JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
A New Population-based Reference for Gestational Age-specific Size-at-birth of Singapore Infants.
Ann. Acad. Med. Singap.
PUBLISHED: 10-25-2014
Show Abstract
Hide Abstract
There is currently a lack of representative data for local gestational age-specific size-at- birth percentile charts. Existing charts also suffer from limitations relating to the measurement of gestational age (GA) and an outdated population. We aim to construct reference values and charts for size-at-birth from 35 to 41 weeks, based on the healthy local population.
Related JoVE Video
COMT Haplotypes Modulate Associations of Antenatal Maternal Anxiety and Neonatal Cortical Morphology.
Am J Psychiatry
PUBLISHED: 10-17-2014
Show Abstract
Hide Abstract
Exposure to antenatal maternal anxiety and complex genetic variations may shape fetal brain development. In particular, the catechol-O-methyltransferase (COMT) gene, located on chromosome 22q11.2, regulates catecholamine signaling in the prefrontal cortex and is implicated in anxiety, pain, and stress responsivity. This study examined whether individual single-nucleotide polymorphisms (SNPs) of the COMT gene and their haplotypes moderate the association between antenatal maternal anxiety and in utero cortical development.
Related JoVE Video
Insights from the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) Cohort Study.
Ann. Nutr. Metab.
PUBLISHED: 10-02-2014
Show Abstract
Hide Abstract
The dramatic emergence of noncommunicable diseases (NCD) in Asia, albeit with ethnic variation, has coincided with the rapid socioeconomic and nutritional transition taking place in the region, with the prevalence of diabetes rising 5-fold in Singapore in less than 4 decades. The Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort study recruited 1,247 expectant mothers of Chinese, Malay, or Indian ethnicity in their first trimester, with detailed longitudinal tracking - through the antenatal period, birth, and the child's first 4 years of life - to examine the potential roles of fetal, developmental, and epigenetic factors in early pathways to metabolic and neurodevelopmental outcomes. Key Messages: A number of findings with a translational and clinical focus have already emerged. In the mothers, we found that changes and differences in food consumption varied across ethnic groups, with persistence of traditional beliefs, during pregnancy and the postpartum period. During pregnancy, higher maternal glucose levels, even in the absence of gestational diabetes mellitus, had graded relations with infant adiposity. Relations between maternal emotional health and birth outcomes and neurodevelopment have been identified. Genotype (25%) and in particular gene × environment interactions (75%) shape interindividual variations in the DNA methylome at birth. The complex effects of fixed genetic variations and different in utero environments can influence the epigenetic status at birth and the later-life phenotype.
Related JoVE Video
Applying evolutionary biology to address global challenges.
Science
PUBLISHED: 09-11-2014
Show Abstract
Hide Abstract
Two categories of evolutionary challenges result from escalating human impacts on the planet. The first arises from cancers, pathogens, and pests that evolve too quickly and the second, from the inability of many valued species to adapt quickly enough. Applied evolutionary biology provides a suite of strategies to address these global challenges that threaten human health, food security, and biodiversity. This Review highlights both progress and gaps in genetic, developmental, and environmental manipulations across the life sciences that either target the rate and direction of evolution or reduce the mismatch between organisms and human-altered environments. Increased development and application of these underused tools will be vital in meeting current and future targets for sustainable development.
Related JoVE Video
Molecular pathways reflecting poor intrauterine growth are found in Wharton's jelly-derived mesenchymal stem cells.
Hum. Reprod.
PUBLISHED: 08-16-2014
Show Abstract
Hide Abstract
Are molecular pathways reflecting the biology of small for gestational age (SGA) neonates preserved in umbilical cord-derived mesenchymal stem cells (MSCs)?
Related JoVE Video
Impaired cardiovascular structure and function in adult survivors of severe acute malnutrition.
Hypertension
PUBLISHED: 06-30-2014
Show Abstract
Hide Abstract
Malnutrition below 5 years remains a global health issue. Severe acute malnutrition (SAM) presents in childhood as oedematous (kwashiorkor) or nonoedematous (marasmic) forms, with unknown long-term cardiovascular consequences. We hypothesized that cardiovascular structure and function would be poorer in SAM survivors than unexposed controls. We studied 116 adult SAM survivors, 54 after marasmus, 62 kwashiorkor, and 45 age/sex/body mass index-matched community controls who had standardized anthropometry, blood pressure, echocardiography, and arterial tonometry performed. Left ventricular indices and outflow tract diameter, carotid parameters, and pulse wave velocity were measured, with systemic vascular resistance calculated. All were expressed as SD scores. Mean (SD) age was 28.8±7.8 years (55% men). Adjusting for age, sex, height, and weight, SAM survivors had mean (SE) reductions for left ventricular outflow tract diameter of 0.67 (0.16; P<0.001), stroke volume 0.44 (0.17; P=0.009), cardiac output 0.5 (0.16; P=0.001), and pulse wave velocity 0.32 (0.15; P=0.03) compared with controls but higher diastolic blood pressures (by 4.3; 1.2-7.3 mm Hg; P=0.007). Systemic vascular resistance was higher in marasmus and kwashiorkor survivors (30.2 [1.2] and 30.8 [1.1], respectively) than controls 25.3 (0.8), overall difference 5.5 (95% confidence interval, 2.8-8.4 mm Hg min/L; P<0.0001). No evidence of large vessel or cardiac remodeling was found, except closer relationships between these indices in former marasmic survivors. Other parameters did not differ between SAM survivor groups. We conclude that adult SAM survivors had smaller outflow tracts and cardiac output when compared with controls, yet markedly elevated peripheral resistance. Malnutrition survivors are thus likely to develop excess hypertension in later life, especially when exposed to obesity.
Related JoVE Video
The biology of developmental plasticity and the Predictive Adaptive Response hypothesis.
J. Physiol. (Lond.)
PUBLISHED: 06-03-2014
Show Abstract
Hide Abstract
Many forms of developmental plasticity have been observed and these are usually beneficial to the organism. The Predictive Adaptive Response (PAR) hypothesis refers to a form of developmental plasticity in which cues received in early life influence the development of a phenotype that is normally adapted to the environmental conditions of later life. When the predicted and actual environments differ, the mismatch between the individual's phenotype and the conditions in which it finds itself can have adverse consequences for Darwinian fitness and, later, for health. Numerous examples exist of the long-term effects of cues indicating a threatening environment affecting the subsequent phenotype of the individual organism. Other examples consist of the long-term effects of variations in environment within a normal range, particularly in the individual's nutritional environment. In mammals the cues to developing offspring are often provided by the mother's plane of nutrition, her body composition or stress levels. This hypothetical effect in humans is thought to be important by some scientists and controversial by others. In resolving the conflict, distinctions should be drawn between PARs induced by normative variations in the developmental environment and the ill effects on development of extremes in environment such as a very poor or very rich nutritional environment. Tests to distinguish between different developmental processes impacting on adult characteristics are proposed. Many of the mechanisms underlying developmental plasticity involve molecular epigenetic processes, and their elucidation in the context of PARs and more widely has implications for the revision of classical evolutionary theory.
Related JoVE Video
Validation of prediction equations for resting energy expenditure in Singaporean Chinese men.
Obes Res Clin Pract
PUBLISHED: 05-23-2014
Show Abstract
Hide Abstract
Accurate prediction of resting energy expenditure (REE) is important in establishing adequate dietary intake goals for effective weight management. Previous studies have shown that the validity of an energy prediction equation may depend on the ethnicity of the population. Validation studies are lacking in the Singaporean Chinese population. A total of 96 healthy Singaporean Chinese males of age 21–40 years and body mass index (BMI) 18.5–30.0 kg/m2 participated in this study. REE was measured by indirect calorimetry and compared with REE predicted using existing equations. Validity was evaluated on the basis of mean bias and percentage of subjects predicted within ±10% of REE measured. In addition, Bland and Altman analyses were performed. No significant difference was observed between the mean levels of measured and predicted REE derived from the Owen equation. The Food and Agriculture Organization/World Health Organization/United Nations University (FAO/WHO/UNU), Harris–Benedict and Mifflin equations significantly overestimated the mean measured REE by 7.5%, 6.0% and 2.4% respectively. Percentage of valid predictions for FAO/WHO/UNU, Harris–Benedict, Mifflin and Owen equations were 60%, 67%, 75% and 73% respectively. Bland and Altman analyses demonstrated poor agreement for all equations. The Owen equation provided a valid estimation of REE in Singaporean Chinese men at a group level. However, the individual errors of the equations were unacceptable high and may have limited utility in making clinical decisions on nutritional requirements.
Related JoVE Video
Infinium monkeys: Infinium 450K array for the Cynomolgus macaque (Macaca fascicularis).
