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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.
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.
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
for most of the 20th century, nongenetic vectors of inheritance and the evolutionary consequences of developmental dynamics leading to novel phenotypes were largely ignored.
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.
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.”
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”
). 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”
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).
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.
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,
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,
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
) 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 term
Definition
Environment
External: 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.
Evolution
Progressive, 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 heritability
The 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 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
Energy derived from the consumption of food and beverages that is available for metabolic processes.
Nutrient partitioning
The 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.
An organism’s observable characteristics or traits, including, but not limited to, its morphology, development, physiology, metabolism, behavior, and products of behavior.
Unidirectional, 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.
Socioenvironmental evolution is a progression of social and/or cultural practices that markedly alters behavior and/or the environments in which humans exist.
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.
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)
As such, ME represent a mechanism by which the environmental exposures that generated the phenotype of the mother are translated directly (via developmental plasticity
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).
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.
Socioenvironmental evolution is a progression of social and/or cultural practices that significantly alters behavior and/or the physical environments in which humans exist.
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
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 1Conceptual depiction of the maternal resources hypothesis.
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).
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.
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.
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.
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.
Effects of common illnesses on infants’ energy intakes from breast milk and other foods during longitudinal community-based studies in Huascar (Lima), Peru.
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,
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.
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.
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,
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.
As a result, physical inactivity and sedentary pastimes (eg, Web surfing and television [TV] viewing) became both ubiquitous features of the post–industrial world
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.
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.
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.
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.
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.
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.
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.
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
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
), 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,
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.
Longitudinal changes in pancreatic beta-cell function and metabolic clearance rate of insulin in pregnant women with normal and abnormal glucose tolerance.
Diabetes Care.1998; 21 ([published correction appears in Diabetes Care 1999;22(6):1013]): 403-408
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.
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.
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
), 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.
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
Figures 2 and 3 depict the hypothesized consequences of the perturbation of maternal-conceptus energy partitioning and fetal outcomes.
Figure 2Hypothesized consequences of excess maternal glucose on fetal pancreatic β-cell function. aHypertrophy and hyperplasia of fetal pancreatic β cells.
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 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 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).
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,
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 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.
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.
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).
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,
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).
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).
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.
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.
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.
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,
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.
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
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
and, most importantly, the frequency of cesarean births is greatest in the population that is most inactive, sedentary, and obese (ie, non-Hispanic black)
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.
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
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
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.
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,
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
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.
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.
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).
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
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
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
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.
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.
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.
Effects of common illnesses on infants’ energy intakes from breast milk and other foods during longitudinal community-based studies in Huascar (Lima), Peru.
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