy. Sprague-Dawley rat dams were mated, then individually housed and provided with a gel treatment on each day of pregnancy. Treatment groups differed only in the FO content of the gel; control (no oil), PV5, PV10, and PV40 [0.05 mL of FO oxidized to a peroxide value (PV) of 5, 10, or 40 meq/kg], or PV40(1 mL) (1 mL of PV40). A subset of dams was culled on gestational day 20 to enable sampling, and the remainder were allowed to give birth. Newborn mortality was recorded. Offspring were sampled on postnatal days 2 and 21, and dams on day 21. There were no signs of unwellness during pregnancy. However, there was markedly increased neonatal mortality affecting the PV40(1 mL) (12.8%) and PV40 (6.3%) groups, but not the control, PV5, or PV10 groups (1%–1.4%). Dietary-oxidized FO altered the expression of placental genes involved in antioxidant pathways and the production of free radicals. Highly oxidized FO was toxic in rat pregnancy leading to a marked increase in mortality even at a human-relevant dose. We observed no toxic effects of FOs with PV ≤10 meq/kg, suggesting that this is an appropriate maximum limit.
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Epidemiological observations and work in experimental models in animals have highlighted the link between the nutritional environment in early life and an increased risk for offspring to develop a range of cardiometabolic and reproductive... more
Epidemiological observations and work in experimental models in animals have highlighted the link between the nutritional environment in early life and an increased risk for offspring to develop a range of cardiometabolic and reproductive disorders in later life. This framework falls under the “Developmental Origins of Health and Disease” (DOHaD) hypothesis via a process termed developmental programming. Altered maternal nutrition, including undernutrition, overnutrition and specific micronutrient deficiencies during critical early windows of developmental plasticity, results in adaptive processes that confer short-term survival advantages but can lead to lifelong adverse impacts on the health of offspring. These effects are amplified postnatally via an obesogenic diet and sedentary behaviour and can also be passed on to future generations. The mechanistic basis of early-life programming remains largely undefined. However, involvement of epigenetic mechanisms, such as altered DNA methylation, histone modifications and miRNAs, has been implicated in addition to permanent structural changes during organ development. Further, at least in animal models, aberrant developmental programming can be reversed via targeted nutritional supplementation during early life, albeit in a sex-specific manner. A better understanding of early nutritional programming and how disease traits are transmitted across future generations is essential for the development of preventative strategies aimed at addressing the current health crisis around obesity and related metabolic disorders.
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An adverse early life environment is associated with increased cardiovascular disease in offspring. Work in animal models has shown that maternal undernutrition (UN) during pregnancy leads to hypertension in adult offspring, with effects... more
An adverse early life environment is associated with increased cardiovascular disease in offspring. Work in animal models has shown that maternal undernutrition (UN) during pregnancy leads to hypertension in adult offspring, with effects thought to be mediated in part via altered renal function. We have previously shown that growth hormone (GH) treatment of UN offspring during the pre-weaning period can prevent the later development of cardiometabolic disorders. However, the mechanistic basis for these observations is not well defined. The present study examined the impact of GH treatment on renal inflammatory markers in adult male offspring as a potential mediator of these reversal effects. Female Sprague-Dawley rats were fed either a chow diet fed ad libitum (CON) or at 50% of CON intake (UN) during pregnancy. All dams were fed the chow diet ad libitum during lactation. CON and UN pups received saline (CON-S/UN-S) or GH (2.5 µg/g/day; CON-GH/UN-GH) from postnatal day 3 until weaning (p21). Post-weaning males were fed a standard chow diet for the remainder of the study (150 days). Histological analysis was performed to examine renal morphological characteristics, and gene expression of inflammatory and vascular markers were assessed. There was evidence of renal hypotrophy and reduced nephron number in the UN-S group. Tumour necrosis factor-α, monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecular-1 and vascular cell adhesion molecule-1 gene expression was increased in UN-S offspring and normalized in the UN-GH group. These findings indicate that pre-weaning GH treatment has the potential to normalize some of the adverse renal and cardiovascular sequelae that arise as a consequence of poor maternal nutrition.