G3 (Bethesda)
PUBLISHED: 05-13-2014
Show Abstract
Hide Abstract
The Infinium Human Methylation450 BeadChip Array (Infinium 450K) is a robust and cost-efficient survey of genome-wide DNA methylation patterns. Macaca fascicularis (Cynomolgus macaque) is an important disease model; however, its genome sequence is only recently published, and few tools exist to interrogate the molecular state of Cynomolgus macaque tissues. Although the Infinium 450K is a hybridization array designed to the human genome, the relative conservation between the macaque and human genomes makes its use in macaques feasible. Here, we used the Infinium 450K array to assay DNA methylation in 11 macaque muscle biopsies. We showed that probe hybridization efficiency was related to the degree of sequence identity between the human probes and the macaque genome sequence. Approximately 61% of the Human Infinium 450K probes could be reliably mapped to the Cynomolgus macaque genome and contain a CpG site of interest. We also compared the Infinium 450K data to reduced representation bisulfite sequencing data generated on the same samples and found a high level of concordance between the two independent methodologies, which can be further improved by filtering for probe sequence identity and mismatch location. We conclude that the Infinium 450K array can be used to measure the DNA methylome of Cynomolgus macaque tissues using the provided filters. We also provide a pipeline for validation of the array in other species using a simple BLAST-based sequence identify filter.
Related JoVE Video
Automated segmentation of visceral and subcutaneous (deep and superficial) adipose tissues in normal and overweight men.
J Magn Reson Imaging
PUBLISHED: 04-17-2014
Show Abstract
Hide Abstract
To develop an automatic segmentation algorithm to classify abdominal adipose tissues into visceral fat (VAT), deep (DSAT), and superficial (SSAT) subcutaneous fat compartments and evaluate its performance against manual segmentation.
Related JoVE Video
Alterations to DNA methylation and expression of CXCL14 are associated with suboptimal birth outcomes.
J. Hum. Genet.
PUBLISHED: 04-15-2014
Show Abstract
Hide Abstract
CXCL14 is a chemokine that has previously been implicated in insulin resistance in mice. In humans, the role of CXCL14 in metabolic processes is not well established, and we sought to determine whether CXCL14 is a risk susceptibility gene important in fetal programming of metabolic disease. For this purpose, we investigated whether CXCL14 is differentially regulated in human umbilical cords of infants with varying birth weights. We found an elevated expression of CXCL14 in human low birth weight (LBW) cords, as well as in cords from nutritionally restricted Macaca fascicularis macaques. To further analyze the regulatory mechanisms underlying the expression of CXCL14, we examined CXCL14 in umbilical cord-derived mesenchymal stem cells (MSCs) that provide an in vitro cell-based system amenable to experimental manipulation. Using both whole frozen cords and MSCs, we determined that site-specific CpG methylation in the CXCL14 promoter is associated with altered expression, and that changes in methylation are evident in LBW infant-derived umbilical cords that may indicate future metabolic compromise through CXCL14.
Related JoVE Video
The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes.
Genome Res.
PUBLISHED: 04-07-2014
Show Abstract
Hide Abstract
Integrating the genotype with epigenetic marks holds the promise of better understanding the biology that underlies the complex interactions of inherited and environmental components that define the developmental origins of a range of disorders. The quality of the in utero environment significantly influences health over the lifecourse. Epigenetics, and in particular DNA methylation marks, have been postulated as a mechanism for the enduring effects of the prenatal environment. Accordingly, neonate methylomes contain molecular memory of the individual in utero experience. However, interindividual variation in methylation can also be a consequence of DNA sequence polymorphisms that result in methylation quantitative trait loci (methQTLs) and, potentially, the interaction between fixed genetic variation and environmental influences. We surveyed the genotypes and DNA methylomes of 237 neonates and found 1423 punctuate regions of the methylome that were highly variable across individuals, termed variably methylated regions (VMRs), against a backdrop of homogeneity. MethQTLs were readily detected in neonatal methylomes, and genotype alone best explained ?25% of the VMRs. We found that the best explanation for 75% of VMRs was the interaction of genotype with different in utero environments, including maternal smoking, maternal depression, maternal BMI, infant birth weight, gestational age, and birth order. Our study sheds new light on the complex relationship between biological inheritance as represented by genotype and individual prenatal experience and suggests the importance of considering both fixed genetic variation and environmental factors in interpreting epigenetic variation.
Related JoVE Video
Epigenetics, plasticity, and evolution: How do we link epigenetic change to phenotype?
J. Exp. Zool. B Mol. Dev. Evol.
PUBLISHED: 03-13-2014
Show Abstract
Hide Abstract
Epigenetic mechanisms are proposed as an important way in which the genome responds to the environment. Epigenetic marks, including DNA methylation and Histone modifications, can be triggered by environmental effects, and lead to permanent changes in gene expression, affecting the phenotype of an organism. Epigenetic mechanisms have been proposed as key in plasticity, allowing environmental exposure to shape future gene expression. While we are beginning to understand how these mechanisms have roles in human biology and disease, we have little understanding of their roles and impacts on ecology and evolution. In this review, we discuss different types of epigenetic marks, their roles in gene expression and plasticity, methods for assaying epigenetic changes, and point out the future advances we require to understand fully the impact of this field.
Related JoVE Video
Ethnic differences translate to inadequacy of high-risk screening for gestational diabetes mellitus in an Asian population: a cohort study.
BMC Pregnancy Childbirth
PUBLISHED: 03-10-2014
Show Abstract
Hide Abstract
Universal and high-risk screening for gestational diabetes mellitus (GDM) has been widely studied and debated. Few studies have assessed GDM screening in Asian populations and even fewer have compared Asian ethnic groups in a single multi-ethnic population.
Related JoVE Video
Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1.
Sci Rep
PUBLISHED: 02-28-2014
Show Abstract
Hide Abstract
The homeostasis of insulin-like growth factor-1 (IGF-1) is essential for metabolism, development and survival. Insufficient IGF-1 is associated with poor recovery from wounds whereas excessive IGF-1 contributes to growth of tumours. We have shown that cyclic glycine-proline (cGP), a metabolite of IGF-1, can normalise IGF-1 function by showing its efficacy in improving the recovery from ischemic brain injury in rats and inhibiting the growth of lymphomic tumours in mice. Further investigation in cell culture suggested that cGP promoted the activity of IGF-1 when it was insufficient, but inhibited the activity of IGF-1 when it was excessive. Mathematical modelling revealed that the efficacy of cGP was a modulated IGF-1 effect via changing the binding of IGF-1 to its binding proteins, which dynamically regulates the balance between bioavailable and non-bioavailable IGF-1. Our data reveal a novel mechanism of auto-regulation of IGF-1, which has physiological and pathophysiological consequences and potential pharmacological utility.
Related JoVE Video
Elevated S-adenosylhomocysteine alters adipocyte functionality with corresponding changes in gene expression and associated epigenetic marks.
Diabetes
PUBLISHED: 02-26-2014
Show Abstract
Hide Abstract
Maternal deficiencies in micronutrients affecting one-carbon metabolism before and during pregnancy can influence metabolic status and the degree of insulin resistance and obesity of the progeny in adulthood. Notably, maternal and progeny plasma S-adenosylhomocysteine (SAH) levels are both elevated after vitamin deficiency in pregnancy. Therefore, we investigated whether this key one-carbon cycle intermediate directly affects adipocyte differentiation and function. We found that expansion and differentiation of murine 3T3-L1 preadipocytes in the presence of SAH impaired both basal and induced glucose uptake as well as lipolysis compared with untreated controls. SAH did not alter preadipocyte factor 1 (Dlk1) or peroxisome proliferator-activated receptor-? 2 (Ppar?2) but significantly reduced expression of CAAT enhancer-binding protein-? (Cebp?), Cebp?, and retinoid x receptor-? (Rxr?) compared with untreated adipocytes. SAH increased Rxr? methylation on a CpG unit (chr2:27,521,057+, chr2:27,521,049+) and CpG residue (chr2:27,521,080+), but not Cebp? methylation, relative to untreated adipocytes. Trimethylated histone H3-Lys27 occupancy was significantly increased on Cebp? and Rxr? promoters in SAH-treated adipocytes, consistent with the reduction in gene expression. In conclusion, SAH did not affect adipogenesis per se but altered adipocyte functionality through epigenetic mechanisms, such that they exhibited altered glucose disposal and lipolysis. Our findings implicate micronutrient imbalance in subsequent modulation of adipocyte function.
Related JoVE Video
Glucose metabolism in adult survivors of severe acute malnutrition.
J. Clin. Endocrinol. Metab.
PUBLISHED: 02-11-2014
Show Abstract
Hide Abstract
The clinical syndromes of severe acute malnutrition may have early life origins because children with marasmus have lower birth weight than those with kwashiorkor. We hypothesized that resultant metabolic effects may persist into adulthood. We investigated whether marasmus survivors (MS) are more insulin resistant and glucose intolerant than kwashiorkor survivors (KS).
Related JoVE Video
Relationships of maternal folate and vitamin B12 status during pregnancy with perinatal depression: The GUSTO study.
