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The Childhood Obesity Epidemic as a Result of Nongenetic Evolution: The Maternal Resources Hypothesis

  • Edward Archer
    Correspondence
    Correspondence: Address to Edward Archer, PhD, MS, Office of Energetics, Nutrition Obesity Research Center, University of Alabama at Birmingham, 1675 University Blvd, Webb 568, Birmingham, AL 35294.
    Affiliations
    Office of Energetics, Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham
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Published:November 16, 2014DOI:https://doi.org/10.1016/j.mayocp.2014.08.006

      Abstract

      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. At menarche, the competitive dominance of adipocytes was further amplified via hormone-induced adipocyte hyperplasia and weight-induced decrements in physical activity. These metabolic and behavioral effects were propagated progressively when obese, inactive, metabolically compromised women produced progressively larger, more inactive, metabolically compromised children. Consequently, the evolution of human energy metabolism was markedly altered. This phenotypic evolution was exacerbated by increments in the use of cesarean sections, which allowed both the larger fetuses and the metabolically compromised mothers who produced them to survive and reproduce. Thus, natural selection was iatrogenically rendered artificial selection, and the frequency of obese, inactive, metabolically compromised phenotypes increased in the global population. By the late 20th century, a metabolic tipping point was reached at which the postprandial insulin response was so intense, the relative number of adipocytes so large, and inactivity so pervasive that the competitive dominance of adipocytes in the sequestering of nutrient energy was inevitable and obesity was unavoidable.

      Abbreviations and Acronyms:

      CVD (cardiovascular disease), EE (energy expenditure), ME (maternal effects), MRH (maternal resources hypothesis), PA (physical activity), PAEE (physical activity energy expenditure), PE (phenotypic evolution), SEE (socioenvironmental evolution), SM (skeletal muscle), T2DM (type 2 diabetes mellitus), TV (television)
      The purpose of this article was to provide a reinterpretation and synthesis of existing empirical evidence in support of a novel theory of the etiology of the childhood obesity epidemic. The foundational theses are as follows: (1) obesity is the consequence of the competitive dominance of adipocytes over other cell types in the acquisition and sequestering of nutrient energy, and (2) the childhood obesity epidemic is the result of nongenetic evolutionary processes altering the interplay between maternal energy resources (eg, body mass and adiposity), maternal patterns of physical activity (PA), and the ensuing metabolic sequelae of pregnancy that affect subsequent fetal outcomes.

      Overview

      The current gene-centric paradigm of inheritance and evolution has limited explanatory or predictive power with respect to the ubiquity, rapidity, and unidirectional nature of the dramatic increase in the prevalence of obesity and other notable phenotypic changes exhibited by infants and children over the past century (eg, increased height and head circumference, body mass, and precocious menarche
      • Kagawa M.
      • Tahara Y.
      • Moji K.
      • Nakao R.
      • Aoyagi K.
      • Hills A.P.
      Secular changes in growth among Japanese children over 100 years (1900-2000).
      • Thompson W.S.
      • Cohle S.D.
      Fifteen-year retrospective study of infant organ weights and revision of standard weight tables.
      • Karvonen M.
      • Hannila M.L.
      • Saari A.
      • Dunkel L.
      New Finnish reference for head circumference from birth to 7 years.
      • Euling S.Y.
      • Herman-Giddens M.E.
      • Lee P.A.
      • et al.
      Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings.
      ). Although it may be true that “nothing in biology makes sense except in the light of evolution,”
      • Dobzhansky T.
      Nothing in biology makes sense except in the light of evolution.
      for most of the 20th century, nongenetic vectors of inheritance and the evolutionary consequences of developmental dynamics leading to novel phenotypes were largely ignored.
      • Lickliter R.
      The origins of variation: evolutionary insights from developmental science.
      • Price T.D.
      • Qvarnström A.
      • Irwin D.E.
      The role of phenotypic plasticity in driving genetic evolution.
      • Noble D.
      • Jablonka E.
      • Joyner M.J.
      • Müller G.B.
      • Omholt S.W.
      Evolution evolves: physiology returns to centre stage.
      This a priori constraint on heritability and evolution has no empirical or theoretical foundation; however, because theory affects research, clinical practice, and public health policy, the exclusion of nongenetic pathways for the intergenerational transmission of obesity and high-risk phenotypes has been unproductive.
      • Joyner M.J.
      • Prendergast F.G.
      Chasing Mendel: five questions for personalized medicine.
      As noted by Harris (1904) more than 100 years ago, “Natural selection may explain the survival of the fittest, but it cannot explain the arrival of the fittest.”
      • Harris J.A.
      A new theory of the origin of species.
      Given the heterogeneity of environments into which an organism may be born and the fact that phenotype-environment interactions are the substrate upon which natural selection acts, evolutionary fitness (ie, enhanced survival and reproduction) necessitates mechanisms by which the salient environmental exposures that generated the (successful) phenotype of the mother are translated to the offspring (ie, the “arrival of the fittest”
      • Harris J.A.
      A new theory of the origin of species.
      ). Because considerable environmental changes commonly occur from one generation to the next, adaptive phenotypes will not necessarily be generated via genetic inheritance. As such, I assert that the “missing heritability”
      • Llewellyn C.H.
      • Trzaskowski M.
      • Plomin R.
      • Wardle J.
      Finding the missing heritability in pediatric obesity: the contribution of genome-wide complex trait analysis.
      in the rapid phenotypic changes exhibited over the past century (ie, inheritance not explained via gene-centric paradigms) will not be found in the genome, and propose a novel conceptualization of inheritance in which nongenetic vectors of evolution (ie, maternal effects [ME] and socioenvironmental and phenotypic evolution [PE]) are the predominant causal elements in the recent rise in the prevalence of childhood obesity.

      Conceptual Foundation

      In this article, I provide a reinterpretation and synthesis of existing evidence to support a novel theory of inheritance and the evolution of the childhood obesity epidemic: the maternal resources hypothesis (MRH). Stated simply, the MRH posits that the childhood obesity epidemic is the result of nongenetic evolutionary processes over the past century, leading to a metabolic tipping point in human energy metabolism at which adipocytes (ie, fat cells) outcompete other cell types in the acquisition and sequestering of nutrient energy. This competitive dominance was established and is maintained by the confluence of excess maternal resources (eg, body mass and adiposity) and inactivity-induced decrements in metabolic control during pregnancy. Given the continuum of fetal metabolic dysfunction induced via the confluence of maternal resources, inactivity, and sedentarism, I posit that the most inactive and obese familial lines have evolved beyond this metabolic tipping point (eg, non-Hispanic blacks and Pima Amerindians).
      • Schulz L.O.
      • Bennett P.H.
      • Ravussin E.
      • et al.
      Effects of traditional and western environments on prevalence of type 2 diabetes in Pima Indians in Mexico and the U.S.
      • Andersen R.E.
      • Crespo C.J.
      • Bartlett S.J.
      • Cheskin L.J.
      • Pratt M.
      Relationship of physical activity and television watching with body weight and level of fatness among children: results from the Third National Health and Nutrition Examination Survey.
      • Sisson S.B.
      • Broyles S.T.
      Social-ecological correlates of excessive TV viewing: difference by race and sex.
      • Getahun D.
      • Strickland D.
      • Lawrence J.M.
      • Fassett M.J.
      • Koebnick C.
      • Jacobsen S.J.
      Racial and ethnic disparities in the trends in primary cesarean delivery based on indications.
      For most individuals in these groups, increasing obesity and metabolic dysfunction are inevitable without significant preconception and prenatal intervention.
      For this novel conceptualization of inheritance, evolution, and the etiology of obesity, there are a number of essential, interrelated, and empirically supported arguments. First, all living cells compete for nutrient energy,
      • Peters A.
      The selfish brain: competition for energy resources.
      and the strategies used for the acquisition, storage, and use of nutrient energy vary across cell types
      • Baron A.D.
      • Brechtel G.
      • Wallace P.
      • Edelman S.V.
      Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans.
      and contexts.
      • Aas V.
      • Rokling-Andersen M.
      • Wensaas A.J.
      • Thoresen G.H.
      • Kase E.T.
      • Rustan A.C.
      Lipid metabolism in human skeletal muscle cells: effects of palmitate and chronic hyperglycaemia.
      Thus, if obesity is defined as an excessive storage of energy as lipid in adipocytes, then it can logically be viewed as a result of the competitive dominance of adipocytes over other cells, tissues, and organs in the acquisition and sequestering of nutrient-energy resources. Second, the recent competitive dominance of adipocytes in children (ie, the childhood obesity epidemic) was established and is maintained and/or exacerbated by 3 parallel, reciprocal evolutionary processes: ME,
      • Badyaev A.V.
      Maternal effects as generators of evolutionary change: a reassessment.
      PE,
      • Arnold S.J.
      Constraints on phenotypic evolution.
      and SEE (socioenvironmental evolution).
      • White L.A.
      Energy and the evolution of culture.
      • Perreault C.
      The pace of cultural evolution.

      Operational Definitions

      The Table
      • Dawkins R.
      The Extended Phenotype.
      • Wolf J.B.
      • Wade M.J.
      What are maternal effects (and what are they not)?.
      • Mousseau T.A.
      • Fox C.W.
      The adaptive significance of maternal effects.
      • Arnold S.J.
      Multivariate inheritance and evolution: a review of concepts.
      • Bernardo J.
      Maternal effects in animal ecology.
      • Broadhurst P.L.
      Analysis of maternal effects in the inheritance of behaviour.
      • Krogh-Madsen R.
      • Thyfault J.P.
      • Broholm C.
      • et al.
      A 2-wk reduction of ambulatory activity attenuates peripheral insulin sensitivity.
      • Thyfault J.P.
      • Krogh-Madsen R.
      Metabolic disruptions induced by reduced ambulatory activity in free-living humans.
      • Bergouignan A.
      • Schoeller D.A.
      • Normand S.
      • et al.
      Effect of physical inactivity on the oxidation of saturated and monounsaturated dietary fatty acids: results of a randomized trial.
      • Day T.
      • Bonduriansky R.
      A unified approach to the evolutionary consequences of genetic and nongenetic inheritance.
      provides operational definitions for the key terms used in this article. The definitions are broad and encompass the multidimensional nature and interdisciplinary structure of my hypotheses, which link nongenetic evolutionary processes and observed epidemiological trends in maternal phenotype to the physiological mechanisms driving the childhood obesity epidemic. Throughout this article, the term evolution is used broadly and refers to progressive, unidirectional changes over time in the variable under examination. This definition subsumes changes in inherited characteristics over successive generations (ie, descent with modification
      • Darwin C.
      On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life.
      ) and more restricted uses (eg, changes in allele frequencies). This use is inclusive of the inheritance of both biological and nonbiological (ie, abiotic) characteristics (eg, an impoverished postnatal environment).
      TableOperational Definitions
      Key termDefinition
      EnvironmentExternal: The totality of the biotic and abiotic factors that are independent of an organism but affect development.