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Research Interests: Endocrinology, Biology, Cytokines, Inflammation, Lactation, and 15 moreMedicine, Signal Transduction, Biological Sciences, Pregnancy, Internal Medicine, Female, Animals, Body Composition, Male, Offspring, Conjugated linoleic acid, Gene Expression Regulation, Medical and Health Sciences, Inflammation Mediators, and Maternal Nutritional Physiological Phenomena
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Obesity is a global epidemic, affecting both developed and developing countries. The related metabolic consequences that arise from being overweight or obese are a paramount global health concern, and represent a significant burden on... more
Obesity is a global epidemic, affecting both developed and developing countries. The related metabolic consequences that arise from being overweight or obese are a paramount global health concern, and represent a significant burden on healthcare systems. Furthermore, being overweight or obese during pregnancy increases the risk of offspring developing obesity and other related metabolic complications in later life, which can therefore perpetuate a transgenerational cycle of obesity. Obesity is associated with a chronic state of low-grade metabolic inflammation. However, the role of maternal obesity-mediated alterations in inflammatory processes as a mechanism underpinning developmental programming in offspring is less understood. Further, the use of anti-inflammatory agents as an intervention strategy to ameliorate or reverse the impact of adverse developmental programming in the setting of maternal obesity has not been well studied. This review will discuss the impact of maternal obesity on key inflammatory pathways, impact on pregnancy and offspring outcomes, potential mechanisms and avenues for intervention.
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It has now well established that alterations in the environment during early life development can have effects on the health of the offspring across the lifecourse and evidence for transmission of these adverse disease traits to future... more
It has now well established that alterations in the environment during early life development can have effects on the health of the offspring across the lifecourse and evidence for transmission of these adverse disease traits to future generations. A key component underpinning this early life developmental programming is that of dysregulation of the growth hormone-insulin-like growth factor (GH-IGF) axis. Phenotypic outcomes in programmed offspring closely resemble those associated with GH deficiency (GHD), including increased fat mass, altered insulin sensitivity and cardiovascular disorders. The GH-IGF axis plays a key developmental role in essentially all tissues and organs and work across a wide range of animal models has suggested that manipulation of this axis in the early life period can ameliorate the effects of adverse developmental programming, albeit in a sex-specific manner. Further understanding of how different exposures in the early life period, including altered nutrition, impact upon this axis is essential to define translatable strategies to reverse the consequences of early life adversity and improve health outcomes across the lifecourse.
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ABSTRACT
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The experimental evidence for fetal programming of obesity, nutritional programming, postnatal nutrition, early origins of the metabolic syndrome, mechanisms underlying the programming of adult disease, and programming of the adipoinsular... more
The experimental evidence for fetal programming of obesity, nutritional programming, postnatal nutrition, early origins of the metabolic syndrome, mechanisms underlying the programming of adult disease, and programming of the adipoinsular axis and altered adipogenesis are discussed.
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Background: Over half of women of reproductive age are now overweight or obese. The impact of maternal high-fat diet (HFD) is emerging as an important factor in the development and health of musculoskeletal tissues in offspring, however... more
Background: Over half of women of reproductive age are now overweight or obese. The impact of maternal high-fat diet (HFD) is emerging as an important factor in the development and health of musculoskeletal tissues in offspring, however there is a paucity of evidence examining its effects on tendon. Alterations in the early life environment during critical periods of tendon growth therefore have the potential to influence tendon health that cross the lifespan. We hypothesised that a maternal HFD would alter biomechanical, morphological and gene expression profiles of adult offspring rotator cuff tendon.Materials and Methods: Female Sprague-Dawley rats were randomly assigned to either: control diet (CD; 10% kcal or 43 mg/g from fat) or HFD (45% kcal or 235 mg/g from fat) 14 days prior to mating and throughout pregnancy and lactation. Eight female and male offspring from each maternal diet group were weaned onto a standard chow diet and then culled at postnatal day 100 for tissue coll...
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Background Previous studies focusing on the association between gestational diabetes and breastfeeding duration have been inconclusive. Objectives We aimed to determine whether maternal gestational hyperglycemia is associated with the... more
Background Previous studies focusing on the association between gestational diabetes and breastfeeding duration have been inconclusive. Objectives We aimed to determine whether maternal gestational hyperglycemia is associated with the duration of breastfeeding and the concentrations of markers linked to breastmilk production. Methods Data from the prospective, multiethnic Growing Up in Singapore Towards Healthy Outcomes study were used to assess the association of fasting plasma glucose (FPG) and 2-h postglucose challenge (2hPG) measured at 26–28 wk of gestation with duration of breastfeeding and concentrations of protein, lactose, citrate, sodium, potassium, and zinc in breastmilk 3 wk postpartum. Results Of the 1035 participants, 5.2% and 9.5% had elevated FPG and 2hPG, respectively, consistent with a diagnosis of gestational diabetes mellitus based on International Association of Diabetes and Pregnancy Study Groups criteria. FPG ≥5.1 mmol/L was associated with a crude reduction i...