J Psychiatr Res
PUBLISHED: 02-06-2014
Show Abstract
Hide Abstract
Studies in the general population have proposed links between nutrition and depression, but less is known about the perinatal period. Depletion of nutrient reserves throughout pregnancy and delayed postpartum repletion could increase the risk of perinatal depression. We examined the relationships of plasma folate and vitamin B12 concentrations during pregnancy with perinatal depression. At 26th-28th weeks of gestation, plasma folate and vitamin B12 were measured in women from the GUSTO mother-offspring cohort study in Singapore. Depressive symptoms were measured with the Edinburgh Postnatal Depression Scale (EPDS) during the same period and at 3-month postpartum. EPDS scores of ?15 during pregnancy or ?13 at postpartum were indicative of probable depression. Of 709 women, 7.2% (n = 51) were identified with probable antenatal depression and 10.4% (n = 74) with probable postnatal depression. Plasma folate concentrations were significantly lower in those with probable antenatal depression than those without (mean ± SD; 27.3 ± 13.8 vs 40.4 ± 36.5 nmol/L; p = 0.011). No difference in folate concentrations was observed in those with and without probable postnatal depression. In adjusted regression models, the likelihood of probable antenatal depression decreases by 0.69 for every unit variation (increase) in folate (OR = 0.69 per SD increase in folate; 95% CI: 0.52, 0.94). Plasma vitamin B12 concentrations were not associated with perinatal depression. Lower plasma folate status during pregnancy was associated with antenatal depression, but not with postnatal depression. Replication in other studies is needed to determine the direction of causality between low folate and antenatal depression.
Related JoVE Video
Maternal adiposity and blood pressure in pregnancy: varying relations by ethnicity and gestational diabetes.
J. Hypertens.
PUBLISHED: 01-07-2014
Show Abstract
Hide Abstract
Greater maternal adiposity is a potentially modifiable risk factor for elevated blood pressure during pregnancy; however, the association has been little studied in Asian populations, and no study has evaluated potential differences in the adiposity-blood pressure relation between ethnic groups or interaction with gestational diabetes.
Related JoVE Video
Thrifty metabolic programming in rats is induced by both maternal undernutrition and postnatal leptin treatment, but masked in the presence of both: implications for models of developmental programming.
BMC Genomics
PUBLISHED: 01-06-2014
Show Abstract
Hide Abstract
Maternal undernutrition leads to an increased risk of metabolic disorders in offspring including obesity and insulin resistance, thought to be due to a programmed thrifty phenotype which is inappropriate for a subsequent richer nutritional environment. In a rat model, both male and female offspring of undernourished mothers are programmed to become obese, however postnatal leptin treatment gives discordant results between males and females. Leptin treatment is able to rescue the adverse programming effects in the female offspring of undernourished mothers, but not in their male offspring. Additionally, in these rats, postnatal leptin treatment of offspring from normally-nourished mothers programmes their male offspring to develop obesity in later life, while there is no comparable effect in their female offspring.
Related JoVE Video
Hair metabolomics: identification of fetal compromise provides proof of concept for biomarker discovery.
Theranostics
PUBLISHED: 01-01-2014
Show Abstract
Hide Abstract
Analysis of the human metabolome has yielded valuable insights into health, disease and toxicity. However, the metabolic profile of complex biological fluids such as blood is highly dynamic and this has limited the discovery of robust biomarkers. Hair grows relatively slowly, and both endogenous compounds and environmental exposures are incorporated from blood into hair during growth, which reflects the average chemical composition over several months. We used hair samples to study the metabolite profiles of women with pregnancies complicated by fetal growth restriction (FGR) and healthy matched controls. We report the use of GC-MS metabolite profiling of hair samples for biomarker discovery. Unsupervised statistical analysis showed complete discrimination of FGR from controls based on hair composition alone. A predictive model combining 5 metabolites produced an area under the receiver-operating curve of 0.998. This is the first study of the metabolome of human hair and demonstrates that this biological material contains robust biomarkers, which may lead to the development of a sensitive diagnostic tool for FGR, and perhaps more importantly, to stable biomarkers for a range of other diseases.
Related JoVE Video
Effect of maternal glycemia on neonatal adiposity in a multiethnic asian birth cohort.
J. Clin. Endocrinol. Metab.
PUBLISHED: 12-20-2013
Show Abstract
Hide Abstract
Context: Gestational hyperglycemia increases the risk of obesity and diabetes in offspring later in life. Objective: We examined the relationship between gestational glycemia and neonatal adiposity in a multiethnic cohort of Singaporean neonates. Design: A prospective mother-offspring cohort study recruited 1247 pregnant mothers (57.2% Chinese, 25.5% Malay, 17.3% Indian) and performed 75-g, 2-hour oral glucose tolerance tests at 26-28 weeks gestation; glucose levels were available for 1081 participants. Neonatal anthropometry (birth weight, length, triceps, and subscapular skinfolds) was measured, and percentage body fat (%BF) was derived using our published equation. Associations of maternal glucose with excessive neonatal adiposity [large for gestational age; %BF; and sum of skinfolds (?SFT) > 90th centile] were assessed using multiple logistic regression analyses. Results: Adjusting for potential confounders we observed strong positive continuous associations across the range of maternal fasting and 2-hour glucose in relation to excessive neonatal adiposity; each 1 SD increase in fasting glucose was associated with 1.31 [95% confidence interval (CI) 1.10-1.55], 1.72 (95% CI 1.31-2.27) and 1.64 (95% CI 1.32-2.03) increases in odds ratios for large for gestational age and %BF and ?SFT greater than the 90th centile, respectively. Corresponding odds ratios for 2-hour glucose were 1.11 (95% CI 0.92-1.33), 1.55 (95% CI 1.10-2.20), and 1.40 (95% CI 1.10-1.79), respectively. The influence of high maternal fasting glucose on neonatal ?SFT was less pronounced in Indians compared with Chinese (interaction P = .005). Conclusions: A continuous relationship between maternal glycemia and excessive neonatal adiposity extends across the range of maternal glycemia. Compared with Chinese infants, Indian infants may be less susceptible to excessive adiposity from high maternal glucose levels.
Related JoVE Video
Body fat partitioning does not explain the inter-ethnic variation in insulin sensitivity among Asian ethnicity: the Singapore Adults Metabolism Study (SAMS).
Diabetes
PUBLISHED: 12-18-2013
Show Abstract
Hide Abstract
We previously showed that ethnicity modifies the association between adiposity and insulin resistance. We sought to determine whether differential body fat partitioning or abnormalities in muscle insulin signaling associated with higher levels of adiposity might underlie this observation. We measured insulin sensitivity index (ISI), %body fat, visceral (VAT) and subcutaneous (SAT) adipose tissue, liver fat and intramyocellular lipids (IMCL) in 101 Chinese, 82 Malays and 81 South Asians as well as p-Akt levels in cultured myoblasts from Chinese and South Asians. Lean Chinese and Malays had higher ISI than South Asians. Although ISI was lower in all ethnic groups when %body fat was higher, this association was stronger in Chinese and Malays such that, in overweight individuals, no ethnic differences were observed. These ethnic differences were observed even when %body fat was replaced with fat in other depots. Myoblasts obtained from lean South Asians had lower p-Akt levels than those from lean Chinese. Higher adiposity was associated with lower p-Akt levels in Chinese but not in South Asians, and no ethnic differences were observed in overweight individuals. With higher %body fat, Chinese exhibited smaller increases in DSAT and IMCL compared to Malays and South Asians, which did not explain the ethnic differences observed. Our study suggests that body fat partitioning does not explain inter-ethnic differences in insulin sensitivity among Asian ethnic groups. While higher adiposity had greater impact on skeletal muscle insulin sensitivity among Chinese, obesity-independent pathway may be more relevant in South Asians.
Related JoVE Video
The Influence of Anxiety and Depressive Symptoms During Pregnancy on Birth Size.
Paediatr Perinat Epidemiol
PUBLISHED: 11-24-2013
Show Abstract
Hide Abstract
Mental health problems during pregnancy can influence fetal growth. However, studies examining the influence of maternal mental health across the normal range of birth outcomes are uncommon. This study examined the associations between symptoms of maternal depression and anxiety during pregnancy on birth size among term Asian infants.
Related JoVE Video
Pid1 induces insulin resistance in both human and mouse skeletal muscle during obesity.
Mol. Endocrinol.