      Internal: The totality of the anatomic, physiologic, and metabolic constituents that form an organism.
      EvolutionProgressive, unidirectional changes over time in the variable under examination; inclusive of changes in inherited characteristics over successive generations and the inheritance of biological and nonbiological (ie, abiotic) characteristics (eg, environmental resources).
      Inheritance or heritabilityThe intergenerational transmission of social and biological traits, attributes, characteristics, and/or features. Inheritance may occur via nongenetic (eg physiologic and cultural), epigenetic, and genetic vectors.
      Maternal effectsMaternal effects are nongenetic vectors of inheritance (ie, intergenerational transmission) in which maternal phenotype (eg, age, body mass, metabolism, and behavior) and extended phenotype
      • Dawkins R.
      The Extended Phenotype.
      directly induce rapid, phenotypic alterations in offspring, independent of the genotype.
      • Wolf J.B.
      • Wade M.J.
      What are maternal effects (and what are they not)?.
      • Mousseau T.A.
      • Fox C.W.
      The adaptive significance of maternal effects.
      • Arnold S.J.
      Multivariate inheritance and evolution: a review of concepts.
      • Bernardo J.
      Maternal effects in animal ecology.
      • Broadhurst P.L.
      Analysis of maternal effects in the inheritance of behaviour.
      Nutrient energyEnergy derived from the consumption of food and beverages that is available for metabolic processes.
      Nutrient partitioningThe metabolic fate of consumed nutrient energy (eg, anabolism, storage, and oxidation). Body composition, physical activity, and hormonal status (eg, puberty, pregnancy, and menopause) are the primary determinants.
      • Krogh-Madsen R.
      • Thyfault J.P.
      • Broholm C.
      • et al.
      A 2-wk reduction of ambulatory activity attenuates peripheral insulin sensitivity.
      • Thyfault J.P.
      • Krogh-Madsen R.
      Metabolic disruptions induced by reduced ambulatory activity in free-living humans.
      • Bergouignan A.
      • Schoeller D.A.
      • Normand S.
      • et al.
      Effect of physical inactivity on the oxidation of saturated and monounsaturated dietary fatty acids: results of a randomized trial.
      PhenotypeAn organism’s observable characteristics or traits, including, but not limited to, its morphology, development, physiology, metabolism, behavior, and products of behavior.
      • Dawkins R.
      The Extended Phenotype.
      Phenotypic evolutionUnidirectional, progressive alterations in ontogeny that are propagated over multiple successive generations and may be quantified as the change over time in the population mean for the trait under examination (eg, height and obesity). Phenotypic evolution is driven by developmental plasticity and adaptations to environmental heterogeneity. Because natural selection acts directly at the level of the phenotype, phenotypic evolution has direct evolutionary consequences and may be induced via genetic, epigenetic, or nongenetic pathways of inheritance.
      • Day T.
      • Bonduriansky R.
      A unified approach to the evolutionary consequences of genetic and nongenetic inheritance.
      Socioenvironmental evolutionSocioenvironmental evolution is a progression of social and/or cultural practices that markedly alters behavior and/or the environments in which humans exist.
      • White L.A.
      Energy and the evolution of culture.
      • Perreault C.
      The pace of cultural evolution.
      Socioenvironmental evolution has direct evolutionary consequences because phenotype-environment interactions are the substrate on which natural selection acts. In social species, conspecifics and the environmental context may have a greater impact on an individual’s survival and reproduction (ie, evolutionary fitness) than his or her genome.

      Background for Key Concepts

      Maternal Effects

      Maternal effects are nongenetic vectors of inheritance (ie, intergenerational transmission) in which maternal phenotype (eg, age, body mass, metabolism, and behavior) and extended phenotype (eg, environmental modifications)
      • Dawkins R.
      The Extended Phenotype.
      induce rapid, phenotypic alterations in offspring, independent of the genotype.
      • Wolf J.B.
      • Wade M.J.
      What are maternal effects (and what are they not)?.
      • Mousseau T.A.
      • Fox C.W.
      The adaptive significance of maternal effects.
      • Arnold S.J.
      Multivariate inheritance and evolution: a review of concepts.
      • Bernardo J.
      Maternal effects in animal ecology.
      • Broadhurst P.L.
      Analysis of maternal effects in the inheritance of behaviour.
      As such, ME represent a mechanism by which the environmental exposures that generated the phenotype of the mother are translated directly (via developmental plasticity
      • Moczek A.P.
      • Sultan S.
      • Foster S.
      • et al.
      The role of developmental plasticity in evolutionary innovation.
      ) into the phenotype of the offspring.
      • Wolf J.B.
      • Wade M.J.
      What are maternal effects (and what are they not)?.
      Maternal effects may be induced via direct physiological effects on the fetus in utero
      • Portha B.
      • Chavey A.
      • Movassat J.
      Early-life origins of type 2 diabetes: fetal programming of the beta-cell mass.
      • Gluckman P.D.
      • Hanson M.A.
      • Bateson P.
      • et al.
      Towards a new developmental synthesis: adaptive developmental plasticity and human disease.
      and/or the transmission of behavior
      • Mousseau T.A.
      • Fox C.W.
      The adaptive significance of maternal effects.
      • Broadhurst P.L.
      Analysis of maternal effects in the inheritance of behaviour.
      from mothers to infants and children via social learning, imitation, and operant and/or classical conditioning.
      • Notten N.
      • Kraaykamp G.
      • Konig R.P.
      Family media matters: unraveling the intergenerational transmission of reading and television tastes.
      • Ricks M.H.
      The social transmission of parental behavior: attachment across generations.
      • Krahnstoever Davison K.
      • Francis L.A.
      • Birch L.L.
      Reexamining obesigenic families: parents’ obesity-related behaviors predict girls’ change in BMI.
      • Skinner B.F.
      Science and Human Behavior.
      Maternal effects are ubiquitous in nature
      • Mousseau T.A.
      • Fox C.W.
      The adaptive significance of maternal effects.
      • Arnold S.J.
      Multivariate inheritance and evolution: a review of concepts.
      and contribute to the variation in phenotypes derived from any given genotype.
      • Wolf J.B.
      • Wade M.J.
      What are maternal effects (and what are they not)?.
      • Mousseau T.A.
      • Fox C.W.
      The adaptive significance of maternal effects.
      • Arnold S.J.
      Multivariate inheritance and evolution: a review of concepts.
      • Bernardo J.
      Maternal effects in animal ecology.
      • Broadhurst P.L.
      Analysis of maternal effects in the inheritance of behaviour.
      • Steiger S.
      Bigger mothers are better mothers: disentangling size-related prenatal and postnatal maternal effects.
      • Wade M.J.
      The evolutionary genetics of maternal effects.
      Maternal effects are causal elements in ontogeny and phenotypic plasticity in response to environmental heterogeneity
      • Wolf J.B.
      • Wade M.J.
      What are maternal effects (and what are they not)?.
      and are of evolutionary significance
      • Badyaev A.V.
      Maternal effects as generators of evolutionary change: a reassessment.
      • Wade M.J.
      The evolutionary genetics of maternal effects.
      because they are an essential component in generating the substrate on which natural selection acts (ie, the phenotype).
      • Badyaev A.V.
      Maternal effects as generators of evolutionary change: a reassessment.
      • Wolf J.B.
      • Wade M.J.
      What are maternal effects (and what are they not)?.
      • Mousseau T.A.
      • Fox C.W.
      The adaptive significance of maternal effects.
      • Day T.
      • Bonduriansky R.
      A unified approach to the evolutionary consequences of genetic and nongenetic inheritance.
      • Wade M.J.
      The evolutionary genetics of maternal effects.
      Within a permissive environment, ME may be cumulative
      • Lande R.
      • Kirkpatrick M.
      Selection response in traits with maternal inheritance.
      • Kirkpatrick M.
      • Lofsvold D.
      The evolution of growth trajectories and other complex quantitative characters.
      and can produce a progressive acceleration or regression of both phenotypic and genotypic evolution, as well as effects that may be in direct contrast to traits favored by natural selection (ie, nonadaptive).
      • Price T.D.
      • Qvarnström A.
      • Irwin D.E.
      The role of phenotypic plasticity in driving genetic evolution.
      • Mousseau T.A.
      • Fox C.W.
      The adaptive significance of maternal effects.
      • Bernardo J.
      Maternal effects in animal ecology.
      • Wells J.C.
      The thrifty phenotype as an adaptive maternal effect.
      Maternal effects occur in 2 developmental contexts—the prenatal (ie, intrauterine) and postnatal environments—and are a major driver of other evolutionary processes—PE and SEE.

      Phenotypic Evolution

      Phenotypic evolution is a unidirectional, progressive alteration in ontogeny that is propagated over multiple successive generations and may be quantified as the change over time in the population mean for the trait under examination (eg, height and obesity). As will be presented in detail in a later section, PE is neither mere phenotypic plasticity nor acute adaptations to environmental heterogeneity but the progressive intergenerational transmission of acquired characteristics over multiple successive generations. Phenotypic evolution may occur in anatomic and/or physiologic traits (eg, height, weight, size at birth, age at menarche, hyperplastic adiposity, and organ mass and function) or behavioral traits (eg, inactivity and sedentarism). Because natural selection acts directly at the level of the phenotype, PE has direct evolutionary consequences and may be induced via genetic, epigenetic, or nongenetic pathways of inheritance.
      • Day T.
      • Bonduriansky R.
      A unified approach to the evolutionary consequences of genetic and nongenetic inheritance.

