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Epigenetics and Childhood Obesity

      To the Editor:
      In his article in the January 2015 issue of Mayo Clinic Proceedings, Archer
      • Archer E.
      The childhood obesity epidemic as a result of nongenetic evolution: the maternal resources hypothesis.
      has, in a novel yet age-old construct, succinctly hypothesized the putative role of epigenetics in a complex multifactorial condition, childhood obesity. His hypothesis is in harmony with the results of a recently published systematic overview of the most recent research findings in the area of epigenetics and obesity, which revealed that the propensity toward adult obesity has early developmental origins and follows an intergenerational cycle.
      • van Dijk S.J.
      • Molloy P.L.
      • Varinli H.
      • Morrison J.L.
      • Muhlhausler B.S.
      Members of EpiSCOPE
      Epigenetics and human obesity.
      Epigenetics, an increasingly recognized discipline, is defined as heritable regulation of gene expression without a change in the base sequence of DNA.
      • Arimondo P.B.
      • Egger G.
      • Tost J.
      Epigenetics.
      Epigenetic marks can alter the transcription of a particular gene, thereby determining whether the gene is “turned on or off” at a given point in time. Epigenetic mechanisms that are best studied so far include addition or deletion of methyl groups to DNA (this occurs predominantly at CpG sites), posttranslational modifications to histone proteins, and noncoding RNA. Although the DNA sequence of genes in an individual (the genome) is largely stable, the epigenome is dynamic and has the potential to be reversibly modified by exposure to a range of environmental factors.
      Over the past decade, increasing effort has been made to understand the role of epigenetic modifications in other complex conditions like cancer, autoimmune rheumatic diseases, and obesity. To date, DNA methylation, either at global, site-specific, or genome-wide levels at single nucleotide resolution, is by far the most studied epigenetic mark in obesity with the help of high-throughput screening methods. Archer’s proposed maternal resource hypothesis is a very useful addition to the insight about developmental origins of health and disease via epigenetic modifications programmed by the perinatal environment.
      Epidemiological studies, including Project Ice Storm
      • Cao-Lei L.
      • Massart R.
      • Suderman M.J.
      • et al.
      DNA methylation signatures triggered by prenatal maternal stress exposure to a natural disaster: Project Ice Storm.
      (a study of the effects of prenatal maternal stress exposure to a storm that impacted Quebec in 1998), have already documented the lasting impact of the prenatal conditions via methylation patterns of offspring.
      • Nicholas L.M.
      • Rattanatray L.
      • MacLaughlin S.M.
      • et al.
      Differential effects of maternal obesity and weight loss in the periconceptional period on the epigenetic regulation of hepatic insulin-signaling pathways in the offspring.
      Recently, no connection was found between the FTO gene and obesity in the Framingham cohort born before 1942 and very strong correlation in those born after 1972, findings that take Lamarck’s notion of environment shaping phenotype to an interesting level.
      • Rosenquist J.N.
      • Lehrer S.F.
      • O'Malley A.J.
      • Zaslavsky A.M.
      • Smoller J.W.
      • Christakis N.A.
      Cohort of birth modifies the association between FTO genotype and BMI.
      • Richards E.J.
      Inherited epigenetic variation—revisiting soft inheritance.
      The first steps are already being made in identifying potential epigenetic biomarkers for obesity that could be detected at birth. Eventually, this finding may help in predicting an individual’s obesity risk at a young age, before the phenotype develops (the “tipping point.” as coined by Archer
      • Archer E.
      The childhood obesity epidemic as a result of nongenetic evolution: the maternal resources hypothesis.
      ), and opens possibilities for introducing targeted strategies to prevent the condition. It is also now clear that several epigenetic markers are modifiable by changing maternal habits during pregnancy, to turn the unfavorable epigenomic switch off and pass it in an off mode to several subsequent generations.
      As Einstein said, “a problem cannot be solved on the same level at which it arose.”

      Perlmutter L, Cortez-Perlmutter J. The Heart and Science of Yoga. Bristol, UK:AMI Publishers: Chapter 28; 237-238.