PUBLISHED: 08-08-2013
Show Abstract
Hide Abstract
Obesity is associated with insulin resistance and abnormal peripheral tissue glucose uptake. However, the mechanisms that interfere with insulin signaling and glucose uptake in human skeletal muscle during obesity are not fully characterized. Using microarray, we have identified that the expression of Pid1 gene, which encodes for a protein that contains a phosphotyrosine-interacting domain, is increased in myoblasts established from overweight insulin-resistant individuals. Molecular analysis further validated that both Pid1 mRNA and protein levels are increased in cell culture models of insulin resistance. Consistent with these results, overexpression of phosphotyrosine interaction domain-containing protein 1 (PID1) in human myoblasts resulted in reduced insulin signaling and glucose uptake, whereas knockdown of PID1 enhanced glucose uptake and insulin signaling in human myoblasts and improved the insulin sensitivity following palmitate-, TNF-?-, or myostatin-induced insulin resistance in human myoblasts. Furthermore, the number of mitochondria in myoblasts that ectopically express PID1 was significantly reduced. In addition to overweight humans, we find that Pid1 levels are also increased in all 3 peripheral tissues (liver, skeletal muscle, and adipose tissue) in mouse models of diet-induced obesity and insulin resistance. An in silico search for regulators of Pid1 expression revealed the presence of nuclear factor-?B (NF-?B) binding sites in the Pid1 promoter. Luciferase reporter assays and chromatin immunoprecipitation studies confirmed that NF-?B is sufficient to transcriptionally up-regulate the Pid1 promoter. Furthermore, we find that myostatin up-regulates Pid1 expression via an NF-?B signaling mechanism. Collectively these results indicate that Pid1 is a potent intracellular inhibitor of insulin signaling pathway during obesity in humans and mice.
Related JoVE Video
Gestational diabetes, maternal obesity, and the NCD burden.
Clin Obstet Gynecol
PUBLISHED: 07-04-2013
Show Abstract
Hide Abstract
A greater proportion of women of reproductive age are now overweight or obese. Gestational diabetes mellitus and maternal obesity are associated with long-term adverse consequences in the offspring and subsequent generations, and are important drivers of the escalating global burden of diabetes and cardiovascular disease. We review the evidence linking gestational diabetes mellitus and maternal obesity with a greater risk of metabolic compromise in the offspring. We use an evolutionary perspective to elucidate the origins of gestational diabetes. Focusing efforts on maternal health is an important approach to combating the growing burden of diabetes and other noncommunicable diseases.
Related JoVE Video
Dietary changes during pregnancy and the postpartum period in Singaporean Chinese, Malay and Indian women: the GUSTO birth cohort study.
Public Health Nutr
PUBLISHED: 06-28-2013
Show Abstract
Hide Abstract
To examine changes in food consumption during pregnancy and the postpartum period in women of major Asian ethnic groups.
Related JoVE Video
Distribution and determinants of eye size and shape in newborn children: a magnetic resonance imaging analysis.
Invest. Ophthalmol. Vis. Sci.
PUBLISHED: 06-15-2013
Show Abstract
Hide Abstract
To determine the eye size and shape obtained by magnetic resonance imaging (MRI), and to determine associations with antenatal factors in newborn children.
Related JoVE Video
Cardiac function and lipid distribution in rats fed a high-fat diet: in vivo magnetic resonance imaging and spectroscopy.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 03-29-2013
Show Abstract
Hide Abstract
Obesity is a major risk factor in the development of cardiovascular disease, type 2 diabetes, and its pathophysiological precondition insulin resistance. Very little is known about the metabolic changes that occur in the myocardium and consequent changes in cardiac function that are associated with high-fat accumulation. Therefore, cardiac function and metabolism were evaluated in control rats and those fed a high-fat diet, using magnetic resonance imaging, magnetic resonance spectroscopy, mRNA analysis, histology, and plasma biochemistry. Analysis of blood plasma from rats fed the high-fat diet showed that they were insulin resistant (P < 0.001). Our high-fat diet model had higher heart weight (P = 0.005) and also increasing trend in septal wall thickness (P = 0.07) compared with control diet rats. Our results from biochemistry, magnetic resonance imaging, and mRNA analysis confirmed that rats on the high-fat diet had moderate diabetes along with mild cardiac hypertrophy. The magnetic resonance spectroscopy results showed the extramyocellular lipid signal only in the spectra from high-fat diet rats, which was absent in the control diet rats. The intramyocellular lipids in high-fat diet rats was higher (8.7%) compared with rats on the control diet (6.1%). This was confirmed by electron microscope and light microscopy studies. Our results indicate that lipid accumulation in the myocardium might be an early indication of the cardiovascular pathophysiology associated with type 2 diabetes.
Related JoVE Video
Prenatal maternal depression associates with microstructure of right amygdala in neonates at birth.
Biol. Psychiatry
PUBLISHED: 03-22-2013
Show Abstract
Hide Abstract
Antenatal maternal cortisol levels associate with alterations in the amygdala, a structure associated with emotion regulation, in the offspring. However, because offspring brain and behavior are commonly assessed years after birth, the timing of such maternal influences is unclear. This study aimed to examine the association between antenatal maternal depressive symptomatology and neonatal amygdala volume and microstructure and thus establish evidence for the transgenerational transmission of vulnerability for affective disorders during prenatal development.
Related JoVE Video
Structural connectivity asymmetry in the neonatal brain.
Neuroimage
PUBLISHED: 02-21-2013
Show Abstract
Hide Abstract
Asymmetry of the neonatal brain is not yet understood at the level of structural connectivity. We utilized DTI deterministic tractography and structural network analysis based on graph theory to determine the pattern of structural connectivity asymmetry in 124 normal neonates. We tracted white matter axonal pathways characterizing interregional connections among brain regions and inferred asymmetry in left and right anatomical network properties. Our findings revealed that in neonates, small-world characteristics were exhibited, but did not differ between the two hemispheres, suggesting that neighboring brain regions connect tightly with each other, and that one region is only a few paths away from any other region within each hemisphere. Moreover, the neonatal brain showed greater structural efficiency in the left hemisphere than that in the right. In neonates, brain regions involved in motor, language, and memory functions play crucial roles in efficient communication in the left hemisphere, while brain regions involved in emotional processes play crucial roles in efficient communication in the right hemisphere. These findings suggest that even at birth, the topology of each cerebral hemisphere is organized in an efficient and compact manner that maps onto asymmetric functional specializations seen in adults, implying lateralized brain functions in infancy.
Related JoVE Video
Human growth: evolutionary and life history perspectives.
Nestle Nutr Inst Workshop Ser
PUBLISHED: 01-22-2013
Show Abstract
Hide Abstract
Evolutionary and life history perspectives allow a fuller understanding of both patterns of growth and development and variations in disease risk. Evolutionary processes act to ensure successful reproduction and not the preservation of health and longevity, and this entails trade-offs both between traits and across the life course. Developmental plasticity adjusts the developmental trajectory so that the phenotype in childhood and through peak reproduction will suit predicted environmental conditions - a capacity that may become maladaptive should early-life predictions be inaccurate. Bipedalism and consequent pelvic narrowing in humans have led to the evolution of secondary altricialism. Shorter inter-birth intervals enabled by appropriate social support structures have allowed increased fecundity/fitness. The age at puberty has fallen over the past two centuries, perhaps resulting from changes in maternal and infant health and nutrition. The timing of puberty is also advanced by conditions of high extrinsic mortality in hunter-gatherers and is reflected in developed countries where a poor or disadvantaged start to life may also accelerate maturation. The postpubertal individual is physically and psychosexually mature, but neural executive function only reaches full maturity in the third decade of life; this mismatch may account for increased adolescent morbidity and mortality in those with earlier pubertal onset.
Related JoVE Video
Non-imprinted epigenetics in fetal and postnatal development and growth.
Nestle Nutr Inst Workshop Ser
PUBLISHED: 01-22-2013
Show Abstract
Hide Abstract
Recent evidence demonstrates that the environment in early life can have important effects on fetal and postnatal growth, on development and on risk of developing common non-communicable diseases in later life. In animals, the environment during early life induces altered phenotypes in ways which are influenced or mediated by epigenetic mechanisms. The latter include DNA methylation, covalent modifications of histones and non-coding RNAs. Most is known about DNA methylation changes, which are gene specific, include effects on non-imprinted genes and function at the level of individual CpG dinucleotides to alter gene expression. Preliminary evidence from human studies suggests a similar important role for epigenetic processes. Tuning of phenotype by the developmental environment has adaptive value because it attempts to match an individuals responses to the environment predicted to be experienced later; hence, such processes have been selected during evolution as conferring fitness advantage. When the phenotype is mismatched, e.g. from inaccurate nutritional cues from the mother or placenta before birth, or from rapid environmental change through improved socioeconomic conditions, risk of non-communicable diseases increases. Evidence is accruing that endocrine or nutritional interventions during early postnatal life can reverse epigenetic and phenotypic changes induced, for example, by unbalanced maternal diet during pregnancy. Elucidation of epigenetic processes may enable early intervention strategies to improve early development and growth.
Related JoVE Video
Related JoVE Video
Antenatal Mental Health and Retinal Vascular Caliber in Pregnant Women.
Transl Vis Sci Technol
PUBLISHED: 01-01-2013
Show Abstract
Hide Abstract
Depression, anxiety, and poor sleep are associated with increased risks of cardiovascular diseases. Previous studies have demonstrated the relationship between negative emotion and retinal microvascular changes among adults, yet no study has been done in pregnant women so far. This study aims to examine the association of antenatal mental health and retinal vascular caliber among Asian pregnant women.
Related JoVE Video
Tissue-specific 5 heterogeneity of PPAR? transcripts and their differential regulation by leptin.