      Socioenvironmental Evolution

      Socioenvironmental evolution is a progression of social and/or cultural practices that significantly alters behavior and/or the physical environments in which humans exist.
      • White L.A.
      Energy and the evolution of culture.
      • Perreault C.
      The pace of cultural evolution.
      It has been posited that SEE can be measured by a population’s “ability to utilize energy for human advancement or needs.”
      • MacCurdy G.G.
      Human Origins: A Manual of Prehistory.
      Socioenvironmental evolution occurs in multiple contexts such as social practices (eg, health care) or changes in the physical environment (eg, sanitation, food supply, labor and time-saving technologies, heating, and air conditioning). Socioenvironmental evolution may be considered both a process and a product of numerous factors including both technological innovation
      • White L.A.
      Energy and the evolution of culture.
      and social learning and imitation (eg, memes).
      • Dawkins R.
      The Selfish Gene.
      Because SEE may affect the development of a phenotype and substantially alter the environmental context and consequent phenotype-environment interactions, it has direct evolutionary consequences. In social species, conspecifics and the environmental context may have a greater impact on an individual’s survival than on his or her genetic inheritance. Socioenvironmental evolution, PE, and ME can have reciprocal relationships as phenotype-environment interactions drive developmental dynamics, which, in turn, drive the evolution of social and environmental milieus. Figure 1 is a conceptual depiction of the MRH.
      Figure thumbnail gr1
      Figure 1Conceptual depiction of the maternal resources hypothesis.

      The Maternal Resources Hypothesis

      The Recent Evolution of Human Energy Metabolism

      Human metabolic, cardiovascular, and musculoskeletal systems evolved in environments in which survival necessitated prodigious amounts of physical exertion and high levels of energy expenditure (EE).
      • Bramble D.M.
      • Lieberman D.E.
      Endurance running and the evolution of Homo.
      Evading predators, the hunting and gathering of food, and the literal “chopping wood and carrying water” of daily existence provided a wholesome dose of PA that obviated the need for deliberate exercise.
      • Archer E.
      • Blair S.N.
      Physical activity and the prevention of cardiovascular disease: from evolution to epidemiology.
      Nevertheless, over the past few centuries, humans have become extremely adept at altering the environments in which they exist, and the evolution of their physical, social, and cultural milieus (ie, SEE) has proceeded much more rapidly than has genetic evolution.
      • Perreault C.
      The pace of cultural evolution.
      Socioenvironmental evolution has altered the evolution of human energy metabolism by inducing substantial decrements in EE imposed by daily life
      • Passmore R.
      • Durnin J.V.
      Human energy expenditure.
      while improving both the quality and the quantity of nutrient-energy availability.
      World Health Organization
      Global Strategy on Diet, Physical Activity, and Health.
      For example, as thermoneutral environments became ubiquitous,
      • Kingma B.
      • Frijns A.
      • van Marken Lichtenbelt W.
      The thermoneutral zone: implications for metabolic studies.
      the energy cost of thermoregulation declined, and improved sanitation (eg, clean water and safer food)

      Semba RD. The impact of improved nutrition on disease prevention. In: Ward JW, Warren C, eds. Silent Victories: The History and Practice of Public Health in Twentieth Century America. Oxford Scholarship Online. Oxford: Oxford University Press; 2009.

      and vaccinations
      • Plotkin S.L.
      • Plotkin S.A.
      A short history of vaccination.
      decreased the energy cost of supporting parasites (eg, fleas)
      • Giorgi M.S.
      • Arlettaz R.
      • Christe P.
      • Vogel P.
      The energetic grooming costs imposed by a parasitic mite (Spinturnix myoti) upon its bat host (Myotis myotis).
      and resisting pathogens (eg, communicable diseases and diarrheal infections).
      • O’Brien K.L.
      • Wolfson L.J.
      • Watt J.P.
      • et al.
      Hib and Pneumococcal Global Burden of Disease Study Team
      Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates.
      Together, these changes not only decreased EE but also dramatically curtailed periods of low-energy consumption via reductions in both illness-induced hypophagia and declines in appetite from elevated ambient temperatures.
      • Brown K.H.
      • Stallings R.Y.
      • de Kanashiro H.C.
      • Lopez de Romaña G.
      • Black R.E.
      Effects of common illnesses on infants’ energy intakes from breast milk and other foods during longitudinal community-based studies in Huascar (Lima), Peru.
      By gradually reducing the energy costs of survival and increasing nutrient-energy availability,

      Semba RD. The impact of improved nutrition on disease prevention. In: Ward JW, Warren C, eds. Silent Victories: The History and Practice of Public Health in Twentieth Century America. Oxford Scholarship Online. Oxford: Oxford University Press; 2009.

      SEE increased the energy available for development, growth, and reproduction. The positive energy balance facilitated by SEE led to the evolution of many human characteristics (ie, PE). For example, improvements in health and nutrition over the past century have led to progressive and cumulative increases in height,
      • Kagawa M.
      • Tahara Y.
      • Moji K.
      • Nakao R.
      • Aoyagi K.
      • Hills A.P.
      Secular changes in growth among Japanese children over 100 years (1900-2000).
      body stature and mass,
      • Ogden C.L.
      • Fryar C.D.
      • Carroll M.D.
      • Flegal K.M.
      Mean body weight, height, and body mass index, United States 1960-2002.
      birthweight,
      • Ananth C.V.
      • Wen S.W.
      Trends in fetal growth among singleton gestations in the United States and Canada, 1985 through 1998.
      • Chike-Obi U.
      • David R.J.
      • Coutinho R.
      • Wu S.Y.
      Birth weight has increased over a generation.
      • Lahmann P.H.
      • Wills R.A.
      • Coory M.
      Trends in birth size and macrosomia in Queensland, Australia, from 1988 to 2005.
      organ mass,
      • Thompson W.S.
      • Cohle S.D.
      Fifteen-year retrospective study of infant organ weights and revision of standard weight tables.
      • Shepard T.H.
      • Shi M.
      • Fellingham G.W.
      • et al.
      Organ weight standards for human fetuses.
      head circumference,
      • Karvonen M.
      • Hannila M.L.
      • Saari A.
      • Dunkel L.
      New Finnish reference for head circumference from birth to 7 years.
      • Ounsted M.
      • Moar V.A.
      • Scott A.
      Head circumference charts updated.
      and fat mass/adiposity.
      • Olds T.S.
      One million skinfolds: secular trends in the fatness of young people 1951-2004.
      In concert with these increments has been a progressive global decline in the age at which adolescents attain sexual maturity, with breast development (ie, thelarche) and menses (ie, menarche) in girls and testicular development in boys beginning a year earlier in many populations.
      • Euling S.Y.
      • Herman-Giddens M.E.
      • Lee P.A.
      • et al.
      Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings.
      This PE has been ubiquitous and significant. A recent examination of the validity of the 1975 “Reference Man”
      • Later W.
      • Bosy-Westphal A.
      • Kossel E.
      • Glüer C.C.
      • Heller M.
      • Müller M.J.
      Is the 1975 Reference Man still a suitable reference?.
      for determining the safety of medication doses and occupational radiation exposure found that men and women in 2010 were heavier, taller, and had more fat and skeletal muscle (SM) mass and larger organ masses.
      Given that reproductive capacity is an essential facet of evolution, and in humans reproduction cannot occur without sufficient maternal resources (ie, body mass and adiposity), these alterations in the phenotype have nongenetic evolutionary consequences (ie, they alter survival and reproductive success independent of changes in gene or allele frequency). Logically, these results are representative of PE because each of the aforementioned characteristics developed with a progressive, unidirectional linearity that was transmitted to successive generations. For example, from 1900 to 2000, the median height for Japanese boys and girls increased by 20 and 19 cm at the age of 13 and 11, respectively.
      • Kagawa M.
      • Tahara Y.
      • Moji K.
      • Nakao R.
      • Aoyagi K.
      • Hills A.P.
      Secular changes in growth among Japanese children over 100 years (1900-2000).
      These changes were neither mere developmental plasticity nor acute adaptations to improved nutrition and/or decreased EE via reductions in pathogen load. These changes in the phenotype were indicative of a gradual, progressive, and enduring intergenerational transmission of greater stature over many generations that was robust to acute variations in environmental influences (eg, food shortages).

