Examining a Developmental Approach to Childhood Obesity The Fetal and Early Childhood Years: Workshop Summary (2015) / Chapter Skim
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4 Opportunities for Intervention and Prevention
4 Opportunities for Intervention and Prevention
Pages 51-90
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From page 51... ...
She echoed Andrea Baccarelli's and others' hope that in the future DNA methylation differences at birth can be used as predictive biomarkers of later adiposity. Additionally, she speculated on the possibility of identifying stable epigenetic markers that could be used to monitor the success of obesity interventions over the life course.
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From page 52... ...
Marie-France Hivert of the Harvard Medical School discussed the physiology of leptin and summarized findings from animal and human observational studies suggesting that leptin exposure during the perinatal period is associated not only with early life weight gain, but also with long-lasting changes in the hypothalamus and other tissues. Additional human data from Hivert's laboratory group suggest that leptin levels in offspring are regulated, at least partially, by epi enetic g changes in the placenta triggered by changes in maternal glucose levels.
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From page 53... ...
It is especially helpful to think about metabolic dysregulation when thinking about the effect of obesity on the brain, said Antonio Convit of the Nathan Kline Institute and the New York University School of Medicine. Convit spoke about how metabolic dysregulation in adolescents leads to reduced cognition and reduced hippocampal volume, with insulin resistance being the primary driver.
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From page 54... ...
Most of the evidence for this comes from work with animal models showing that maternal dietary and protein restriction, as well as maternal over-nutrition, can induce long-term metabolic changes within offspring. According to Lillycrop, both maternal under- and overnutrition often induce similar metabolic changes, with both cases being associated with dyslipidemia, insulin resistance, and obesity in offspring and with the phenotypic changes in both cases being accompanied by changes in the methylation of key metabolic genes.
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From page 55... ...
The affected genes often play key roles in metabolism and appetite control, suggesting to Lillycrop that the observed methylation changes underpin the long-term changes that have been observed in offspring metabolism and disease risk. Human Evidence That Early Environment Can Induce Epigenetic and Phenotypic Changes A number of research groups have begun to examine whether the same phenomena being observed in animals are occurring in humans.
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From page 56... ...
This so-called mismatch between the pre- and postnatal environment, Lillycrop explained, has been suggested to account for some of the rapid rises in rates of obesity and diabetes in the developing world as populations move from rural to urban areas. Biomarker Detection Given increasing evidence from both animal and human studies suggesting that early life nutrition can alter the epigenome and that reset epigenetic markers persist and contribute to alterations in metabolism and disease risk, Lillycrop concluded that it should be possible to detect such changes early in life and use them to estimate metabolic capacity and disease risk.
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From page 57... ...
Having found some stable CpG methylation sites, the researchers wanted to see if the CpG sites were associated with a phenotype. They found associations between methylation of four of the CpG sites in the promoter region of PGC-1a at 5 to 7 years and percent fat mass from 9 to 14 years, again in both boys and girls.
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From page 58... ...
Finally, are there epigenetic markers that can be changed through intervention, and, if so, when and how? Given that researchers are now in a position to begin to address these questions, either with current cohorts or new ones, Lillycrop expressed the hope that "we should then start to be able to stem the tide of this everincreasing rise in rates of obesity." MATERNAL HEALTH AND DIET'S EFFECT ON OFFSPRING'S METABOLIC FUNCTIONING2 The value added by his work, Kevin Grove of the Oregon National Primate Research Center began, is use of a nonhuman primate model to examine the impact of maternal obesity on offspring energy balance and risk of obesity.
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From page 59... ...
(2011) were caused by diet alone, the effects are exacerbated by obesity, insulin resistance, and high triglyceridemia.
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From page 60... ...
Turning to the downstream metabolic effects on the offspring and touching on some of what Jacob Friedman had discussed during his presentation (see Chapter 3) , Grove mentioned that signs of abnormal development of metabolic systems in very young animals include increased liver triglycerides, hepatic insulin resistance, muscle insulin resistance, decreased pancreatic alpha cell mass, and cardiac hypertrophy.
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From page 61... ...
They also raised the question for Grove, what is going on metabolically in juvenile monkeys born to mothers fed a high-fat diet? Interestingly, Grove said, animals put on a healthy diet after weaning actually normalize their body weight.
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From page 62... ...