PLoS ONE
PUBLISHED: 01-01-2013
Show Abstract
Hide Abstract
The genes encoding nuclear receptors comprise multiple 5untranslated exons, which give rise to several transcripts encoding the same protein, allowing tissue-specific regulation of expression. Both human and mouse peroxisome proliferator activated receptor (PPAR) ? genes have multiple promoters, although their function is unknown. Here we have characterised the rat PPAR? promoter region and have identified three alternative PPAR? transcripts, which have different transcription start sites owing to the utilisation of distinct first exons. Moreover these alternative PPAR? transcripts were differentially expressed between adipose tissue and liver. We show that while the major adipose (P1) and liver (P2) transcripts were both induced by dexamethasone, they were differentially regulated by the PPAR? agonist, clofibric acid, and leptin. Leptin had no effect on the adipose-specific P1 transcript, but induced liver-specific P2 promoter activity via a STAT3/Sp1 mechanism. Moreover in Wistar rats, leptin treatment between postnatal day 3-13 led to an increase in P2 but not P1 transcription in adipose tissue which was sustained into adulthood. This suggests that the expression of the alternative PPAR? transcripts are in part programmed by early life exposure to leptin leading to persistent change in adipose tissue fatty acid metabolism through specific activation of a quiescent PPAR? promoter. Such complexity in the regulation of PPAR? may allow the expression of PPAR? to be finely regulated in response to environmental factors.
Related JoVE Video
Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy.
Pediatr. Res.
PUBLISHED: 12-21-2011
Show Abstract
Hide Abstract
We sought to determine whether 18- to 22-mo neurodevelopmental outcomes predicted functional outcomes at 7-8 y for survivors of the CoolCap study of therapeutic hypothermia for neonates with hypoxic-ischemic encephalopathy.
Related JoVE Video
Epigenetics and metabolism in 2011: Epigenetics, the life-course and metabolic disease.
Nat Rev Endocrinol
PUBLISHED: 12-20-2011
Show Abstract
Hide Abstract
Clinical and experimental studies suggest that early life experiences, perhaps spanning multiple generations, affect lifelong risk of metabolic dysfunction through epigenetic mechanisms. Data published in 2011 suggest that epigenetic analysis could potentially have utility as a marker of early metabolic pathology and might enable early life prophylaxis.
Related JoVE Video
Developmental plasticity and epigenetic mechanisms underpinning metabolic and cardiovascular diseases.
Epigenomics
PUBLISHED: 11-30-2011
Show Abstract
Hide Abstract
The importance of developmental factors in influencing the risk of later-life disease has a strong evidence base derived from multiple epidemiological, clinical and experimental studies in animals and humans. During early life, an organism is able to adjust its phenotypic development in response to environmental cues. Such developmentally plastic responses evolved as a fitness-maximizing strategy to cope with variable environments. There are now increasing data that these responses are, at least partially, underpinned by epigenetic mechanisms. A mismatch between the early and later-life environments may lead to inappropriate early life-course epigenomic changes that manifest in later life as increased vulnerability to disease. There is also growing evidence for the transgenerational transmission of epigenetic marks. This article reviews the evidence that susceptibility to metabolic and cardiovascular disease in humans is linked to changes in epigenetic marks induced by early-life environmental cues, and discusses the clinical, public health and therapeutic implications that arise.
Related JoVE Video
Developmental origins of health and disease: moving from biological concepts to interventions and policy.
Int J Gynaecol Obstet
PUBLISHED: 11-22-2011
Show Abstract
Hide Abstract
The rising incidence of noncommunicable diseases (NCDs), especially in young adults, presents great humanitarian and economic challenges to high-resource and, increasingly, to low-resource countries. No longer considered to be diseases of affluence, NCDs are exacerbated by urbanization and changes in social and lifestyle factors such as diet and family size. New research emphasizes the importance of early life factors in establishing the risk of NCDs through inadequate responses to later challenges, such as an obesogenic environment. A new focus on interventions to promote a good start to life in at-risk populations necessitates revision of public health policy, with implications for the health, education, and empowerment of women and children in particular.
Related JoVE Video
Influence of birth weight on internalizing traits modulated by serotonergic genes.
Pediatrics
PUBLISHED: 10-03-2011
Show Abstract
Hide Abstract
Fetal growth predicts childhood behavioral problems associated with brain serotonergic systems. We hypothesized that allelic variations in genes involved in serotonergic function would moderate associations between birth weight (BW) and internalizing traits in childhood.
Related JoVE Video
Myostatin promotes the wasting of human myoblast cultures through promoting ubiquitin-proteasome pathway-mediated loss of sarcomeric proteins.
Am. J. Physiol., Cell Physiol.
PUBLISHED: 09-07-2011
Show Abstract
Hide Abstract
Myostatin is a negative regulator of skeletal muscle growth and in fact acts as a potent inducer of "cachectic-like" muscle wasting in mice. The mechanism of action of myostatin in promoting muscle wasting has been predominantly studied in murine models. Despite numerous reports linking elevated levels of myostatin to human skeletal muscle wasting conditions, little is currently known about the signaling mechanism(s) through which myostatin promotes human skeletal muscle wasting. Therefore, in this present study we describe in further detail the mechanisms behind myostatin regulation of human skeletal muscle wasting using an in vitro human primary myotube atrophy model. Treatment of human myotube populations with myostatin promoted dramatic myotubular atrophy. Mechanistically, myostatin-induced myotube atrophy resulted in reduced p-AKT concomitant with the accumulation of active dephosphorylated Forkhead Box-O (FOXO1) and FOXO3. We further show that addition of myostatin results in enhanced activation of atrogin-1 and muscle-specific RING finger protein 1 (MURF1) and reduced expression of both myosin light chain (MYL) and myosin heavy chain (MYH). In addition, we found that myostatin-induced loss of MYL and MYH proteins is dependent on the activity of the proteasome and mediated via SMAD3-dependent regulation of FOXO1 and atrogin-1. Therefore, these data suggest that the mechanism through which myostatin promotes muscle wasting is very well conserved between species, and that myostatin-induced human myotube atrophy is mediated through inhibition of insulin-like growth factor (IGF)/phosphoinositide 3-kinase (PI3-K)/AKT signaling and enhanced activation of the ubiquitin-proteasome pathway and elevated protein degradation.
Related JoVE Video
Epigenetic epidemiology: the rebirth of soft inheritance.
Ann. Nutr. Metab.
PUBLISHED: 08-12-2011
Show Abstract
Hide Abstract
Non-communicable diseases (NCDs), such as cardiovascular disease and type 2 diabetes, constitute the main cause of death worldwide. Eighty percent of these deaths occur in low- and middle-income countries, especially as these countries undergo socio-economic improvement following reductions in the burden of infectious disease. The World Health Organization predicts a substantial increase in the incidence of NCDs over the next decade globally. NCDs are generally preventable, but current approaches are clearly inadequate. New initiatives are needed to implement such prevention, and there needs to be greater recognition that early-life interventions are likely to be the most efficacious. Devising appropriate prevention strategies necessitates an understanding of how the developmental environment influences risk. Progress in this field has been slow due to an excessive emphasis on fixed genomic variations (hard inheritance) as the major determinants of disease susceptibility. However, new evidence demonstrates the much greater importance of early-life developmental factors, involving epigenetic processes and soft inheritance in modulating an individuals vulnerability to NCD. This also offers opportunities for novel epigenetic biomarkers of risk or interventions targeting epigenetic pathways to be devised for use in early life. This may pave the way to much more effective, customised interventions to promote health across the life course.
Related JoVE Video
Losing the war against obesity: the need for a developmental perspective.
Sci Transl Med
PUBLISHED: 07-29-2011
Show Abstract
Hide Abstract
Developed countries are struggling to control epidemics of obesity and related chronic diseases; thus, we can expect only limited success from applying the current approaches to the developing world, which is experiencing an alarming increase in such disorders. This failure results in part from the fact that our focus on adult life-styles, although important, ignores data that suggest that biological and cultural factors operating early in life affect adult health status. To stem the rising obesity burden in developing countries, scientists and policy-makers must address obesity-promoting factors from early development to adulthood.
Related JoVE Video
Progressive, transgenerational changes in offspring phenotype and epigenotype following nutritional transition.
PLoS ONE
PUBLISHED: 07-06-2011
Show Abstract
Hide Abstract
Induction of altered phenotypes during development in response to environmental input involves epigenetic changes. Phenotypic traits can be passed between generations by a variety of mechanisms, including direct transmission of epigenetic states or by induction of epigenetic marks de novo in each generation. To distinguish between these possibilities we measured epigenetic marks over four generations in rats exposed to a sustained environmental challenge. Dietary energy was increased by 25% at conception in F0 female rats and maintained at this level to generation F3. F0 dams showed higher pregnancy weight gain, but lower weight gain and food intake during lactation than F1 and F2 dams. On gestational day 8, fasting plasma glucose concentration was higher and ?-hydroxybutyrate lower in F0 and F1 dams than F2 dams. This was accompanied by decreased phosphoenolpyruvate carboxykinase (PEPCK) and increased PPAR? and carnitine palmitoyl transferase-1 mRNA expression. PEPCK mRNA expression was inversely related to the methylation of specific CpG dinucleotides in its promoter. DNA methyltransferase (Dnmt) 3a2, but not Dnmt1 or Dnmt3b, expression increased and methylation of its promoter decreased from F1 to F3 generations. These data suggest that the regulation of energy metabolism during pregnancy and lactation within a generation is influenced by the maternal phenotype in the preceding generation and the environment during the current pregnancy. The transgenerational effects on phenotype were associated with altered DNA methylation of specific genes in a manner consistent with induction de novo of epigenetic marks in each generation.