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An adverse early life environment is associated with increased cardiovascular disease in offspring. Work in animal models has shown that maternal undernutrition (UN) during pregnancy leads to hypertension in adult offspring, with effects... more
An adverse early life environment is associated with increased cardiovascular disease in offspring. Work in animal models has shown that maternal undernutrition (UN) during pregnancy leads to hypertension in adult offspring, with effects thought to be mediated in part via altered renal function. We have previously shown that growth hormone (GH) treatment of UN offspring during the pre-weaning period can prevent the later development of cardiometabolic disorders. However, the mechanistic basis for these observations is not well defined. The present study examined the impact of GH treatment on renal inflammatory markers in adult male offspring as a potential mediator of these reversal effects. Female Sprague-Dawley rats were fed either a chow diet fed ad libitum (CON) or at 50% of CON intake (UN) during pregnancy. All dams were fed the chow diet ad libitum during lactation. CON and UN pups received saline (CON-S/UN-S) or GH (2.5 µg/g/day; CON-GH/UN-GH) from postnatal day 3 until weani...
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Research Interests: Endocrinology, Obesity, Biology, Medicine, Animal Production, and 15 moreGrowth Hormone, Internal Medicine, Blood Glucose, Hypertension, Blood Pressure, Female, Animals, Male, Clinical Sciences, Analysis of Variance, Body Weight, Energy Intake, Adverse effect, Fetal Growth Retardation, and Maternal Nutritional Physiological Phenomena
Research Interests: Analytical Chemistry, Obesity, Biology, Metabolomics, Prediction, and 15 moreAdipose tissue, Identification, Fatty acids, Placenta, Preeclampsia, Clinical Sciences, Early Pregnancy, Fetal Growth Restriction, Fat, Fetus, Metabolome, Biochemistry and cell biology, Restriction, Maternal Obesity, and palmitoleic acid
Research Interests: Endocrinology, Biology, Biological Sciences, Insulin Resistance, Internal Medicine, and 15 moreBlood Glucose, Insulin, Insulin Secretion, Animal Feed, Female, Animals, Lipid metabolism, Insulin Receptor, Caloric Restriction, Fasting Insulin, Glycogen, High fat diet, Dietary fats, C Peptide, and Fetal Growth Retardation
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Research Interests: Endocrinology, Biology, Cytokines, Inflammation, Macrophages, and 15 moreGene expression, Growth Hormone, Malnutrition, Internal Medicine, Macrophage, Female, Animals, Male, Bone marrow, Haematopoiesis, Lipopolysaccharides, Enzyme Linked Immunosorbent Assay, Bone Marrow Cells, Interleukin, and Inflammation Mediators
Research Interests: Endocrinology, Biology, Cardiovascular disease, Medicine, Biological Sciences, and 15 moreInternal Medicine, Hypertension, Hyperinsulinemia, Metabolic diseases, Blood Pressure, Female, Animals, Leptin, Hyperphagia, Fetal Programming, Food intake, Body Weight, Fetus, Medical and Health Sciences, and In Utero
Maternal undernutrition (UN) is associated with the development of obesity and metabolic complications in adult offspring. This study investigated the impact of preweaning growth hormone (GH) treatment on adipocyte functionality in adult... more
Maternal undernutrition (UN) is associated with the development of obesity and metabolic complications in adult offspring. This study investigated the impact of preweaning growth hormone (GH) treatment on adipocyte functionality in adult male offspring. Sprague-Dawley rats were assigned either standard (C) or undernourished (UN) diet (50% ad libitum) throughout gestation. Postnatal day 3-21, male C/UN pups received either saline (CS, UNS) or GH (2.5 µg/g/d; CGH, UNGH) by subcutaneous injection. Primary adipocytes were isolated following the collagenase digestion of adipose tissue. Primary adipocytes from UN offspring had significantly increased the secretion of pro-inflammatory cytokines accompanied by increased cytokine/cytokine receptor expression. This correlated with increased TLR4/NF-κB signaling. While increased inflammatory potential was not observed in adipocytes derived from UNGH offspring, there was a clear alteration in the expression of genes relating to carbohydrate and lipid metabolism along with nutrient transporters. Overall, preweaning GH treatment alters detrimental patterns of development, which predispose UN offspring to obesity and insulin resistance.