      The Late 20th Century and Increments in Maternal Resources

      Until the middle of the 20th century, SEE and PE were adaptive, given that in most species, mothers with greater energy resources (ie, physiological or environmental) beget more robust offspring,
      • Steiger S.
      Bigger mothers are better mothers: disentangling size-related prenatal and postnatal maternal effects.
      and it is well established that human mothers with adequate or ample physiological and environmental resources produce healthier, more robust infants and children than do women with fewer resources.
      World Health Organization
      Global Strategy on Diet, Physical Activity, and Health.
      Nevertheless, I posit that as the century drew to a close, sustained SEE and PE began driving ME that led to the childhood obesity epidemic.
      By the late 20th century, humans in industrialized nations were immersed in environments explicitly engineered to reduce manual labor,
      • Church T.S.
      • Thomas D.M.
      • Tudor-Locke C.
      • et al.
      Trends over 5 decades in U.S. occupation-related physical activity and their associations with obesity.
      • Archer E.
      • Lavie C.J.
      • McDonald S.M.
      • et al.
      Maternal inactivity: 45-year trends in mothers’ use of time.
      • Archer E.
      • Shook R.P.
      • Thomas D.M.
      • et al.
      45-year trends in women’s use of time and household management energy expenditure.
      increase physical comfort (eg, the ubiquity of chairs and thermoneutral environments
      • Kingma B.
      • Frijns A.
      • van Marken Lichtenbelt W.
      The thermoneutral zone: implications for metabolic studies.
      ), and afford passive entertainment.
      • Taveras E.M.
      • Hohman K.H.
      • Price S.
      • Gortmaker S.L.
      • Sonneville K.
      Televisions in the bedrooms of racial/ethnic minority children: how did they get there and how do we get them out?.
      As a result, physical inactivity and sedentary pastimes (eg, Web surfing and television [TV] viewing) became both ubiquitous features of the post–industrial world
      World Health Organization
      Global Strategy on Diet, Physical Activity, and Health.
      and leading global risk factors for mortality and morbidity.
      • Lee I.M.
      • Shiroma E.J.
      • Lobelo F.
      • Puska P.
      • Blair S.N.
      • Katzmarzyk P.T.
      Lancet Physical Activity Series Working Group
      Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy.
      Importantly, the confluence of passive transportation, spectator-based entertainment, and decrements in occupational and household PA
      • Church T.S.
      • Thomas D.M.
      • Tudor-Locke C.
      • et al.
      Trends over 5 decades in U.S. occupation-related physical activity and their associations with obesity.
      • Archer E.
      • Shook R.P.
      • Thomas D.M.
      • et al.
      45-year trends in women’s use of time and household management energy expenditure.
      • Fisher E.B.
      • Fitzgibbon M.L.
      • Glasgow R.E.
      • et al.
      Behavior matters.
      led to significant declines in PA energy expenditure (PAEE) and increments in sedentary behaviors in children, women, and mothers.
      • Church T.S.
      • Thomas D.M.
      • Tudor-Locke C.
      • et al.
      Trends over 5 decades in U.S. occupation-related physical activity and their associations with obesity.
      • Archer E.
      • Lavie C.J.
      • McDonald S.M.
      • et al.
      Maternal inactivity: 45-year trends in mothers’ use of time.
      • Archer E.
      • Shook R.P.
      • Thomas D.M.
      • et al.
      45-year trends in women’s use of time and household management energy expenditure.
      From the 1960s to 2010, estimated maternal household PAEE decreased approximately 1200 to 1500 kcal/wk as the time spent in sedentary leisure (eg, watching TV) increased to more than 2.5 h/d.
      • Archer E.
      • Shook R.P.
      • Thomas D.M.
      • et al.
      45-year trends in women’s use of time and household management energy expenditure.
      Most pregnant women currently spend more than 50% of their waking hours in sedentary behavior, and more than 15% of pregnant women spend more than 5 h/d in leisure-time screen-based media use.
      • Evenson K.R.
      • Wen F.
      Prevalence and correlates of objectively measured physical activity and sedentary behavior among US pregnant women.
      Recent work suggests that by the 1990s, women and mothers allocated more time to screen-based media use (eg, watching TV) than to all forms of PA combined.
      • Archer E.
      • Shook R.P.
      • Thomas D.M.
      • et al.
      45-year trends in women’s use of time and household management energy expenditure.
      In concert with progressive increments in sedentarism, inactivity, and PAEE were progressive decrements in population-level metabolic control
      • Ioannou G.N.
      • Bryson C.L.
      • Boyko E.J.
      Prevalence and trends of insulin resistance, impaired fasting glucose, and diabetes.
      • Li C.
      • Ford E.S.
      • McGuire L.C.
      • Mokdad A.H.
      • Little R.R.
      • Reaven G.M.
      Trends in hyperinsulinemia among nondiabetic adults in the U.S.
      • Selvin E.
      • Parrinello C.M.
      • Sacks D.B.
      • Coresh J.
      Trends in prevalence and control of diabetes in the United States, 1988-1994 and 1999-2010.
      and substantial increases in maternal pregravid obesity,
      • Heslehurst N.
      • Ells L.J.
      • Simpson H.
      • Batterham A.
      • Wilkinson J.
      • Summerbell C.D.
      Trends in maternal obesity incidence rates, demographic predictors, and health inequalities in 36,821 women over a 15-year period.
      gestational weight gain,
      • Helms E.
      • Coulson C.C.
      • Galvin S.L.
      Trends in weight gain during pregnancy: a population study across 16 years in North Carolina.
      and gestational diabetes.
      • Dabelea D.
      • Snell-Bergeon J.K.
      • Hartsfield C.L.
      • Bischoff K.J.
      • Hamman R.F.
      • McDuffie R.S.
      Kaiser Permanente of Colorado GDM Screening Program
      Increasing prevalence of gestational diabetes mellitus (GDM) over time and by birth cohort: Kaiser Permanente of Colorado GDM Screening Program.

      The Necessity of PA for Metabolic Health

      Skeletal muscle activation via PA is an absolute requirement for metabolic health.
      • Pate R.R.
      • Pratt M.
      • Blair S.N.
      • et al.
      Physical activity and public health: a recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine.
      Therefore, as mothers spent more time in sedentary behavior and the intensity, frequency, and volume of maternal PA decreased,
      • Archer E.
      • Lavie C.J.
      • McDonald S.M.
      • et al.
      Maternal inactivity: 45-year trends in mothers’ use of time.
      • Archer E.
      • Shook R.P.
      • Thomas D.M.
      • et al.
      45-year trends in women’s use of time and household management energy expenditure.
      there were marked reductions in SM activation and energy flux. Because SM is the principal tissue for both insulin-mediated glucose disposal
      • Baron A.D.
      • Brechtel G.
      • Wallace P.
      • Edelman S.V.
      Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans.
      and fatty acid oxidation
      • Aas V.
      • Rokling-Andersen M.
      • Wensaas A.J.
      • Thoresen G.H.
      • Kase E.T.
      • Rustan A.C.
      Lipid metabolism in human skeletal muscle cells: effects of palmitate and chronic hyperglycaemia.
      and an essential element of energy metabolism,
      • Bergouignan A.
      • Rudwill F.
      • Simon C.
      • Blanc S.
      Physical inactivity as the culprit of metabolic inflexibility: evidence from bed-rest studies.
      progressive reductions in maternal PA and PAEE over the past century would result in progressive decrements in metabolic,
      • Baron A.D.
      • Brechtel G.
      • Wallace P.
      • Edelman S.V.
      Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans.
      • Krogh-Madsen R.
      • Thyfault J.P.
      • Broholm C.
      • et al.
      A 2-wk reduction of ambulatory activity attenuates peripheral insulin sensitivity.
      • Bergouignan A.
      • Schoeller D.A.
      • Normand S.
      • et al.
      Effect of physical inactivity on the oxidation of saturated and monounsaturated dietary fatty acids: results of a randomized trial.
      • DeFronzo R.A.
      Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM.
      • Ferraro R.T.
      • Eckel R.H.
      • Larson D.E.
      • et al.
      Relationship between skeletal muscle lipoprotein lipase activity and 24-hour macronutrient oxidation.
      • Mikus C.R.
      • Oberlin D.J.
      • Libla J.L.
      • Taylor A.M.
      • Booth F.W.
      • Thyfault J.P.
      Lowering physical activity impairs glycemic control in healthy volunteers.
      glycemic,
      • Mikus C.R.
      • Oberlin D.J.
      • Libla J.L.
      • Taylor A.M.
      • Booth F.W.
      • Thyfault J.P.
      Lowering physical activity impairs glycemic control in healthy volunteers.
      • Kavouras S.A.
      • Panagiotakos D.B.
      • Pitsavos C.
      • et al.
      Physical activity, obesity status, and glycemic control: the ATTICA study.
      • Short K.R.
      Regulation of glycemic control by physical activity: a role for mitochondria?.
      and lipidemic
      • Berg A.
      • Frey I.
      • Baumstark M.W.
      • Halle M.
      • Keul J.
      Physical activity and lipoprotein lipid disorders.
      • Zderic T.W.
      • Hamilton M.T.
      Physical inactivity amplifies the sensitivity of skeletal muscle to the lipid-induced downregulation of lipoprotein lipase activity.
      • Hamilton M.T.
      • Hamilton D.G.
      • Zderic T.W.
      Role of low energy expenditure and sitting in obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease.
      control. This loss of metabolic control led to both transient hyperglycemia (ie, glycemic excursions) and hyperlipidemia,
      • Li C.
      • Ford E.S.
      • McGuire L.C.
      • Mokdad A.H.
      • Little R.R.
      • Reaven G.M.
      Trends in hyperinsulinemia among nondiabetic adults in the U.S.
      • Cohen J.D.
      • Cziraky M.J.
      • Cai Q.
      • et al.
      30-year trends in serum lipids among United States adults: results from the National Health and Nutrition Examination Surveys II, III, and 1999-2006.
      • Olmos P.R.
      • Rigotti A.
      • Busso D.
      • et al.
      Maternal hypertriglyceridemia: a link between maternal overweight-obesity and macrosomia in gestational diabetes.
      the former driven by reductions in insulin signaling resulting from replete myocyte glycogen stores,
      • Litherland G.J.
      • Morris N.J.
      • Walker M.
      • Yeaman S.J.
      Role of glycogen content in insulin resistance in human muscle cells.
      • Jensen J.
      • Rustad P.I.
      • Kolnes A.J.
      • Lai Y.C.
      The role of skeletal muscle glycogen breakdown for regulation of insulin sensitivity by exercise.
      and the latter from reduced SM energy demands and consequent decrements in total fatty acid oxidation,
      • Berg A.
      • Frey I.
      • Baumstark M.W.
      • Halle M.
      • Keul J.
      Physical activity and lipoprotein lipid disorders.
      • Zderic T.W.
      • Hamilton M.T.
      Physical inactivity amplifies the sensitivity of skeletal muscle to the lipid-induced downregulation of lipoprotein lipase activity.
      • Hamilton M.T.
      • Hamilton D.G.
      • Zderic T.W.
      Role of low energy expenditure and sitting in obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease.
      • Jensen M.D.
      Fate of fatty acids at rest and during exercise: regulatory mechanisms.
      increments in hepatic and adipocyte de novo lipogenesis,
      • Blanc S.
      • Normand S.
      • Pachiaudi C.
      • Fortrat J.O.
      • Laville M.
      • Gharib C.
      Fuel homeostasis during physical inactivity induced by bed rest.
      • Wilke M.S.
      • French M.A.
      • Goh Y.K.
      • Ryan E.A.
      • Jones P.J.
      • Clandinin M.T.
      Synthesis of specific fatty acids contributes to VLDL-triacylglycerol composition in humans with and without type 2 diabetes.
      • Bellou E.
      • Siopi A.
      • Galani M.
      • et al.
      Acute effects of exercise and calorie restriction on triglyceride metabolism in women.
      and lipid accumulation in adipose tissue.
      • Hamilton M.T.
      • Areiqat E.
      • Hamilton D.G.
      • Bey L.
      Plasma triglyceride metabolism in humans and rats during aging and physical inactivity.
      • Slentz C.A.
      • Houmard J.A.
      • Kraus W.E.
      Exercise, abdominal obesity, skeletal muscle, and metabolic risk: evidence for a dose response.