Related JoVE Video
Evaluation of methylation status of the eNOS promoter at birth in relation to childhood bone mineral content.
Calcif. Tissue Int.
PUBLISHED: 05-06-2011
Show Abstract
Hide Abstract
Our previous work has shown associations between childhood adiposity and perinatal methylation status of several genes in umbilical cord tissue, including endothelial nitric oxide synthase (eNOS). There is increasing evidence that eNOS is important in bone metabolism; we therefore related the methylation status of the eNOS gene promoter in stored umbilical cord to childhood bone size and density in a group of 9-year-old children. We used Sequenom MassARRAY to assess the methylation status of two CpGs in the eNOS promoter, identified from our previous study, in stored umbilical cords of 66 children who formed part of a Southampton birth cohort and who had measurements of bone size and density at age 9 years (Lunar DPXL DXA instrument). Percentage methylation varied greatly between subjects. For one of the two CpGs, eNOS chr7:150315553 + , after taking account of age and sex, there were strong positive associations between methylation status and the childs whole-body bone area (r = 0.28, P = 0.02), bone mineral content (r = 0.34, P = 0.005), and areal bone mineral density (r = 0.34, P = 0.005) at age 9 years. These associations were independent of previously documented maternal determinants of offspring bone mass. Our findings suggest an association between methylation status at birth of a specific CpG within the eNOS promoter and bone mineral content in childhood. This supports a role for eNOS in bone growth and metabolism and implies that its contribution may at least in part occur during early skeletal development.
Related JoVE Video
Developmental origins of noncommunicable disease: population and public health implications.
Am. J. Clin. Nutr.
PUBLISHED: 04-27-2011
Show Abstract
Hide Abstract
Noncommunicable diseases (NCDs), including cardiovascular disease, diabetes, chronic lung disease, allergy, some forms of cancer, cognitive decline, osteoporosis, sarcopenia, and affective disorders, are the worlds biggest killers. Eighty percent of these deaths occur in low- and middle-income countries, especially as these countries undergo socioeconomic improvement after reductions in infectious disease. The World Health Organization predicts a global increase of 17% in NCDs over the next decade. NCDs are preventable, but new initiatives are needed to institute such prevention, especially in early life. In this article, we emphasize that all children are affected by their early developmental conditions, not just children exposed to a very deficient environment, and that this has long-term consequences for their predisposition to NCDs. We highlight the biomedical implications of this developmental origins of health and disease (DOHaD) concept of NCDs and discuss the implications for health policy.
Related JoVE Video
Human myostatin negatively regulates human myoblast growth and differentiation.
Am. J. Physiol., Cell Physiol.
PUBLISHED: 04-20-2011
Show Abstract
Hide Abstract
Myostatin, a member of the transforming growth factor-? superfamily, has been implicated in the potent negative regulation of myogenesis in murine models. However, little is known about the mechanism(s) through which human myostatin negatively regulates human skeletal muscle growth. Using human primary myoblasts and recombinant human myostatin protein, we show here that myostatin blocks human myoblast proliferation by regulating cell cycle progression through targeted upregulation of p21. We further show that myostatin regulates myogenic differentiation through the inhibition of key myogenic regulatory factors including MyoD, via canonical Smad signaling. In addition, we have for the first time demonstrated the capability of myostatin to regulate the Notch signaling pathway during inhibition of human myoblast differentiation. Treatment with myostatin results in the upregulation of Hes1, Hes5, and Hey1 expression during differentiation; moreover, when we interfere with Notch signaling, through treatment with the ?-secretase inhibitor L-685,458, we find enhanced myotube formation despite the presence of excess myostatin. Therefore, blockade of the Notch pathway relieves myostatin repression of differentiation, and myostatin upregulates Notch downstream target genes. Immunoprecipitation studies demonstrate that myostatin treatment of myoblasts results in enhanced association of Notch1-intracellular domain with Smad3, providing an additional mechanism through which myostatin targets and represses the activity of the myogenic regulatory factor MyoD. On the basis of these results, we suggest that myostatin function and mechanism of action are very well conserved between species, and that myostatin regulation of postnatal myogenesis involves interactions with numerous downstream signaling mediators, including the Notch pathway.
Related JoVE Video
Epigenetic gene promoter methylation at birth is associated with childs later adiposity.
Diabetes
PUBLISHED: 04-06-2011
Show Abstract
Hide Abstract
Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans.
Related JoVE Video
The role of developmental plasticity and epigenetics in human health.
Birth Defects Res. C Embryo Today
PUBLISHED: 03-23-2011
Show Abstract
Hide Abstract
Considerable epidemiological, experimental and clinical data have amassed showing that the risk of developing disease in later life is dependent on early life conditions, mainly operating within the normative range of developmental exposures. This relationship reflects plastic responses made by the developing organism as an evolved strategy to cope with immediate or predicted circumstances, to maximize fitness in the context of the range of environments potentially faced. There is now increasing evidence, both in animals and humans, that such developmental plasticity is mediated in part by epigenetic mechanisms. However, recognition of the importance of developmental plasticity as an important factor in influencing later life health-particularly within the medical and public health communities-is low, and we argue that this indifference cannot be sustained in light of the growing understanding of developmental processes and the rapid rise in the prevalence of obesity and metabolic disease globally.
Related JoVE Video
Associations between DNA methylation of a glucocorticoid receptor promoter and acute stress responses in a large healthy adult population are largely explained by lifestyle and educational differences.
Psychoneuroendocrinology
PUBLISHED: 03-16-2011
Show Abstract
Hide Abstract
Glucocorticoids are the key regulators of the biological stress response and act by binding to glucocorticoid receptors (GR). Expression of GR is altered by DNA methylation. Methylation patterns in GR promoters have been shown to be highly variable between individuals, but little is known about the functional consequences of this variation for the acute stress response. The present study investigated associations between methylation status of the GR 1-C promoter and cortisol, cardiovascular and perceived stress responses to a psychosocial stress protocol in a large healthy adult population.
Related JoVE Video
Gene expression profiling in the Cynomolgus macaque Macaca fascicularis shows variation within the normal birth range.
BMC Genomics
PUBLISHED: 02-22-2011
Show Abstract
Hide Abstract
Although an adverse early-life environment has been linked to an increased risk of developing the metabolic syndrome, the molecular mechanisms underlying altered disease susceptibility as well as their relevance to humans are largely unknown. Importantly, emerging evidence suggests that these effects operate within the normal range of birth weights and involve mechanisms of developmental palsticity rather than pathology.
Related JoVE Video
Developmental plasticity and developmental origins of non-communicable disease: theoretical considerations and epigenetic mechanisms.
Prog. Biophys. Mol. Biol.
PUBLISHED: 01-08-2011
Show Abstract
Hide Abstract
There is now evidence that developmental influences have lifelong effects on cardiovascular and metabolic function and that elements of the heritable or familial component of susceptibility to cardiovascular disease, obesity and other non-communicable diseases (NCD) can be transmitted across generations by non-genomic means. In animals the developmental environment induces altered phenotypes through genetic, physiological (especially endocrine) and epigenetic mechanisms. The latter include DNA methylation, covalent modifications of histones and non-coding RNAs. Such tuning of phenotype has potential adaptive value and may confer Darwinian fitness advantage because it either adjusts the phenotype to current circumstances and/or attempts to match an individuals responses to the environment predicted to be experienced later. When the phenotype is mismatched to the later environment, e.g. from inaccurate nutritional cues from the mother or placenta before birth, or from rapid environmental change through improved socio-economic conditions, risk of NCD increases. Such mechanisms are also thought to play roles in ageing and early onset of puberty, reinforcing a life-course perspective on such adaptive responses, especially the detrimental later effects of trade-offs. Epigenetic changes induced during development are highly gene-specific and function at the level of individual CpG dinucleotides in both gene promoter and intergenic regions. Evidence is accruing that endocrine or nutritional interventions during early postnatal life can reverse epigenetic and phenotypic changes induced, for example, by unbalanced maternal diet during pregnancy. Elucidation of epigenetic processes may permit perinatal identification of individuals most at risk of later NCD and enable early intervention strategies to reduce such risk.
Related JoVE Video
A model for phenotype change in a stochastic framework.