While the behavioral differences were sex-dependent, Grove said that he suspects that the underlying cause is probably the same, given that both sexes also had increased cortisol levels. Other social abnormalities detected in the monkeys born to mothers fed high-fat diets include more shrieks during novel peer interactions, which were not sex-dependent; less initiation of contact, but more successful contacts when they are not the initiator; more time spent alone, again regardless of sex; and less social play, in fact, almost nonexistent social play.
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From page 63... ...
(2013) demonstrated that, indeed, this negative feedback loop exists in lean individuals, and those young adults who are lean and who have relatively low leptin levels at baseline have a higher weight gain over the next 2 years.
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From page 64... ...
. Hivert said that they were surprised to find that maternal leptin levels were not associated with lower subsequent gestational weight gain, but rather that higher leptin levels predicted a higher subsequent gestational weight gain, even after accounting for current maternal weight status (unpublished data)
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From page 65... ...
So again, as with the animal data, human data suggest that the peri natal period is a critical period with respect to leptin exposure, with infants still being sensitive to leptin and with lower levels of leptin in infancy being associated with greater weight gain and adiposity at the age of 3. Hivert suggested that the association may be mediated through hypothalamic development, adipose tissue changes, or even the microbiome.
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From page 66... ...
(2010) results suggest that higher maternal glycemia may lead to leptin gene DNA methylation adaptations that limit maternal leptin levels, with higher methylation in the leptin gene promoter region and therefore a lower expression of the leptin gene on the maternal side.
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From page 67... ...
He suggested that the similarity in phenotype may be due to malnutrition at both ends of the spectrum. Before embarking on a review of intervention studies, Vickers commented on the similarity in phenotypic outcomes, in terms of efficacy in reversing metabolic disturbances, for a wide range of interventions tested 5 This section summarizes information and opinions presented by Mark Vickers, M.Sc., Ph.D., University of Auckland, New Zealand.
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From page 68... ...
and program leptin resistance in offspring, independent of any change in maternal body weight or body composition. Leptin Leptin was one of the first interventions tested as a means to reverse metabolic disturbances arising as a consequence of developmental programming.
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From page 69... ...
(2007) demonstrated that changes in PPAR-alpha and 11-beta-HSD2 methylation states as a result of leptin administration were directionally dependent on prior maternal nutritional status, with completely opposite effects observed depending on whether the mother was undernourished or not.
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From page 70... ...
The offspring of under nourished mothers also had markedly increased systolic blood pressure, but the offspring that had been administered growth hormone as neonates were still benefiting with normalized blood pressure and fat mass as mature adults at 150 days of age (Reynolds et al., 2013)
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From page 71... ...
Recent studies have reported that vitamin D deficiency in pregnancy can result in insulin resistance, altered inflammatory profiles, and an increased risk of early postnatal obesity in offspring (Morales et al., 2015; Zhang et al., 2014)
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From page 72... ...
. Because probiotic modification of the early gut microbiota may restrain excessive weight gain during the first years of life, it has been suggested that infant formula be supplemented with oligosaccharides to compensate for the lack of some of what is naturally present in human milk.
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From page 73... ...
Altogether, the human microbiome weighs a total of approximately 3 pounds, he said. Two striking features of the human microbiome, in Nierman's opinion, are, first, that probably half of the microbial genes in the human body are functionally unknown and, second, that the vast majority of organisms in 6 This section summarizes information and opinions presented by William Nierman, Ph.D., J
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From page 74... ...
The respiratory microbiome, on the other hand, shows what Nierman described as "wild variation" month to month even at 2 years of age. Nierman emphasized the site-specific nature of the human microbiome -- for example, with the respiratory, gut, and skin microbiomes each being
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From page 75... ...
coli O157:H7 strain is a highly virulent pathogen that can cause severe diarrhea and kidney failure. Obesity and the Microbiome Although there have been several studies of an association between the microbiome and obesity, many of them in animal models, Nierman stated that no single taxonomic signature of obesity in the microbiota of the human gut has been found (Finucane et al., 2014)
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From page 76... ...
Hullar provided a brief overview of the epigenetic mechanisms of bacteria in the human gut, with a focus on DNA methylation; discussed how microbial metabolites of the host diet may influence host health via epigenetic mechanisms involving DNA methylation, noncoding RNAs, microRNAs (miRNA, in particular) , or histone deacetylase inhibition; and concluded with a discussion of her research in obesity and the microbiome.