      The ME of Inactivity and Insulin Resistance

      Although inactivity has dire effects on human energy metabolism
      • Krogh-Madsen R.
      • Thyfault J.P.
      • Broholm C.
      • et al.
      A 2-wk reduction of ambulatory activity attenuates peripheral insulin sensitivity.
      • Thyfault J.P.
      • Krogh-Madsen R.
      Metabolic disruptions induced by reduced ambulatory activity in free-living humans.
      • Olsen R.H.
      • Krogh-Madsen R.
      • Thomsen C.
      • Booth F.W.
      • Pedersen B.K.
      Metabolic responses to reduced daily steps in healthy nonexercising men.
      • Friedrichsen M.
      • Mortensen B.
      • Pehmøller C.
      • Birk J.B.
      • Wojtaszewski J.F.
      Exercise-induced AMPK activity in skeletal muscle: role in glucose uptake and insulin sensitivity.
      and health,
      • Lee I.M.
      • Shiroma E.J.
      • Lobelo F.
      • Puska P.
      • Blair S.N.
      • Katzmarzyk P.T.
      Lancet Physical Activity Series Working Group
      Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy.
      given the recent SEE and PE, it is substantially more pathologic to pregnant women and their fetuses. Human pregnancy is characterized by numerous metabolic changes that promote the accretion of adipose tissue in concert with impaired insulin sensitivity and insulin resistance.
      • Barbour L.A.
      • McCurdy C.E.
      • Hernandez T.L.
      • Kirwan J.P.
      • Catalano P.M.
      • Friedman J.E.
      Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes.
      As explained previously, SM is the principal tissue for glucose disposal, and normal pregnancies will exhibit a hormone-induced 40% to 60% reduction in insulin-mediated glucose disposal.
      • Catalano P.M.
      • Huston L.
      • Amini S.B.
      • Kalhan S.C.
      Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus.
      This decrement in insulin sensitivity drives a 200% to 300% increase in insulin secretion to maintain maternal glycemic control.
      • Catalano P.M.
      • Huston L.
      • Amini S.B.
      • Kalhan S.C.
      Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus.
      I posit that progressive reductions in maternal PA and PAEE and consequent reductions in SM activation over the past half-century act synergistically with the naturally occurring metabolic sequelae of pregnancy (ie, hormone-induced insulin resistance and increased adiposity) to exacerbate the negative metabolic consequences of inactivity
      • Krogh-Madsen R.
      • Thyfault J.P.
      • Broholm C.
      • et al.
      A 2-wk reduction of ambulatory activity attenuates peripheral insulin sensitivity.
      • Thyfault J.P.
      • Krogh-Madsen R.
      Metabolic disruptions induced by reduced ambulatory activity in free-living humans.
      • Olsen R.H.
      • Krogh-Madsen R.
      • Thomsen C.
      • Booth F.W.
      • Pedersen B.K.
      Metabolic responses to reduced daily steps in healthy nonexercising men.
      • Friedrichsen M.
      • Mortensen B.
      • Pehmøller C.
      • Birk J.B.
      • Wojtaszewski J.F.
      Exercise-induced AMPK activity in skeletal muscle: role in glucose uptake and insulin sensitivity.
      and drive fetal abnormalities. The reductions in insulin sensitivity and increments in transient hyperglycemia and hyperlipidemia
      • Olmos P.R.
      • Rigotti A.
      • Busso D.
      • et al.
      Maternal hypertriglyceridemia: a link between maternal overweight-obesity and macrosomia in gestational diabetes.
      substantially increase the availability of energy substrates to the intrauterine environment. Because the human placenta evolved in a context of intense competition between maternal resources and fetal demands (ie, low to moderate maternal body mass and adiposity in concert with moderate to high levels of maternal EE, PA, and PAEE
      • Power M.L.
      • Schulkin J.
      The Evolution of the Human Placenta.
      • Dufour D.L.
      • Sauther M.L.
      Comparative and evolutionary dimensions of the energetics of human pregnancy and lactation.
      • Gluckman P.
      • Hanson M.
      The Fetal Matrix: Evolution, Development and Disease.
      ), the current context of high maternal resources in combination with low PA represents an evolutionary mismatch. Given that the partitioning of nutrient energy between the mother and the conceptus is a major determinant of fetal outcomes,
      World Health Organization
      Promoting Optimal Fetal Development: Report of a Technical Consultation.
      the perturbation of the intrauterine milieu via the mismatch of increased maternal metabolic resources (eg, body mass and adiposity) and inactivity-driven decrements in PAEE has significant metabolic consequences for the offspring.
      • Whitaker R.C.
      • Dietz W.H.
      Role of the prenatal environment in the development of obesity.
      Excess intrauterine energy substrates stimulate the hypertrophy and hyperplasia of both pancreatic β cells
      • Portha B.
      • Chavey A.
      • Movassat J.
      Early-life origins of type 2 diabetes: fetal programming of the beta-cell mass.
      • Martens G.A.
      • Pipeleers D.
      Glucose, regulator of survival and phenotype of pancreatic beta cells.
      • Steinke J.
      • Driscoll S.G.
      The extractable insulin content of pancreas from fetuses and infants of diabetic and control mothers.
      • Kervran A.
      • Guillaume M.
      • Jost A.
      The endocrine pancreas of the fetus from diabetic pregnant rat.
      • O’Dowd J.F.
      • Stocker C.J.
      Endocrine pancreatic development: impact of obesity and diet.
      • Catalano P.M.
      • Drago N.M.
      • Amini S.B.
      Longitudinal changes in pancreatic beta-cell function and metabolic clearance rate of insulin in pregnant women with normal and abnormal glucose tolerance.
      and adipocytes,
      • Chandler-Laney P.C.
      • Bush N.C.
      • Rouse D.J.
      • Mancuso M.S.
      • Gower B.A.
      Maternal glucose concentration during pregnancy predicts fat and lean mass of prepubertal offspring.
      • Herrera E.
      • Amusquivar E.
      Lipid metabolism in the fetus and the newborn.
      • Kalkhoff R.K.
      Impact of maternal fuels and nutritional state on fetal growth.
      • Long N.M.
      • Rule D.C.
      • Zhu M.J.
      • Nathanielsz P.W.
      • Ford S.P.
      Maternal obesity upregulates fatty acid and glucose transporters and increases expression of enzymes mediating fatty acid biosynthesis in fetal adipose tissue depots.
      • Dunlop M.
      • Court J.M.
      Lipogenesis in developing human adipose tissue.
      up-regulate fetal fatty acid and glucose transporters,
      • Long N.M.
      • Rule D.C.
      • Zhu M.J.
      • Nathanielsz P.W.
      • Ford S.P.
      Maternal obesity upregulates fatty acid and glucose transporters and increases expression of enzymes mediating fatty acid biosynthesis in fetal adipose tissue depots.
      increase the direct free fatty acid uptake and storage as triglyceride in fetal adipocytes,
      • Shadid S.
      • Koutsari C.
      • Jensen M.D.
      Direct free fatty acid uptake into human adipocytes in vivo: relation to body fat distribution.
      • Szabo A.J.
      • Szabo O.
      Placental free-fatty-acid transfer and fetal adipose-tissue development: an explantation of fetal adiposity in infants of diabetic mothers.
      alter myogenesis and increase collagen accumulation and cross-linking in fetal SM,
      • Tong J.F.
      • Yan X.
      • Zhu M.J.
      • Ford S.P.
      • Nathanielsz P.W.
      • Du M.
      Maternal obesity downregulates myogenesis and beta-catenin signaling in fetal skeletal muscle.
      • Huang Y.
      • Zhao J.X.
      • Yan X.
      • et al.
      Maternal obesity enhances collagen accumulation and cross-linking in skeletal muscle of ovine offspring.
      and increase the expression of enzymes mediating de novo lipogenesis.
      • Long N.M.
      • Rule D.C.
      • Zhu M.J.
      • Nathanielsz P.W.
      • Ford S.P.
      Maternal obesity upregulates fatty acid and glucose transporters and increases expression of enzymes mediating fatty acid biosynthesis in fetal adipose tissue depots.
      These points are critical. First, fetal adipose de novo fatty acid synthesis is a primary mechanism for the accumulation of lipid in fetal adipocytes.
      • Kasser T.R.
      • Martin R.J.
      • Allen C.E.
      Effect of gestational alloxan diabetes and fasting on fetal lipogenesis and lipid deposition in pigs.
      Second, maternal glucose is the major substrate for fetal lipogenesis, is highly correlated with newborn body fat,
      • Friis C.M.
      • Qvigstad E.
      • Paasche Roland M.C.
      • et al.
      Newborn body fat: associations with maternal metabolic state and placental size.
      and is a predictor of the fat mass of prepubertal offspring.
      • Chandler-Laney P.C.
      • Bush N.C.
      • Rouse D.J.
      • Mancuso M.S.
      • Gower B.A.
      Maternal glucose concentration during pregnancy predicts fat and lean mass of prepubertal offspring.
      In the third trimester, maternal PA will be at its lowest point,
      • Melzer K.
      • Schutz Y.
      • Boulvain M.
      • Kayser B.
      Pregnancy-related changes in activity energy expenditure and resting metabolic rate in Switzerland.
      • Weissgerber T.L.
      • Wolfe L.A.
      • Davies G.A.
      • Mottola M.F.
      Exercise in the prevention and treatment of maternal-fetal disease: a review of the literature.
      and, therefore, maternal glycemic control will be at its nadir. Consequently, fetal lipogenesis and adipocyte hyperplasia will be maximized as compared with metabolically healthy (eg, lean and active) mothers because of a number of processes. First, maternal hyperglycemic excursions will drive fetal hyperglycemia, which, in turn, results in fetal hyperinsulinemia (via enhanced β-cell mass and function) and drives growth factors that result in excessive fetal growth and adiposity.
      • Milner R.D.
      • Hill D.J.
      Fetal growth control: the role of insulin and related peptides.
      • Pohlandt F.
      • Heinze E.
      • Fussgänger F.
      • Mayer V.
      • Teller W.
      Insulin secretion in human neonates during long-term infusion of glucose.
      • Beinze E.
      • Nguyen Thi C.
      • Vetter U.
      • Fussgänger R.D.
      Interrelationship of insulin and somatomedin activity in fetal rats.
      • Hill D.J.
      • Sheffrin R.A.
      • Milner R.D.
      Raised plasma somatomedin activity and cartilage metabolic activity (35S sulphate uptake in vitro) in the fetus of the mildly diabetic pregnant rat.
      Second, maternal inactivity decreases maternal SM fatty acid oxidation and consequently promotes lipid transfer to the fetus by increasing the maternal-to-fetal fatty acid concentration gradient.
      • Herrera E.
      • Amusquivar E.
      Lipid metabolism in the fetus and the newborn.
      Given the strong inverse relationship between the oxidation of dietary fat in SM and obesity (ie, obese individuals partition more fatty acids to storage as lipid in adipocytes, whereas lean individuals oxidize a greater relative amount
      • Westerterp K.R.
      Dietary fat oxidation as a function of body fat.
      ), the cumulative effect of alterations in fetal myogenesis and impaired SM morphology in concert with a greater number of adipocytes and increased pancreatic β-cell function (ie, enhanced insulin secretion) produce metabolically compromised infants predisposed to lifelong inactivity, metabolic dysfunction, and obesity owing to the competitive dominance of adipocytes in the acquisition and sequestering of nutrient energy.
      In addition, although SEE led to large and significant decrements in maternal activity and glycemic control, it led to substantial declines in maternal smoking.
      • Singh G.K.
      • Kogan M.D.
      Persistent socioeconomic disparities in infant, neonatal, and postneonatal mortality rates in the United States, 1969-2001.
      Unfortunately, despite the maternal and fetal health benefits associated with reductions in tobacco use, the mild fetal hypoxia induced via smoking
      • Sazak S.
      • Kayiran S.M.
      • Paksoy Y.
      Umbilical cord serum erythropoietin levels and maternal smoking in pregnancy.
      may have played a role in delaying the negative effects of inactivity on maternal glycemic control and consequent mother-conceptus energy partitioning by altering fetal glucose transporter regulation
      • Baumann M.U.
      • Deborde S.
      • Illsley N.P.
      Placental glucose transfer and fetal growth.
      and growth.
      • Miller H.C.
      • Hassanein K.
      • Hensleigh P.A.
      Fetal growth retardation in relation to maternal smoking and weight gain in pregnancy.
      Figures 2 and 3 depict the hypothesized consequences of the perturbation of maternal-conceptus energy partitioning and fetal outcomes.
      Figure thumbnail gr2
      Figure 2Hypothesized consequences of excess maternal glucose on fetal pancreatic β-cell function. aHypertrophy and hyperplasia of fetal pancreatic β cells.
      • Martens G.A.
      • Pipeleers D.
      Glucose, regulator of survival and phenotype of pancreatic beta cells.
      • Steinke J.
      • Driscoll S.G.
      The extractable insulin content of pancreas from fetuses and infants of diabetic and control mothers.
      • Kervran A.
      • Guillaume M.
      • Jost A.
      The endocrine pancreas of the fetus from diabetic pregnant rat.
      bAn inactive lifestyle as a child and adolescent is a necessary condition for risk to be actualized. cHyperglycemia may be transient (eg, acute excursions induced via mild insulin resistance) or chronic (frank diabetes). T2DM = type 2 diabetes mellitus.
      Figure thumbnail gr3
      Figure 3Hypothesized consequences of excess intrauterine energy on fetal adipocyte development. aDetermined by maternal adiposity, energy intake, physical activity, and total daily energy expenditure. bObesity as categorized by body mass index >30 kg/m2.