Research Interests: Endocrinology, Biology, Cytokines, Inflammation, Adipose tissue, and 15 moreGrowth Hormone, Malnutrition, Internal Medicine, Blood Glucose, Female, Animals, Male, Growth Factors, Lipid metabolism, Clinical Sciences, Carbohydrate metabolism, Adipocytes, Adipocyte, Biochemistry and cell biology, and Interleukin
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Research Interests: Endocrinology, Medicine, Humans, Child, Internal Medicine, and 15 moreInsulin, Clinical, Clinical Sciences, Liter, Body Weight, Body Height, Glucose Tolerance Test, Protein Binding, Fasting Insulin, Growth Retardation, Insulin Like Growth Factor, Plasma Glucose, Paediatrics and reproductive medicine, Intrauterine growth retardation , and Fetal Growth Retardation
Research Interests: Endocrinology, Biology, Diet, Disease susceptibility, Animal Production, and 15 moreEnergy Metabolism, Hyperinsulinemia, Calorie restriction, Female, Animals, Eating, Food intake, Clinical Sciences, Growth Retardation, Energy Intake, Injections, High fat diet, Dietary fats, Hypertriglyceridemia, and Fetal Growth Retardation
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Guidelines advising pregnant women to avoid food and beverages with high fat and sugar have led to an increase in the consumption of “diet” options sweetened by artificial sweeteners (AS). Yet, there is limited information regarding the... more
Guidelines advising pregnant women to avoid food and beverages with high fat and sugar have led to an increase in the consumption of “diet” options sweetened by artificial sweeteners (AS). Yet, there is limited information regarding the impact of AS intake during pregnancy on the long-term risk of cardiometabolic and reproductive complications in adult offspring. This study examined the influence of maternal acesulfame-K (Ace-K) and fructose consumption on metabolic and reproductive outcomes in offspring. Pregnant C57BL/6 mice received standard chow ad-libitum with either water (CD), fructose (Fr; 20% kcal intake), or AS (AS; 12.5 mM Ace-K) throughout pregnancy and lactation (n = 8/group). Postweaning offspring were maintained on a CD diet for the remainder of the experiment. Body weight, food intake, and water intake were measured weekly. Oral glucose tolerance tests (OGTT) were undertaken at 12 weeks, and the offspring were culled at week 14. Female, but not male, AS groups exhibi...
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IntroductionIn rats, a maternal high-fat diet (HFD) leads to adverse metabolic changes in the adult offspring, similar to the children of mothers with obesity during pregnancy. Supplementation with a high dose of fish oil (FO) to pregnant... more
IntroductionIn rats, a maternal high-fat diet (HFD) leads to adverse metabolic changes in the adult offspring, similar to the children of mothers with obesity during pregnancy. Supplementation with a high dose of fish oil (FO) to pregnant rats fed a HFD has been shown to prevent the development of insulin resistance in adult offspring. However, the effects of supplementation at a translationally relevant dose remain unknown.AimTo determine whether supplementation with a human-relevant dose of FO to pregnant rats can prevent the long-term adverse metabolic and cardiovascular effects of a maternal HFD on adult offspring.MethodsFemale rats (N = 100, 90 days of age) were assigned to HFD (45% kcal from fat) or control diet (CD) for 14 days prior to mating and throughout pregnancy and lactation. Following mating, dams received a gel containing 0.05 ml of FO (human equivalent 2–3 ml) or a control gel on each day of pregnancy. This produced 4 groups, CD with control gel, CD with FO gel, HFD...
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Obesity and related metabolic disorders arise as a consequence of an imbalance between energy intake and energy expenditure. Observations in human populations and experimental evidence have provided evidence that alterations in the... more
Obesity and related metabolic disorders arise as a consequence of an imbalance between energy intake and energy expenditure. Observations in human populations and experimental evidence have provided evidence that alterations in the early-life nutritional environment can lead to perturbations in the systems regulating energy balance, thus predisposing to obesity and metabolic dysfunction in later life. This concept is preferentially termed the “developmental origins of health and disease” and needs to be viewed as a transgenerational phenomenon that can perpetuate a cycle of disease across generations. The mechanisms by which early-life nutritional insults have long-term effects on offspring health remain poorly defined. However, intervention studies have implicated altered wiring of the hypothalamic circuits, epigenetic effects, and programmed changes in adipogenesis in the observed long-term changes to the regulation of energy balance. Here we summarize the current evidence for ear...
