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In replyEpigenetics and Childhood Obesity

      I sincerely welcome the letter from Drs Kaushik, Pettus, and Malkani and the opportunity to continue the increasingly vigorous scientific discourse that my theory
      • Archer E.
      The childhood obesity epidemic as a result of nongenetic evolution: the maternal resources hypothesis.
      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 work
      • Archer E.
      The childhood obesity epidemic as a result of nongenetic evolution: the maternal resources hypothesis.
      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).
      In my article, the term nongenetic is not synonymous with the term epigenetic. In my reply to a previous letter to the editor,
      • Archer E.
      In reply—maternal, paternal, and societal efforts are needed to “cure” childhood obesity.
      I offered a detailed explanation of my use of the term nongenetic, and I direct readers to that response. I will not belabor that point here but will provide further support for my position that genetic/epigenetic research is an incongruous level of analysis for the examination of obesity and T2DM and as such represents an extremely costly, unnecessary, and irrelevant tangent for clinically relevant scientific progress.

      Scientific Progress and Relevant Levels of Analysis

      Science can be described as the pursuit of explanation and prediction (ie, lawful relations) and when possible, control of the natural world. Given that the foundation of medicine is the prediction and control of biological processes, science is the essence of the clinician’s professional life. Although scientific examinations may be performed at many levels of analysis (eg, from cells to society), for many biological phenomena there is a single level of analysis that subsumes both ultimate and proximate causes and therefore is the most relevant to achieve the scientific (and clinical) ends of explanation, prediction, and control. For example, if a physician seeks to explain to a parent why his or her child has fetal alcohol syndrome (FAS), the most relevant level of analysis is the mother’s behavior because it is the mother’s prenatal ethanol consumption
      • Hill L.M.
      • Kleinberg F.
      Effects of drugs and chemicals on the fetus and newborn (second of two parts).
      • Esper L.H.
      • Furtado E.F.
      Identifying maternal risk factors associated with Fetal Alcohol Spectrum Disorders: a systematic review.
      (ie, the ultimate cause) that alters the trajectory of the child’s prenatal and postnatal development (ie, the proximate causes). It is patently obvious that gene expression was substantially altered, but the level of analysis with the most explanatory and predictive power is the mother’s prenatal behavior.
      • Esper L.H.
      • Furtado E.F.
      Identifying maternal risk factors associated with Fetal Alcohol Spectrum Disorders: a systematic review.
      The molecular level of analysis (eg, genetic/epigenetic) offers the clinician no additional information relevant to the explanation, prediction, or control (eg, prevention) of FAS. Thus, as with childhood obesity, gene expression is merely one of the many components in the proximate causal pathway of the FAS phenotype that are subsumed by the ultimate cause.

      Levels of Analysis Relevant to Scientific Progress in Obesity and T2DM Research

      Funding for biomedical research has increased exponentially over the past few decades as the National Institutes of Health research expenditures increased from less than $5 billion in 1970 to approximately $30 billion in 2010.

      National Science Foundation. Federal funds for R&D. National Science Foundation website. http://www.nsf.gov/statistics/fedfunds/. Updated June 5, 2013. Accessed February 21, 2015.

      American Association for the Advancement of Science. Trends in federal research by discipline, FY 1970-2012. American Association for the Advancement of Science website. http://www.aaas.org/page/historical-trends-federal-rd. Updated February 27, 2015. Accessed February 21, 2015.

      This increase was greater than that for all other scientific disciplines combined. Nevertheless, the sheer volume of tangential and irrelevant information produced by the massive influx of funding has obscured both scientific common sense and basic knowledge as the competition for grants, publications, and professional tenure gained prominence over problem solving. Fundable but trivial research became more important than the scientific ends of explanation, prediction, and control.
      I wrote the article on the maternal resource hypothesis to provide a synthesis and integration of a century of knowledge in the hope that it will assist in overcoming the information overload and the pursuit of trivial research that currently pervades obesity and nutrition science. To that end, my theory explicitly states that the ultimate cause of childhood obesity and predisposition to T2DM is nongenetic evolution via accumulative maternal effects. The proximate causal elements are (1) maternal prenatal energy metabolism, of which body composition and physical activity are the greatest determinants, and (2) maternal postnatal physical activity, which substantially influences the child’s lifelong physical activity behaviors and consequent disease risk. As such, all other levels of analysis (eg, genetic, epigenetic, microbiomic, economic) are merely interesting but costly and irrelevant tangents to scientific progress in preventing obesity and T2DM.