      The Counterfactual Support for the MRH

      The aforementioned results are in direct contrast to those obtained for women in nonindustrialized nations who have not experienced similar SEE and PE over the past century. These women have relatively high levels of PA in concert with low energy resources (ie, low body mass, adiposity, and nutrient-energy intake).
      • Prentice A.M.
      • Ward K.A.
      • Goldberg G.R.
      • et al.
      Critical windows for nutritional interventions against stunting.
      Given that the evolutionary forces that induced increments in maternal energy resources and decrements in PA are not present, the net result is a decrease in the energy available to the intrauterine milieu. In the absence of maternal resources to buffer fetal demands,
      • Prentice A.M.
      • Ward K.A.
      • Goldberg G.R.
      • et al.
      Critical windows for nutritional interventions against stunting.
      the competition between fetal energy requirements and maternal energy needs results in intrauterine growth restriction
      World Health Organization
      Promoting Optimal Fetal Development: Report of a Technical Consultation.
      and associated pathologies.
      • Barker D.J.
      • Lampl M.
      • Roseboom T.
      • Winder N.
      Resource allocation in utero and health in later life.
      In congruence with the thrifty phenotype (ie, Barker) hypothesis,
      • Barker D.J.
      • Martyn C.N.
      • Osmond C.
      • Hales C.N.
      • Fall C.H.
      Growth in utero and serum cholesterol concentrations in adult life.
      • Hales C.N.
      • Barker D.J.
      Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis.
      the MRH posits that in the context of high levels of PA and low nutrient-energy intake, maternal myocytes and other metabolically active tissues (eg, organs) outcompete both maternal adipocytes and fetal tissues for nutrient energy. This results in the loss of maternal body mass and permanently alters fetal development and consequent energy metabolism while predisposing offspring to chronic noncommunicable diseases (eg, type 2 diabetes mellitus [T2DM] and cardiovascular disease [CVD]) when the postnatal environment permits low levels of PA in combination with adequate nutrition. Figure 4 depicts fetal outcomes as maternal resources and PA vary.
      Figure thumbnail gr4
      Figure 4Hypothesized consequences of maternal energy balance on fetal development. aMaternal resources determined by socioenvironmental evolution and phenotypic evolution of familial line, prenatal body mass, adiposity, and energy intake. bSmall for gestational age (SGA): predisposed to visceral adiposity type 2 diabetes mellitus and cardiovascular disease. cLarge for gestational age (LGA): predisposed to obesity, type 2 diabetes mellitus, and cardiovascular disease.
      The MRH and the extant evidence suggest a continuum of metabolic control and mother-conceptus energy partitioning with both restricted
      • Prentice A.M.
      • Ward K.A.
      • Goldberg G.R.
      • et al.
      Critical windows for nutritional interventions against stunting.
      and excess maternal resources,
      • Pedersen J.
      The Pregnant Diabetic and Her Newborn: Problems and Management.
      pathologically altering the metabolic health of offspring.
      • Wells J.C.
      The thrifty phenotype: an adaptation in growth or metabolism?.
      As such, the ideas presented herein subsume and extend both the Barker
      • Hales C.N.
      • Barker D.J.
      Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis.
      and Pedersen
      • Pedersen J.
      The Pregnant Diabetic and Her Newborn: Problems and Management.
      hypotheses and offer a nongenetic mechanism for the intergenerational transmission of obese and other high-risk phenotypes. Stated simply, the MRH posits that the risk of obesity, T2DM, and CVD is propagated progressively via the interplay between maternal energy resources, maternal patterns of PA, and the ensuing metabolic sequelae of pregnancy.

      Postnatal ME

      The intergenerational transmission of behavior is well accepted in social animals such as humans.
      • Skinner B.F.
      Science and Human Behavior.
      • Jablonka E.
      • Lamb M.J.
      Précis of Evolution in Four Dimensions.
      Because the primary ecological niche of an infant is the social environment that caregivers create, the processes of postnatal ME provide nongenetic mechanisms by which the environmental exposures generated by the behavioral phenotype of the mother (or caregiver) directly alters the behavioral phenotype of infants and children. Numerous potential mechanisms have been posited, including social learning and modeling (ie, observational, operant, and/or classical conditioning).
      • Notten N.
      • Kraaykamp G.
      • Konig R.P.
      Family media matters: unraveling the intergenerational transmission of reading and television tastes.
      • Ricks M.H.
      The social transmission of parental behavior: attachment across generations.
      • Krahnstoever Davison K.
      • Francis L.A.
      • Birch L.L.
      Reexamining obesigenic families: parents’ obesity-related behaviors predict girls’ change in BMI.
      • Skinner B.F.
      Science and Human Behavior.
      • Franks P.W.
      • Ravussin E.
      • Hanson R.L.
      • et al.
      Habitual physical activity in children: the role of genes and the environment.
      • Conrad K.M.
      • Flay B.R.
      • Hill D.
      Why children start smoking cigarettes: predictors of onset.
      • Pavlov I.P.
      Conditional Reflexes.
      It is well established that a mother’s TV viewing behavior affect her progeny’s TV behavior
      • Notten N.
      • Kraaykamp G.
      • Konig R.P.
      Family media matters: unraveling the intergenerational transmission of reading and television tastes.
      ; therefore, as with the intergenerational transmission of smoking behavior,
      • Conrad K.M.
      • Flay B.R.
      • Hill D.
      Why children start smoking cigarettes: predictors of onset.
      children who grow up with an inactive, sedentary caregiver may be more likely to be sedentary, inactive, and obese as adults.
      • Franks P.W.
      • Ravussin E.
      • Hanson R.L.
      • et al.
      Habitual physical activity in children: the role of genes and the environment.
      • Thompson A.L.
      • Adair L.S.
      • Bentley M.E.
      Maternal characteristics and perception of temperament associated with infant TV exposure.
      For example, if a woman develops the habit of breast-feeding while watching TV, her infant may associate the sights and sounds of the TV with feeding behavior. Given that maternal attention and feeding are powerful reinforcers,
      • Skinner B.F.
      The phylogeny and ontogeny of behavior: contingencies of reinforcement throw light on contingencies of survival in the evolution of behavior.
      the process of classical conditioning may (metaphorically speaking) turn the TV into Pavlov’s dinner bell.
      • Pavlov I.P.
      Conditional Reflexes.
      The conjoined behaviors of feeding and TV viewing will be continuously reinforced when TV and food are used to control infant behavior (ie, used as a babysitter).
      • Sisson S.B.
      • Broyles S.T.
      Social-ecological correlates of excessive TV viewing: difference by race and sex.
      • Taveras E.M.
      • Hohman K.H.
      • Price S.
      • Gortmaker S.L.
      • Sonneville K.
      Televisions in the bedrooms of racial/ethnic minority children: how did they get there and how do we get them out?.
      This conceptualization of the intergenerational transmission of inactivity and sedentary behavior is supported by research reporting strong relationships between mother-daughter body mass index and obesogenic behaviors (eg, eating in front of the TV).
      • Sonneville K.R.
      • Rifas-Shiman S.L.
      • Kleinman K.P.
      • Gortmaker S.L.
      • Gillman M.W.
      • Taveras E.M.
      Associations of obesogenic behaviors in mothers and obese children participating in a randomized trial.
      Maternal TV viewing and obesity are associated with greater infant TV exposure,
      • Thompson A.L.
      • Adair L.S.
      • Bentley M.E.
      Maternal characteristics and perception of temperament associated with infant TV exposure.
      with infants as young as 3 months old exposed to an average of more than 2.5 hours of TV and/or videos daily and nearly 40% of infants exposed to more than 3 hours of TV daily before the age of 12 months.
      • Thompson A.L.
      • Adair L.S.
      • Bentley M.E.
      Maternal characteristics and perception of temperament associated with infant TV exposure.
      Having a TV in the bedroom is one of the most powerful predictors of childhood obesity,
      • Dennison B.A.
      • Erb T.A.
      • Jenkins P.L.
      Television viewing and television in bedroom associated with overweight risk among low-income preschool children.
      and large-scale epidemiological studies have found that one of the strongest determinants of obesity and cardiometabolic risk factors in later life was TV viewing in early life.
      • Chen Y.Y.
      • Lee Y.S.
      • Wang J.P.
      • et al.
      Longitudinal study of childhood adiposity and the risk of developing components of metabolic syndrome—the Da Qing children cohort study.
      In addition to the metabolic effects of postnatal ME, there are cognitive effects. TV viewing before the age of 3 is associated with cognitive delays, decrements in language development, attention issues, and sleep disorders.
      • Christakis D.A.
      • Zimmerman F.J.
      • DiGiuseppe D.L.
      • McCarty C.A.
      Early television exposure and subsequent attentional problems in children.