      With Archer’s commendable article, we are going beyond Darwinism back by a few centuries to Lamarck’s soft inheritance theory, or even all the way to the Vedas, the oldest books in the library of mankind that say, “You are the architects of your destiny” and of the generations to come. Once we unravel all we can about epigenetics as well as we have done with genetics, we may realize we are no closer to understanding the mysteries of our existence and human behavior. What is clear from the burgeoning field of epigenetics is that the historical argument of nature vs nurture might best be reconciled by a context of nature via nurture.

      References

        • Archer E.
        The childhood obesity epidemic as a result of nongenetic evolution: the maternal resources hypothesis.
        Mayo Clin Proc. 2015; 90: 77-92
        • van Dijk S.J.
        • Molloy P.L.
        • Varinli H.
        • Morrison J.L.
        • Muhlhausler B.S.
        • Members of EpiSCOPE
        Epigenetics and human obesity.
        Int J Obes (Lond). 2015; 39: 85-97
        • Arimondo P.B.
        • Egger G.
        • Tost J.
        Epigenetics.
        Biochimie. 2012; 94 ([editorial]): 2191-2192
        • Cao-Lei L.
        • Massart R.
        • Suderman M.J.
        • et al.
        DNA methylation signatures triggered by prenatal maternal stress exposure to a natural disaster: Project Ice Storm.
        PLoS One. 2014; 9: e107653
        • Nicholas L.M.
        • Rattanatray L.
        • MacLaughlin S.M.
        • et al.
        Differential effects of maternal obesity and weight loss in the periconceptional period on the epigenetic regulation of hepatic insulin-signaling pathways in the offspring.
        FASEB J. 2013; 27: 3786-3796
        • Rosenquist J.N.
        • Lehrer S.F.
        • O'Malley A.J.
        • Zaslavsky A.M.
        • Smoller J.W.
        • Christakis N.A.
        Cohort of birth modifies the association between FTO genotype and BMI.
        Proc Natl Acad Sci U S A. 2015; 112: 354-359
        • Richards E.J.
        Inherited epigenetic variation—revisiting soft inheritance.
        Nat Rev Genet. 2006; 7: 395-401
      1. Perlmutter L, Cortez-Perlmutter J. The Heart and Science of Yoga. Bristol, UK:AMI Publishers: Chapter 28; 237-238.

      Linked Article

      • The Childhood Obesity Epidemic as a Result of Nongenetic Evolution: The Maternal Resources Hypothesis
        Mayo Clinic ProceedingsVol. 90Issue 1
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          Over the past century, socioenvironmental evolution (eg, reduced pathogenic load, decreased physical activity, and improved nutrition) led to cumulative increments in maternal energy resources (ie, body mass and adiposity) and decrements in energy expenditure and metabolic control. These decrements reduced the competition between maternal and fetal energy demands and increased the availability of energy substrates to the intrauterine milieu. This perturbation of mother-conceptus energy partitioning stimulated fetal pancreatic β-cell and adipocyte hyperplasia, thereby inducing an enduring competitive dominance of adipocytes over other tissues in the acquisition and sequestering of nutrient energy via intensified insulin secretion and hyperplastic adiposity.
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      • Correction
        Mayo Clinic ProceedingsVol. 90Issue 8
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          In the Letter to the Editor entitled “Epigenetics and Childhood Obesity” published in the May 2015 issue of Mayo Clinic Proceedings (Mayo Clin Proc. 2015;90(5):693), the publisher was incorrect in the last reference. Reference 8 should read: Perlmutter L, Cortez-Perlmutter J. The Heart and Science of Yoga. AMI Publishers, Averill Park, NY, Chapter 28; 237-238.
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      • In reply—Epigenetics and Childhood Obesity
        Mayo Clinic ProceedingsVol. 90Issue 5
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          I sincerely welcome the letter from Drs Kaushik, Pettus, and Malkani and the opportunity to continue the increasingly vigorous scientific discourse that my theory1 has fomented in disciplines as disparate as pediatrics, sociology, evolutionary genetics, and public health. It is not often that a scientist finds his or her work1 associated with quotes from Einstein and Vedic texts. Although I sincerely appreciate the compliment these authors offer me, I think it necessary to address 2 important issues: first, their interpretation of my use of the term nongenetic, and second, the assumption that the genome and/or epigenome are productive levels of analysis with respect to obesity and type 2 diabetes mellitus (T2DM).
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