Math Biosci Eng
PUBLISHED: 06-29-2010
Show Abstract
Hide Abstract
In some species, an inducible secondary phenotype will develop some time after the environmental change that evokes it. Nishimura (2006) [4] showed how an individual organism should optimize the time it takes to respond to an environmental change ("waiting time). If the optimal waiting time is considered to act over the population, there are implications for the expected value of the mean fitness in that population. A stochastic predator-prey model is proposed in which the prey have a fixed initial energy budget. Fitness is the product of survival probability and the energy remaining for non-defensive purposes. The model is placed in the stochastic domain by assuming that the waiting time in the population is a normally distributed random variable because of biological variance inherent in mounting the response. It is found that the value of the mean waiting time that maximises fitness depends linearly on the variance of the waiting time.
Related JoVE Video
Maternal protein restriction with or without folic acid supplementation during pregnancy alters the hepatic transcriptome in adult male rats.
Br. J. Nutr.
PUBLISHED: 03-09-2010
Show Abstract
Hide Abstract
Feeding pregnant rats a protein-restricted (PR) diet induces altered expression of candidate genes in the liver of the adult offspring, which can be prevented by supplementation of the PR diet with folic acid (PRF). We investigated the effect of maternal nutrition during pregnancy on the liver transcriptome in their adult male offspring. Pregnant rats were fed control, PR or PRF diets. Male offspring were killed on day 84. The liver transcriptome was analysed by microarray (six livers per maternal dietary group) followed by post hoc analysis of relative mRNA levels and gene ontology. These results were confirmed for selected genes by real-time RT-PCR. There were 311 genes that differed significantly ( >or= 1.5-fold change; P < 0.05) between PR offspring (222 increased) and control offspring, while 191 genes differed significantly between PRF offspring (forty-five increased) compared with offspring of control dams. There were sixteen genes that were significantly altered in both PR and PRF offspring compared with controls. Ion transport, developmental process, and response to reactive oxygen species (RROS) and steroid hormone response (SHR) ontologies were altered in PR offspring. Folic acid supplementation prevented changes within RROS and SHR response pathways, but not in ion transport or developmental process. There was no effect of maternal PR on mRNA expression of imprinted genes. Insulin 1 and Pleckstrin homology-like domain family A member 2 were increased significantly in PRF compared with PR offspring. The present findings show that the pattern of induced changes in the adult liver transcriptome were dependent on maternal protein and folic acid intakes during pregnancy.
Related JoVE Video
Developmental origins of health and disease: reducing the burden of chronic disease in the next generation.
Genome Med
PUBLISHED: 02-24-2010
Show Abstract
Hide Abstract
Despite a wealth of underpinning experimental support, there has been considerable resistance to the concept that environmental factors acting early in life (usually in fetal life) have profound effects on vulnerability to disease later in life, often in adulthood. This has resulted in an unwillingness among public health decision makers to implement relatively simple approaches, based upon an understanding of developmental plasticity and intergenerational influences, to reducing the burden of disease particularly in low socioeconomic groups.
Related JoVE Video
Developmental origins of metabolic disease: life course and intergenerational perspectives.
Trends Endocrinol. Metab.
PUBLISHED: 01-14-2010
Show Abstract
Hide Abstract
Recent evidence demonstrates important maternal effects on an offsprings risk of developing metabolic disease. These effects extend across the full range of maternal environments and partly involve epigenetic mechanisms. The maternal effects can be explained in evolutionary terms, and there is some evidence for their transmission into succeeding generations. Unbalanced maternal diet or body composition, ranging from poor to rich environments, adversely influences the offsprings response to later challenges such as an obesogenic diet or physical inactivity, increasing the risk of disease. Adopting a life course approach that takes into account intergenerational effects has important implications for prevention of non-communicable diseases, particularly in populations undergoing rapid economic transition.
Related JoVE Video
Ten putative contributors to the obesity epidemic.
Crit Rev Food Sci Nutr
PUBLISHED: 12-05-2009
Show Abstract
Hide Abstract
The obesity epidemic is a global issue and shows no signs of abating, while the cause of this epidemic remains unclear. Marketing practices of energy-dense foods and institutionally-driven declines in physical activity are the alleged perpetrators for the epidemic, despite a lack of solid evidence to demonstrate their causal role. While both may contribute to obesity, we call attention to their unquestioned dominance in program funding and public efforts to reduce obesity, and propose several alternative putative contributors that would benefit from equal consideration and attention. Evidence for microorganisms, epigenetics, increasing maternal age, greater fecundity among people with higher adiposity, assortative mating, sleep debt, endocrine disruptors, pharmaceutical iatrogenesis, reduction in variability of ambient temperatures, and intrauterine and intergenerational effects as contributing factors to the obesity epidemic are reviewed herein. While the evidence is strong for some contributors such as pharmaceutical-induced weight gain, it is still emerging for other reviewed factors. Considering the role of such putative etiological factors of obesity may lead to comprehensive, cause specific, and effective strategies for prevention and treatment of this global epidemic.
Related JoVE Video
Evolution in health and medicine Sackler colloquium: Making evolutionary biology a basic science for medicine.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 11-16-2009
Show Abstract
Hide Abstract
New applications of evolutionary biology in medicine are being discovered at an accelerating rate, but few physicians have sufficient educational background to use them fully. This article summarizes suggestions from several groups that have considered how evolutionary biology can be useful in medicine, what physicians should learn about it, and when and how they should learn it. Our general conclusion is that evolutionary biology is a crucial basic science for medicine. In addition to looking at established evolutionary methods and topics, such as population genetics and pathogen evolution, we highlight questions about why natural selection leaves bodies vulnerable to disease. Knowledge about evolution provides physicians with an integrative framework that links otherwise disparate bits of knowledge. It replaces the prevalent view of bodies as machines with a biological view of bodies shaped by evolutionary processes. Like other basic sciences, evolutionary biology needs to be taught both before and during medical school. Most introductory biology courses are insufficient to establish competency in evolutionary biology. Premedical students need evolution courses, possibly ones that emphasize medically relevant aspects. In medical school, evolutionary biology should be taught as one of the basic medical sciences. This will require a course that reviews basic principles and specific medical applications, followed by an integrated presentation of evolutionary aspects that apply to each disease and organ system. Evolutionary biology is not just another topic vying for inclusion in the curriculum; it is an essential foundation for a biological understanding of health and disease.
Related JoVE Video
Epigenetic mechanisms that underpin metabolic and cardiovascular diseases.
Nat Rev Endocrinol
PUBLISHED: 06-02-2009
Show Abstract
Hide Abstract
Cellular commitment to a specific lineage is controlled by differential silencing of genes, which in turn depends on epigenetic processes such as DNA methylation and histone modification. During early embryogenesis, the mammalian genome is wiped clean of most epigenetic modifications, which are progressively re-established during embryonic development. Thus, the epigenome of each mature cellular lineage carries the record of its developmental history. The subsequent trajectory and pattern of development are also responsive to environmental influences, and such plasticity is likely to have an epigenetic basis. Epigenetic marks may be transmitted across generations, either directly by persisting through meiosis or indirectly through replication in the next generation of the conditions in which the epigenetic change occurred. Developmental plasticity evolved to match an organism to its environment, and a mismatch between the phenotypic outcome of adaptive plasticity and the current environment increases the risk of metabolic and cardiovascular disease. These considerations point to epigenetic processes as a key mechanism that underpins the developmental origins of chronic noncommunicable disease. Here, we review the evidence that environmental influences during mammalian development lead to stable changes in the epigenome that alter the individuals susceptibility to chronic metabolic and cardiovascular disease, and discuss the clinical implications.
Related JoVE Video
The influence of birth size on intelligence in healthy children.
Pediatrics
PUBLISHED: 06-02-2009
Show Abstract
Hide Abstract
Birth parameters have been hypothesized to have an influence on IQ. However, studies within the range of normal birth size have been sparse. With this study we examined the associations between birth length, birth weight, head circumference, and gestational age within the normal birth size range in relation to childhood IQ in Asian children.
Related JoVE Video
Maternal undernutrition leads to endothelial dysfunction in adult male rat offspring independent of postnatal diet.
Br. J. Nutr.
PUBLISHED: 06-02-2009
Show Abstract
Hide Abstract
Increasing evidence suggests a role for prenatal environment in the onset of cardiovascular and metabolic disease in later life. In the rat, undernutrition in utero and a postnatal high-fat diet gives rise to a phenotype similar to the metabolic syndrome. As endothelial dysfunction is a feature of both CVD and the metabolic syndrome we investigated the impact of maternal undernutrition and/or postnatal high-fat on endothelial function. Virgin Wistar rats were mated and randomly assigned to groups to receive food either ad libitum (control) or at 30% of ad libitum intake throughout gestation. At postnatal day 250, a cohort from each group was challenged with a high-fat diet (D12451, 45% energy from fat; Research Diets, Inc., New Brunswick, NJ, USA) for the remainder of the study. At 1 year of age, small mesenteric arteries were dissected and mounted on a wire myograph and responses to phenylephrine, endothelin, acetylcholine, leptin and sodium nitroprusside assessed. Vasoconstriction to endothelin was significantly enhanced in all groups compared with controls (-log effective concentration equal to 50% of the maximal response (pEC50); P < 0.001). Endothelium-dependent vasodilatation to acetylcholine was significantly blunted in all groups compared with controls (% maximum response; P < 0.01), while dilatation to leptin and sodium nitroprusside was similar in all groups. These data demonstrate that both maternal undernutrition and postnatal high fat lead to vascular alterations and suggest that maternal undernutrition alone is at least as detrimental to offspring endothelial function as a long-term exposure to a high-fat diet in the offspring.