      Screen-Based Media as a Caregiver (ie, TV as a Babysitter)

      I posit that current obese phenotypes are predisposed at birth via prenatal ME and that these predispositions are permanently entrenched by the infant’s and child’s early social environments. Over the past 50 years, the use of screen-based media has increased considerably,
      • Robinson J.P.
      IT, TV and time displacement: what Alexander Szalai anticipated but couldn’t know.
      and by the late 1990s, mothers and children were spending the vast majority of their leisure time watching TV.
      • Archer E.
      • Lavie C.J.
      • McDonald S.M.
      • et al.
      Maternal inactivity: 45-year trends in mothers’ use of time.
      • Robinson J.P.
      IT, TV and time displacement: what Alexander Szalai anticipated but couldn’t know.
      Screen-based media (eg, TV) is often used as a surrogate caregiver (ie, “babysitter”)
      • Taveras E.M.
      • Hohman K.H.
      • Price S.
      • Gortmaker S.L.
      • Sonneville K.
      Televisions in the bedrooms of racial/ethnic minority children: how did they get there and how do we get them out?.
      for precisely the same reason that it is detrimental to infants and children: it captures their attention and keeps them relatively immobile. In a non–media-enhanced world, the child will stimulate his or her nervous system via movement and “exploration” facilitated by the activation of SM. Because osteocytes, myocytes, and adipocytes share a common pool of progenitor cells, reduced PA leads to a reduction in the physiological resources (eg, muscle development, strength, and coordination) necessary for lifelong PA, and every kilocalorie of energy that is not used to build muscle and bone may be used to further increase adipocyte size and/or number.
      • Zderic T.W.
      • Hamilton M.T.
      Physical inactivity amplifies the sensitivity of skeletal muscle to the lipid-induced downregulation of lipoprotein lipase activity.
      • Hamilton M.T.
      • Hamilton D.G.
      • Zderic T.W.
      Role of low energy expenditure and sitting in obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease.
      • Yan X.
      • Zhu M.J.
      • Dodson M.V.
      • Du M.
      Developmental programming of fetal skeletal muscle and adipose tissue development.
      As such, the predisposition to obesity would be instantiated via accelerated hyperplastic adiposity, inactivity, decrements in the physiological resources necessary for movement (eg, strength and coordination), and the initiation of a positive feedback loop that negatively alters health trajectories over successive generations via mother-daughter transmission.

      Iatrogenic Artificial Selection

      The excessive fetal growth induced via evolutionary processes has resulted in larger and fatter infants over the past few generations (eg, increased neonatal organ mass, head circumference, fat mass, and birthweight
      • Thompson W.S.
      • Cohle S.D.
      Fifteen-year retrospective study of infant organ weights and revision of standard weight tables.
      • Karvonen M.
      • Hannila M.L.
      • Saari A.
      • Dunkel L.
      New Finnish reference for head circumference from birth to 7 years.
      • Chike-Obi U.
      • David R.J.
      • Coutinho R.
      • Wu S.Y.
      Birth weight has increased over a generation.
      • Ounsted M.
      • Moar V.A.
      • Scott A.
      Head circumference charts updated.
      ). Because the evolution of infant head circumference
      • Elvander C.
      • Högberg U.
      • Ekéus C.
      The influence of fetal head circumference on labor outcome: a population-based register study.
      has progressed more quickly than the evolution of the birth canal,
      • Wells J.C.
      • DeSilva J.M.
      • Stock J.T.
      The obstetric dilemma: an ancient game of Russian roulette, or a variable dilemma sensitive to ecology?.
      the prevalence of dystocia-related cesarean sections (ie, surgically assisted births) has increased substantially.
      • Getahun D.
      • Strickland D.
      • Lawrence J.M.
      • Fassett M.J.
      • Koebnick C.
      • Jacobsen S.J.
      Racial and ethnic disparities in the trends in primary cesarean delivery based on indications.
      • Taffel S.M.
      • Placek P.J.
      • Liss T.
      Trends in the United States cesarean section rate and reasons for the 1980-85 rise.
      • Elvander C.
      • Högberg U.
      • Ekéus C.
      The influence of fetal head circumference on labor outcome: a population-based register study.
      This SEE (ie, progression of medical technology and practice) allowed both larger fetuses and the mothers who produced them to survive and reproduce, thereby increasing the frequency of metabolically compromised, obese phenotypes in the global population. As such, “natural selection” was iatrogenically and unintentionally rendered “artificial selection.” The artificial selection of metabolically compromised infants is clearly supported by numerous facts: familial line is a major predictor of both dystocia
      • Berg-Lekås M.L.
      • Högberg U.
      • Winkvist A.
      Familial occurrence of dystocia.
      and cesarean birth,
      • Varner M.W.
      • Fraser A.M.
      • Hunter C.Y.
      • Corneli P.S.
      • Ward R.H.
      The intergenerational predisposition to operative delivery.
      childhood obesity has a strong relationship with cesarean birth,
      • Blustein J.
      • Attina T.
      • Liu M.
      • et al.
      Association of caesarean delivery with child adiposity from age 6 weeks to 15 years.
      and, most importantly, the frequency of cesarean births is greatest in the population that is most inactive, sedentary, and obese (ie, non-Hispanic black)
      • Andersen R.E.
      • Crespo C.J.
      • Bartlett S.J.
      • Cheskin L.J.
      • Pratt M.
      Relationship of physical activity and television watching with body weight and level of fatness among children: results from the Third National Health and Nutrition Examination Survey.
      • Sisson S.B.
      • Broyles S.T.
      Social-ecological correlates of excessive TV viewing: difference by race and sex.
      • Getahun D.
      • Strickland D.
      • Lawrence J.M.
      • Fassett M.J.
      • Koebnick C.
      • Jacobsen S.J.
      Racial and ethnic disparities in the trends in primary cesarean delivery based on indications.
      and has had the largest increments in TV viewing over the past 50 years.
      • Robinson J.
      • Godbey G.
      Time for Life: The Surprising Ways Americans Use Their Time.

      Metabolic Tipping Point

      The greatest declines in maternal activity (via our data
      • Archer E.
      • Lavie C.J.
      • McDonald S.M.
      • et al.
      Maternal inactivity: 45-year trends in mothers’ use of time.
      • Archer E.
      • Shook R.P.
      • Thomas D.M.
      • et al.
      45-year trends in women’s use of time and household management energy expenditure.
      ) occurred from the 1960s to the 1970s, although prior research suggests that the declines began earlier.
      • Gershuny J.
      • Robinson J.P.
      Historical changes in the household division of labor.
      This suggests that the female children of the increasingly inactive mothers of the 1950s through the 1970s would themselves be having metabolically compromised children and grandchildren 20 to 50 years later (ie, from the early 1970s to late 2000s). As these metabolically compromised female children matured and transitioned through puberty, adipocyte number and mass were further exacerbated via the hormonal milieu
      • Loomba-Albrecht L.A.
      • Styne D.M.
      Effect of puberty on body composition.
      and obesogenic environment (eg, inactive caregivers producing inactive children and adolescents). When these women reproduced, the anatomic, physiologic, metabolic, and behavioral trajectories induced by the previous generation’s phenotype (ie, the ME) were propagated progressively as the ontogeny of their offspring was initiated at a point further along the continuum of phenotypic plasticity (ie, advanced baseline). This evolutionary process of accumulative ME
      • Badyaev A.V.
      Maternal effects as generators of evolutionary change: a reassessment.
      was facilitated by medicalized childbirth and led to anatomic, physiologic, metabolic, and behavioral tipping points that ensured an escalating competitive dominance of adipocytes in the acquisition and sequestering of nutrient energy in many human subpopulations (eg, African Americans). Within a few generations, the postprandial insulin response was so intense (via enhanced β-cell mass and function and inactivity-induced insulin resistance), the relative number of adipocytes so large, and inactivity so pervasive that the competitive dominance of adipocytes in the acquisition and sequestering of nutrient energy was inevitable and obesity was unavoidable.