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Objective:Maternal obesity is associated with obesity and metabolic disorders in offspring. However, there remains a paucity of data on strategies to reverse the effects of maternal obesity on maternal and offspring health. With maternal... more
Objective:Maternal obesity is associated with obesity and metabolic disorders in offspring. However, there remains a paucity of data on strategies to reverse the effects of maternal obesity on maternal and offspring health. With maternal undernutrition, taurine supplementation improves outcomes in offspring mediated in part via improved glucose–insulin homeostasis. The efficacy of taurine supplementation in the setting of maternal obesity on health and well-being of offspring is unknown. We examined the effects of taurine supplementation on outcomes related to growth and metabolism in offspring in a rat model of maternal obesity.Design:Wistar rats were randomised to: 1) control diet during pregnancy and lactation (CON); 2) CON with 1.5% taurine in drinking water (CT); 3) maternal obesogenic diet (MO); or 4) MO with taurine (MOT). Offspring were weaned onto the control diet for the remainder of the study.Results:At day 150, offspring body weights and adipose tissue weights were incre...
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We examined whether maternal fish oil supplementation during pregnancy could prevent development of insulin resistance in adult male offspring of rat dams fed a high-fat diet. Time-mated Sprague-Dawley rat dams were randomised into four... more
We examined whether maternal fish oil supplementation during pregnancy could prevent development of insulin resistance in adult male offspring of rat dams fed a high-fat diet. Time-mated Sprague-Dawley rat dams were randomised into four treatment groups: Con-Con, dams fed a control diet (fat: 15% kcal) and administered water by gavage; Con-FO, control diet with unoxidised fish oil by gavage; HF-Con, high-fat diet (fat: 45% kcal) and water by gavage; and HF-FO, high-fat diet and unoxidised fish oil by gavage. Dams were fed the allocated diet ad libitum during pregnancy and lactation, but daily gavage occurred only during pregnancy. After weaning, male offspring consumed a chow diet ad libitum until adulthood. Maternal high-fat diet led to increased food consumption, adiposity, systolic blood pressure, and triglycerides and plasma leptin in adult HF-Con offspring. HF-Con offspring also exhibited lower insulin sensitivity than Con-Con rats. Male offspring from HF-FO group were similar ...
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Research Interests: Endocrinology, Biology, Lactation, Animal Production, Biological Sciences, and 15 morePregnancy, Internal Medicine, Female, Animals, Leptin, Dietary Supplements, Rats, Dyslipidemia, Offspring, Conjugated linoleic acid, Biology Reproduction, Estrous cycle, Medical and Health Sciences, Hyperlipidemias, and Maternal Nutritional Physiological Phenomena
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Research Interests: Endocrinology, Biology, Cytokines, Inflammation, Medicine, and 15 moreGene expression, Biological Sciences, Insulin Resistance, Adipose tissue, Growth Hormone, Internal Medicine, Blood Glucose, Insulin, Female, Animals, Male, Body Weight, Offspring, Medical and Health Sciences, and Maternal Nutritional Physiological Phenomena
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Research Interests: Endocrinology, Biology, Gene expression, Disease susceptibility, Animal Production, and 15 moreMalnutrition, Internal Medicine, Insulin, Hypothalamus, Female, Animals, Body Composition, Leptin, Hyperphagia, Clinical Sciences, Appetite Regulation, Adaptive Response, High fat diet, Dietary fats, and Environmental factor
Growing evidence has demonstrated that maternal artificial sweetener (AS) consumption may not be a beneficial alternative when compared to sugar-sweetened beverages and potentially leads to metabolic dysfunction in adult offspring.... more
Growing evidence has demonstrated that maternal artificial sweetener (AS) consumption may not be a beneficial alternative when compared to sugar-sweetened beverages and potentially leads to metabolic dysfunction in adult offspring. Compromised skin integrity and wound healing associated with type 2 diabetes can lead to complications such as diabetic pressure injury (PI). In this context, the skin plays an important role in the maintenance of metabolic homeostasis, yet there is limited information on the influence of sugar- or AS-sweetened beverages during pregnancy on developmental programming and offspring skin homeostasis. This study examined the impact of maternal fructose or acesulfame-k consumption on offspring wound healing. Female C57Bl/6 mice received a chow diet ad libitum with either water (CD), fructose (FR; 34.7 mM fructose), or AS (AS; 12.5 mM Acesulfame-K) throughout pregnancy and lactation. PIs were induced in offspring at 9 weeks of age (n = 6/sex/diet). PIs and heal...