      Accumulative and “Corrective” Maternal Effects

      The scientific literature on maternal effects and metabolic functioning in both humans and other animals (eg, sheep, rodents) is unequivocal.
      • Brooks A.A.
      • Johnson M.R.
      • Steer P.J.
      • Pawson M.E.
      • Abdalla H.I.
      Birth weight: nature or nurture?.
      • Kurnianto E.
      • Shinjo A.
      • Suga D.
      Prenatal and postnatal maternal effects on body weight in cross-fostering experiment on two subspecies of mice.
      • Wu Q.
      • Mizushima Y.
      • Komiya M.
      • Matsuo T.
      • Suzuki M.
      Body fat accumulation in the male offspring of rats fed high-fat diet.
      • Patterson C.M.
      • Dunn-Meynell A.A.
      • Levin B.E.
      Three weeks of early-onset exercise prolongs obesity resistance in DIO rats after exercise cessation.
      • Patterson C.M.
      • Levin B.E.
      Role of exercise in the central regulation of energy homeostasis and in the prevention of obesity.
      • Gardner D.S.
      • Buttery P.J.
      • Daniel Z.
      • Symonds M.E.
      Factors affecting birth weight in sheep: maternal environment.
      Ovum transfer, animal breeding, and cross-fostering studies have clearly documented that the intrauterine milieu and early postnatal periods can induce or ameliorate metabolic dysfunction in a single generation, independent of genotype. Recently, an embryo transfer study by Garg et al
      • Garg M.
      • Thamotharan M.
      • Dai Y.
      • Lee P.W.
      • Devaskar S.U.
      Embryo-transfer of the F2 postnatal calorie restricted female rat offspring into a control intra-uterine environment normalizes the metabolic phenotype.
      found that the inheritance of pathologic metabolic phenotypes can be ameliorated when the embryo is transferred and gestated in a “normal metabolic environment.” These results taken together provide unambiguous empirical support for the maternal resource hypothesis and my contention that genetic/epigenetic research is an incongruous level of analysis for the examination of obesity and T2DM and represents an extremely costly, irrelevant tangent for clinically relevant scientific progress.

      Acknowledgments

      The content of this letter is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.

      References

        • Archer E.
        The childhood obesity epidemic as a result of nongenetic evolution: the maternal resources hypothesis.
        Mayo Clin Proc. 2015; 90: 77-92
        • Archer E.
        In reply—maternal, paternal, and societal efforts are needed to “cure” childhood obesity.
        Mayo Clin Proc. 2015; 90 ([letter]): 555-557
        • Hill L.M.
        • Kleinberg F.
        Effects of drugs and chemicals on the fetus and newborn (second of two parts).
        Mayo Clin Proc. 1984; 59: 755-765
        • Esper L.H.
        • Furtado E.F.
        Identifying maternal risk factors associated with Fetal Alcohol Spectrum Disorders: a systematic review.
        Eur Child Adolesc Psychiatry. 2014; 23: 877-889
      1. National Science Foundation. Federal funds for R&D. National Science Foundation website. http://www.nsf.gov/statistics/fedfunds/. Updated June 5, 2013. Accessed February 21, 2015.

      2. American Association for the Advancement of Science. Trends in federal research by discipline, FY 1970-2012. American Association for the Advancement of Science website. http://www.aaas.org/page/historical-trends-federal-rd. Updated February 27, 2015. Accessed February 21, 2015.

        • Brooks A.A.
        • Johnson M.R.
        • Steer P.J.
        • Pawson M.E.
        • Abdalla H.I.
        Birth weight: nature or nurture?.
        Early Hum Dev. 1995; 42: 29-35
        • Kurnianto E.
        • Shinjo A.
        • Suga D.
        Prenatal and postnatal maternal effects on body weight in cross-fostering experiment on two subspecies of mice.
        Exp Anim. 1998; 47: 97-103
        • Wu Q.
        • Mizushima Y.
        • Komiya M.
        • Matsuo T.
        • Suzuki M.
        Body fat accumulation in the male offspring of rats fed high-fat diet.
        J Clin Biochem Nutr. 1998; 25: 71-79
        • Patterson C.M.
        • Dunn-Meynell A.A.
        • Levin B.E.
        Three weeks of early-onset exercise prolongs obesity resistance in DIO rats after exercise cessation.
        Am J Physiol Regul Integr Comp Physiol. 2008; 294: R290-R301
        • Patterson C.M.
        • Levin B.E.
        Role of exercise in the central regulation of energy homeostasis and in the prevention of obesity.
        Neuroendocrinology. 2008; 87: 65-70
        • Gardner D.S.
        • Buttery P.J.
        • Daniel Z.
        • Symonds M.E.
        Factors affecting birth weight in sheep: maternal environment.
        Reproduction. 2007; 133: 297-307
        • Garg M.
        • Thamotharan M.
        • Dai Y.
        • Lee P.W.
        • Devaskar S.U.
        Embryo-transfer of the F2 postnatal calorie restricted female rat offspring into a control intra-uterine environment normalizes the metabolic phenotype.
        Metabolism. 2013; 62: 432-441

      Linked Article

      • Epigenetics and Childhood Obesity
        Mayo Clinic ProceedingsVol. 90Issue 5
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          In his article in the January 2015 issue of Mayo Clinic Proceedings, Archer1 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.
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