Related JoVE Video
Impaired perinatal growth and longevity: a life history perspective.
Curr Gerontol Geriatr Res
PUBLISHED: 05-22-2009
Show Abstract
Hide Abstract
Life history theory proposes that early-life cues induce highly integrated responses in traits associated with energy partitioning, maturation, reproduction, and aging such that the individual phenotype is adaptively more appropriate to the anticipated environment. Thus, maternal and/or neonatally derived nutritional or endocrine cues suggesting a threatening environment may favour early growth and reproduction over investment in tissue reserve and repair capacity. These may directly affect longevity, as well as prioritise insulin resistance and capacity for fat storage, thereby increasing susceptibility to metabolic dysfunction and obesity. These shifts in developmental trajectory are associated with long-term expression changes in specific genes, some of which may be underpinned by epigenetic processes. This normative process of developmental plasticity may prove to be maladaptive in human environments in transition towards low extrinsic mortality and energy-dense nutrition, leading to the development of an inappropriate phenotype with decreased potential for longevity and/or increased susceptibility to metabolic disease.
Related JoVE Video
IGF-1 derived small neuropeptides and analogues: a novel strategy for the development of pharmaceuticals for neurological conditions.
Br. J. Pharmacol.
PUBLISHED: 05-11-2009
Show Abstract
Hide Abstract
Insulin-like growth factor-1 (IGF-1) is neuroprotective and improves long-term function after brain injury. However, its clinical application to neurological disorders is limited by its large molecular size, poor central uptake and mitogenic potential. Glycine-proline-glutamate (GPE) is naturally cleaved from the IGF-1 N-terminal and it is also neuroprotective after ischemic injury, which provided a novel strategy of drug discovery for neurological disorders. GPE is not enzymatically stable, thus intravenous infusion of GPE becomes necessary for stable and potent neuroprotection. The broad effective dose range and treatment window of 3-7 h after the lesion suggest its potential for treating acute brain injuries. G-2meth-PE, a GPE analogue designed to be more enzymatic resistant, has a prolonged plasma half-life and is more potent in neuroprotection. Neuroprotection by GPE and its analogue may involve modulation of inflammation, promotion of astrocytosis, inhibition of apoptosis and vascular remodelling. Acute administration of GPE also prevents 6-OHDA-induced nigrostrial dopamine depletion. Delayed treatment with GPE does not prevent dopamine loss, but improves long-term function. Cyclo-glycyl-proline (cyclic Gly-Pro) is an endogenous DKP that may be derived from GPE. Cyclic Gly-Pro and its analogue cyclo-L-glycyl-L-2-allylproline (NNZ 2591) are both neuroprotective after ischaemic injury. NNZ2591 is highly enzymatic resistant and centrally accessible. Its peripheral administration improves somatosensory-motor function and long-term histological outcome after brain injury. Our research suggests that small neuropeptides have advantages over growth factors in the treatment of brain injury, and that modified neuropeptides designed to overcome the limitations of their endogenous counterparts represent a novel strategy of pharmaceutical discovery for neurological disorders.
Related JoVE Video
Pre- and postnatal nutritional histories influence reproductive maturation and ovarian function in the rat.
PLoS ONE
PUBLISHED: 04-30-2009
Show Abstract
Hide Abstract
While prepubertal nutritional influences appear to play a role in sexual maturation, there is a need to clarify the potential contributions of maternal and childhood influences in setting the tempo of reproductive maturation. In the present study we employed an established model of nutritional programming to evaluate the relative influences of prenatal and postnatal nutrition on growth and ovarian function in female offspring.
Related JoVE Video
NNZ-2566: a Gly-Pro-Glu analogue with neuroprotective efficacy in a rat model of acute focal stroke.
J. Neurol. Sci.
PUBLISHED: 01-20-2009
Show Abstract
Hide Abstract
The N-terminal cleavage product of human insulin-like growth factor-1 (IGF-1) in the brain is the tripeptide molecule Glypromate (Gly-Pro-Glu). Glypromate has demonstrated neuroprotective effects in numerous in vitro and in vivo models of brain injury and is in clinical trials for the prevention of cognitive impairment following cardiac surgery. NNZ-2566 is a structural analogue of Glypromate, resulting from alpha-methylation of the proline moiety, which has improved the elimination half-life and oral bioavailability over the parent peptide. In vivo, NNZ-2566 reduces injury size in rats subjected to focal stroke. An intravenous infusion of NNZ-2566 of 4 h duration (3-10 mg/kg/h), initiated 3 h after endothelin-induced middle-cerebral artery constriction, significantly reduced infarct area as assessed on day 5. Neuroprotective efficacy in the MCAO model was also observed following oral administration of the drug (30-60 mg/kg), when formulated as a microemulsion. In vitro, NNZ-2566 significantly attenuates apoptotic cell death in primary striatal cultures, suggesting attenuation of apoptosis is one mechanism of action underlying its neuroprotective effects. NNZ-2566 is currently in clinical trials for the treatment of cognitive deficits following traumatic brain injury, and these data further support the development of the drug as a neuroprotective agent for acute brain injury.
Related JoVE Video
Transcriptional profiling of rats subjected to gestational undernourishment: implications for the developmental variations in metabolic traits.
PLoS ONE
PUBLISHED: 01-06-2009
Show Abstract
Hide Abstract
A link has been established between prenatal nutrition and the development of metabolic and cardiovascular diseases later in life, a process referred to as developmental programming. It has been suggested that the trajectory of development is shifted by alterations in the maternal nutritional state leading to changes in developmental plasticity, in part underpinned by epigenetic changes in gene regulation. However, to date, only candidate gene approaches have been used to assess expression and molecular changes in the offspring of maternally undernourished animals. Furthermore, most work has focused on animals at an age where the programmed phenotype is already manifest and little is known about changes in gene expression in the offspring prior to development of obesity and related metabolic disorders. Gene expression profiles of liver, retroperitoneal white adipose fat, and biceps femoris skeletal muscle tissue from young adult male rats (55 days old) in which nutritional status had been manipulated in utero by maternal undernutrition (UN) were compared to the profiles of offspring of ad libitum fed mothers serving as the control group (AD) (8 offspring/group). The expression profiles were determined using the Illumina RatRef-12 BeadChip. No significant changes in expression were identified for skeletal muscle or white adipose tissue. However, studies of liver tissue showed 249 differentially expressed genes (143 up regulated, 106 down regulated). Although the animals at day 55 have yet to develop obesity they already show biochemical abnormalities and by day 110 express a phenotype characterized by increased adiposity and altered insulin sensitivity. An analysis of pathways affected suggests that intrauterine programming of UN animals to favor fat as an energy source results in mitochondrial dysfunction which initially affects the postnatal hepatic function and subsequently, via the resultant metabolic changes in other organs leads to the evolution of a phenotype similar to that of the metabolic syndrome.
Related JoVE Video
Early life opportunities for prevention of diabetes in low and middle income countries.
BMC Public Health
Show Abstract
Hide Abstract
The global burden of diabetes and other non-communicable diseases is rising dramatically worldwide and is causing a double poor health burden in low- and middle-income countries. Early life influences play an important part in this scenario because maternal lifestyle and conditions such as gestational diabetes and obesity affect the risk of diabetes in the next generation. This indicates important periods during the lifecourse when interventions could have powerful affects in reducing incidence of non-communicable diseases. However, interventions to promote diet and lifestyle in prospective parents before conception have not received sufficient attention, especially in low- and middle-income countries undergoing socio-economic transition.
Related JoVE Video
The ubiquitin ligase Mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli.
Cell Metab.
Show Abstract
Hide Abstract
Recent research reveals that dysfunction and subsequent loss of mitochondria (mitophagy) is a potent inducer of skeletal muscle wasting. However, the molecular mechanisms that govern the deregulation of mitochondrial function during muscle wasting are unclear. In this report, we show that different muscle-wasting stimuli upregulated mitochondrial E3 ubiquitin protein ligase 1 (Mul1), through a mechanism involving FoxO1/3 transcription factors. Overexpression of Mul1 in skeletal muscles and myoblast cultures was sufficient for the induction of mitophagy. Consistently, Mul1 suppression not only protected against mitophagy but also partially rescued the muscle wasting observed in response to muscle-wasting stimuli. In addition, upregulation of Mul1, while increasing mitochondrial fission, resulted in ubiquitination and degradation of the mitochondrial fusion protein Mfn2. Collectively, these data explain the molecular basis for the loss of mitochondrial number during muscle wasting.
Related JoVE Video

What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.