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From page 77... ...
Regardless, Hullar suggested that methylation patterns may influence microbial gene expression and add another layer of complexity in understanding how microbial metabolism in the human gut affects host health. Epigenetics Between the Host and Microbiome Both pathogenic and commensal bacteria exploit a diverse set of epigenetic mechanisms such as DNA methylation, histone modifications, and noncoding RNAs to alter host gene expression.
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From page 78... ...
Host exposure to microbial fermentation products varies, in part, based on the distribution of the different microbial metabolic pathways present in the gut and may influence disease risk associated with obesity. This moves beyond the idea of caloric excess causing obesity and incorporates the idea that microbial fermentation of dietary compounds may alter host gene expression (Hullar and Fu, 2014)
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From page 79... ...
Westernized diets, which are high in fat and sugar, select for a gut microbiome composition that is associated with disease risks common to industrialized societies, such as obesity, cardiovascular disease risk, and certain cancers. Exposure to microbial metabolites from a Westernized diet may influence the epi enetic g regulation of gene expression in host pathways associated with higher disease risk (Lukovac et al., 2014)
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From page 80... ...
TOXIC STRESS AND CHILDHOOD OBESITY9 Antonio Convit of the New York University School of Medicine remarked that he would be talking about the toxic effects of over-nutrition on the brain rather than toxic stress per se. He agreed with earlier remarks that the greater focus of discussion around childhood obesity should be on metabolic dysregulation, which he said is "certainly what has the biggest impact on the brain." For example, data on lean versus obese children with 9 This section summarizes information and opinions presented by Antonio Convit, M.D., Nathan Kline Institute and New York University School of Medicine, New York.
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From page 81... ...
, obese children without marked insulin resistance performed second best, and obese children with insulin resistance had the worst marks among obese children with type 2 diabetes. Compared to adults, Convit said, children with metabolic dysregulation are much more cognitively impaired.
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From page 82... ...
Not all factors that contribute to metabolic syndrome are equal, in Convit's opinion. Based on a multivariate analysis of all factors, insulin resistance appears to be the driver, not cholesterol, blood pressure, or any other measured factor.
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From page 83... ...
But with insulin resistance, endothelial dysfunction compromises the ability to relax the capillary bed. The same may be true with inflammation, he said.
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, BMI and insulin resistance explained about 20 percent of the variance in arterial size (Tirsi et al., 2013)
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From page 85... ...
According to Convit, slow wave sleep is important not just for recuperation and cleaning toxins out of the brain, but has also been shown to be associated with insulin resistance and inflammation. The more slow wave sleep that a child has, the more insulin sensitive he or she is and the less inflammation he or she has.
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From page 86... ...
The Mismatch Hypothesis Gillman asked whether a high-fat diet in utero followed by a high-fat postnatal diet would be "good" based on the mismatch hypothesis, saying, "That's a perfect match." Kevin Grove replied that it depends on the severity. With significant placental insufficiency and a small-for-gestational-age outcome, he suggested that, yes, long-term fat may be "the answer." The metabolic outcomes being observed suggest that high-fat-diet offspring may deal better with fat than control-diet offspring.
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From page 87... ...
Testing Dietary Interventions in Animals Versus Humans In Jacob Friedman's opinion, the next necessary step to studying all of the various nutritional interventions being studied in animal models is to test them in "higher" organisms and to be aware of what might be different in humans. In an effort to translate some of what has been learned in animal models to humans, his research team conducted what he said was the first randomized control diet–treated study (Hernandez et al., 2014)
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From page 88... ...
(2013) study on the production of the short-chain fatty acid butyrate by four different metabolic pathways -- the researchers created sequencing primers
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From page 89... ...
Despite the great progress of the HMP, Hullar replied that there is more work to be done to expand the microbial genome reference database. Microbiome Transplants Jacob Friedman expressed fascination with an observation made in the Netherlands that transplanting a bacterial microbiome from a healthy teenager into an individual with metabolic syndrome can lower the recipient's insulin resistance and improve his or her health.
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From page 90... ...
He is currently in the process of trying to obtain funding for a study to longitudinally track people before and after bariatric surgery and to assess the effect of surgery on the brain. He said that existing evidence suggests that bariatric surgery and massive weight loss improve cognition, but the mechanism is unknown.
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