      Consequences of the MRH for Obesity Research

      Most obesity research is based on the conceptual framework of energy balance derived from the first law of thermodynamics.
      • Hebert J.R.
      • Allison D.B.
      • Archer E.
      • Lavie C.J.
      • Blair S.N.
      Scientific decision making, policy decisions, and the obesity pandemic.
      The fundamental a priori assumption is that relative imbalances between nutrient-energy consumption and EE cause the excessive storage and sequestering of energy as lipid in adipocytes. This paradigm assumes a temporality that has no empirical foundation and merely provides a valid description of the increase in the storage and sequestering of energy (ie, an analytic truth). As such, these paradigms offer no insight into the causal mechanisms or the temporal nature of the increase. I argue that because all tissues compete for energy, obesity is the result of adipocytes outcompeting other cells, tissues, and organs in postprandial periods. The initial trajectory that engenders this competitive dominance of adipocytes (and consequent obesity) is initiated in utero because of ME induced via reduced metabolic control, leading to the confluence of an intensified insulin response (via enhanced β-cell mass and function), decreased fatty acid oxidation via decrements in myogenesis and myocyte morphology, and the law of mass action (ie, a larger relative number of fat cells disposing of a larger percentage of energy intake).
      This conceptualization is strongly supported by extant research, given that increments in fat mass are a function of adiposity,
      • Forbes G.B.
      Body fat content influences the body composition response to nutrition and exercise.
      adipocyte number is a primary determinant of obesity,
      • Spalding K.L.
      • Arner E.
      • Westermark P.O.
      • et al.
      Dynamics of fat cell turnover in humans.
      • Björntorp P.
      The regulation of adipose tissue distribution in humans.
      and early development is a major determinant of adipocyte number.
      • Spalding K.L.
      • Arner E.
      • Westermark P.O.
      • et al.
      Dynamics of fat cell turnover in humans.
      • Björntorp P.
      The regulation of adipose tissue distribution in humans.
      • Häger A.
      • Sjöstrm L.
      • Arvidsson B.
      • Björntorp P.
      • Smith U.
      Body fat and adipose tissue cellularity in infants: a longitudinal study.
      As such, the infant born to an inactive mother would be metabolically compromised via the confluence of the prenatal ME (eg, adipocyte hyperplasia and reduced myogenesis) and the postnatal ME (eg, learned inactivity). This hypothesis is strongly supported by the facts that the adipose tissue of young obese children differs both qualitatively and quantitatively from the adipose tissue of lean children
      • Knittle J.L.
      • Timmers K.
      • Ginsberg-Fellner F.
      • Brown R.E.
      • Katz D.P.
      The growth of adipose tissue in children and adolescents: cross-sectional and longitudinal studies of adipose cell number and size.
      and that adipocyte number increases throughout early development.
      • Häger A.
      • Sjöstrm L.
      • Arvidsson B.
      • Björntorp P.
      • Smith U.
      Body fat and adipose tissue cellularity in infants: a longitudinal study.
      In addition, monozygotic twins concordant for birthweight exhibit similar adipocyte numbers, whereas in those discordant for birthweight, the smaller twin displays both lower body weight and adipocyte number.
      • Ginsberg-Fellner F.
      Growth of adipose tissue in infants, children and adolescents: variations in growth disorders.
      I posit that these results suggest an in utero “training effect” in which the chronic partitioning of energy to storage in adipose tissue induces numerous metabolic sequelae that lead to obesity via adipogenic nutrient partitioning and an exacerbated recruitment and differentiation of mesenchymal cells to mature adipocytes.
      • Sjöström L.
      • William-Olsson T.
      Prospective studies on adipose tissue development in man.
      Importantly, the increase in the storage and sequestering of nutrient energy in adipocytes reduces the substrates and metabolic stimuli that inhibit hunger and appetitive processes (eg, adenosine triphosphate/adenosine diphosphate ratio, hepatic energy flux, and glucose and fatty acid oxidation).
      • Friedman M.I.
      Control of energy intake by energy metabolism.
      • Mayer J.
      Correlation between metabolism and feeding behavior and multiple etiology of obesity.
      As such, this sequestration engenders a perception of fatigue
      • Wlodek D.
      • Gonzales M.
      Decreased energy levels can cause and sustain obesity.
      (and consequent inactivity and inactivity-induced decrements in metabolic control), depression,
      • Kalarchian M.A.
      • Marcus M.D.
      Psychiatric comorbidity of childhood obesity.
      decreased energy,
      • Wlodek D.
      • Gonzales M.
      Decreased energy levels can cause and sustain obesity.
      and an accelerated development of hunger and consequent shorter intermeal interval and/or increased energy density per meal. These phenomena result in a positive feedback loop that leads to excessive food and beverage consumption, which exacerbates the vicious cycle of adipogenic nutrient-energy partitioning, increasing adiposity, decreased metabolic control, and obesity.
      Logically, people do not develop excessive adiposity simply by being in positive energy balance; if this were true, the increase in muscle mass and parallel decrease in relative body fat as exhibited by bodybuilders would be impossible. As such, the genesis of obesity is predicated on a greater allocation, storage, and sequestering of lipid in adipocytes as a function of adipocyte number, pancreatic β-cell function (ie, insulin secretion), and SM energy metabolism (ie, glucose and fatty acid oxidation and glycogen synthesis).

      Obesity as an Inherited, Chronic Condition

      The MRH suggests that the energy metabolism of affected individuals is permanently altered in utero, and strategies such as reductions in energy intake (ie, “dieting”) and other energy manipulations (eg, exercise) will be offset, not by a regulatory mechanism per se, but by the fact that the nature of the nutrient-energy partitioning will not be altered via the loss of lipid content in adipocytes or an increase in fatty acid oxidation by other tissues. Because it can be assumed that human energy metabolism evolved under intense selective pressures, it will be robust to acute perturbations. In other words, as long as the predisposing metabolic impairments exist, the individual will continue to store a greater amount of energy as lipid in adipocytes than does an individual with normal SM metabolism, pancreatic β-cell function, and adipocyte number. Hence, for most individuals, obesity is a chronic condition of adipocyte dominance in the acquisition and sequestering of nutrient energy that cannot be “cured” via “moving more and eating less.”

      Practical Implications of the MRH

      Given the breadth, scope, and strength of the evidence that supports the MRH, there are a number of practical implications. First, the acknowledgment that obesity is the result of nongenetic evolutionary forces and not gluttony and sloth
      • Prentice A.M.
      • Jebb S.A.
      Obesity in Britain—gluttony or sloth.
      may help to alter the moralizing and demoralizing social and scientific discourse that pervades both public and clinical settings. Second, the conceptual framework of tissues competing for nutrient-energy substrates has consequences for both the research community and clinicians. Future research may be most productive if funding is directed away from naive examinations of energy balance per se and redirected to investigations of interventions that alter the competitive strategies of various tissues. From the standpoint of the clinician, accurate patient phenotyping (inclusive of family obstetric history and metabolic profiling) may allow the targeting of women most likely to be a part of populations that have evolved beyond the metabolic tipping point and therefore require significant preconception intervention.

      Summary of the MRH

      The MRH posits that the childhood obesity epidemic is the result of the evolutionary processes of ME, PE, and SEE, leading to a metabolic tipping point in human energy metabolism at which adipocytes outcompete other cell types in the acquisition and sequestering of nutrient energy. The recent competitive dominance of adipocytes was achieved via the confluence of multiple evolutionary processes. Over the past century, SEE and PE facilitated increments in maternal resources (eg, body mass and adiposity), inactivity, and sedentarism that induced decrements in maternal metabolic control (eg, insulin sensitivity). This PE pathologically increased the energy substrates available to fetuses, causing mothers to produce progressively larger, fatter, more inactive, and consequently more metabolically compromised and less physically fit
      • Gahche J.
      • Fakhouri T.
      • Carroll D.D.
      • Burt V.L.
      • Wang C.-Y.
      • Fulton J.E.
      Cardiorespiratory Fitness Levels Among U.S. Youth Aged 12–15 Years: United States, 1999–2004 and 2012.
      offspring predisposed to chronic noncommunicable diseases.
      • Carson V.
      • Janssen I.
      Volume, patterns, and types of sedentary behavior and cardio-metabolic health in children and adolescents: a cross-sectional study.
      Increments in the use of cesarean sections allowed the frequency of metabolically compromised female offspring in the population to increase. When these women reproduced, the ME of hyperplastic adiposity, intensified pancreatic β-cell function, altered SM myogenesis, and inactivity were progressively propagated to successive generations, thereby making obesity inevitable in many human familial lines. The consequences of the MRH suggest that recent evolutionary trends have not been adaptive
      • Olshansky S.J.
      • Passaro D.J.
      • Hershow R.C.
      • et al.
      A potential decline in life expectancy in the United States in the 21st century.
      and that the evolutionary fitness (ie, survival
      • Olshansky S.J.
      • Passaro D.J.
      • Hershow R.C.
      • et al.
      A potential decline in life expectancy in the United States in the 21st century.
      and reproduction
      • Martinez G.
      • Daniels K.
      • Chandra A.
      Fertility of men and women aged 15–44 years in the United States: National Survey of Family Growth, 2006–2010.
      ) of some human familial lines is in decline.

      Conclusion

      The MRH posits that obesity is the result of the competitive dominance of adipocytes over other tissues in the acquisition and sequestering of nutrient energy and that the current population-wide dominance of adipocytes (ie, the childhood obesity epidemic) is the result of nongenetic evolutionary processes altering the interplay between maternal energy resources, maternal patterns of PA, and the ensuing metabolic sequelae of pregnancy over multiple generations. Given that maternal metabolic control is a strong determinant of fetal metabolic outcomes and health (eg, risk of obesity, T2DM, and CVD), the health and well-being of future generations depend on policies and preconception interventions that can ameliorate the effects of more than a century of nongenetic evolutionary processes and overcome the current competitive dominance of adipocytes.

      Acknowledgments

      The author would like to thank his esteemed colleagues and critics for the conversations and feedback that led to this paper, especially Samantha McDonald, Chip Lavie, John Sievenpiper, Chris Kuzawa, Diana Thomas, Michael Dweck, Wendy Kohrt, Bob Malina, Tonia Schwartz, Steve Heymsfield, Russ Pate, Mike Pratt, Gregory Pavela, Emily Dhurandhar, Kathryn Kaiser, Krista Casazza, and finally my mentors David B. Allison and Steven N. Blair.

      Supplemental Online Material

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