The Childhood Obesity Epidemic as a Result of Nongenetic Evolution: The Maternal Resources Hypothesis
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SPECIAL ARTICLE
The Childhood Obesity Epidemic as a Result of
Nongenetic Evolution: The Maternal Resources
Hypothesis
Edward Archer, PhD, MS
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 b-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 adi-
pocytes so large, and inactivity so pervasive that the competitive dominance of adipocytes in the seques-
tering of nutrient energy was inevitable and obesity was unavoidable.
ª 2014 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2014;nn(n):1-16
From the Office of
T
he purpose of this article was to pro- predictive power with respect to the ubiquity,
Energetics, Nutrition
vide a reinterpretation and synthesis rapidity, and unidirectional nature of the dra- Obesity Research Center,
of existing empirical evidence in sup- matic increase in the prevalence of obesity and University of Alabama at
port of a novel theory of the etiology of the other notable phenotypic changes exhibited by Birmingham, Birmingham.
childhood obesity epidemic. The foundational infants and children over the past century (eg,
theses are as follows: (1) obesity is the conse- increased height and head circumference, body
quence of the competitive dominance of adipo- mass, and precocious menarche1-4). Although
cytes over other cell types in the acquisition and it may be true that “nothing in biology makes
sequestering of nutrient energy, and (2) the sense except in the light of evolution,”5 for
childhood obesity epidemic is the result of most of the 20th century, nongenetic vectors
nongenetic evolutionary processes altering the of inheritance and the evolutionary conse-
interplay between maternal energy resources quences of developmental dynamics leading to
(eg, body mass and adiposity), maternal pat- novel phenotypes were largely ignored.6-8 This
terns of physical activity (PA), and the ensuing a priori constraint on heritability and evolution
metabolic sequelae of pregnancy that affect has no empirical or theoretical foundation; how-
subsequent fetal outcomes. ever, because theory affects research, clinical
practice, and public health policy, the exclusion
OVERVIEW of nongenetic pathways for the intergenerational
The current gene-centric paradigm of inheri- transmission of obesity and high-risk pheno-
tance and evolution has limited explanatory or types has been unproductive.9
Mayo Clin Proc. n XXX 2014;nn(n):1-16 n http://dx.doi.org/10.1016/j.mayocp.2014.08.006 1
www.mayoclinicproceedings.org n ª 2014 Mayo Foundation for Medical Education and ResearchMAYO CLINIC PROCEEDINGS
As noted by Harris (1904) more than 100 Amerindians).12-15 For most individuals in these
years ago, “Natural selection may explain the groups, increasing obesity and metabolic
survival of the fittest, but it cannot explain dysfunction are inevitable without significant
the arrival of the fittest.”10 Given the heteroge- preconception and prenatal intervention.
neity of environments into which an organism For this novel conceptualization of inheri-
may be born and the fact that phenotype- tance, evolution, and the etiology of obesity,
environment interactions are the substrate there are a number of essential, interrelated,
upon which natural selection acts, evolu- and empirically supported arguments. First, all
tionary fitness (ie, enhanced survival and living cells compete for nutrient energy,16 and
reproduction) necessitates mechanisms by the strategies used for the acquisition, storage,
which the salient environmental exposures and use of nutrient energy vary across cell types17
that generated the (successful) phenotype of and contexts.18 Thus, if obesity is defined as an
the mother are translated to the offspring (ie, excessive storage of energy as lipid in adipocytes,
the “arrival of the fittest”10). Because consider- then it can logically be viewed as a result of the
able environmental changes commonly occur competitive dominance of adipocytes over other
from one generation to the next, adaptive phe- cells, tissues, and organs in the acquisition and
notypes will not necessarily be generated via sequestering of nutrient-energy resources. Sec-
genetic inheritance. As such, I assert that the ond, the recent competitive dominance of adipo-
“missing heritability”11 in the rapid pheno- cytes in children (ie, the childhood obesity
typic changes exhibited over the past century epidemic) was established and is maintained
(ie, inheritance not explained via gene- and/or exacerbated by 3 parallel, reciprocal
centric paradigms) will not be found in the evolutionary processes: ME,19 PE,20 and SEE
genome, and propose a novel conceptualiza- (socioenvironmental evolution).21,22
tion of inheritance in which nongenetic vec-
tors of evolution (ie, maternal effects [ME] Operational Definitions
and socioenvironmental and phenotypic evo- The Table23-32 provides operational defini-
lution [PE]) are the predominant causal ele- tions for the key terms used in this article.
ments in the recent rise in the prevalence of The definitions are broad and encompass the
childhood obesity. multidimensional nature and interdisciplinary
structure of my hypotheses, which link nonge-
Conceptual Foundation netic evolutionary processes and observed
In this article, I provide a reinterpretation and epidemiological trends in maternal phenotype
synthesis of existing evidence to support a novel to the physiological mechanisms driving the
theory of inheritance and the evolution of the childhood obesity epidemic. Throughout this
childhood obesity epidemic: the maternal re- article, the term evolution is used broadly and
sources hypothesis (MRH). Stated simply, the refers to progressive, unidirectional changes
MRH posits that the childhood obesity epidemic over time in the variable under examination.
is the result of nongenetic evolutionary pro- This definition subsumes changes in inherited
cesses over the past century, leading to a meta- characteristics over successive generations
bolic tipping point in human energy metabolism (ie, descent with modification33) and more
at which adipocytes (ie, fat cells) outcompete restricted uses (eg, changes in allele fre-
other cell types in the acquisition and seques- quencies). This use is inclusive of the inheri-
tering of nutrient energy. This competitive tance of both biological and nonbiological
dominance was established and is maintained (ie, abiotic) characteristics (eg, an impover-
by the confluence of excess maternal resources ished postnatal environment).
(eg, body mass and adiposity) and inactivity-
induced decrements in metabolic control during BACKGROUND FOR KEY CONCEPTS
pregnancy. Given the continuum of fetal meta-
bolic dysfunction induced via the confluence Maternal Effects
of maternal resources, inactivity, and sedentar- Maternal effects are nongenetic vectors of inher-
ism, I posit that the most inactive and obese itance (ie, intergenerational transmission) in
familial lines have evolved beyond this metabolic which maternal phenotype (eg, age, body
tipping point (eg, non-Hispanic blacks and Pima mass, metabolism, and behavior) and extended
n n
2 Mayo Clin Proc. XXX 2014;nn(n):1-16 http://dx.doi.org/10.1016/j.mayocp.2014.08.006
www.mayoclinicproceedings.orgMATERNAL RESOURCES HYPOTHESIS
TABLE. Operational 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 The intergenerational transmission of social and biological traits, attributes, characteristics, and/or features. Inheritance may
heritability 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 phenotype23 directly induce rapid, phenotypic alterations in
offspring, independent of the genotype.24-28
Nutrient energy 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.29-31
Phenotype An organism’s observable characteristics or traits, including, but not limited to, its morphology, development, physiology,
metabolism, behavior, and products of behavior.23
Phenotypic evolution 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.32
Socioenvironmental Socioenvironmental evolution is a progression of social and/or cultural practices that markedly alters behavior and/or the
evolution environments in which humans exist.21,22 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.
phenotype (eg, environmental modifications)23 genotypic evolution, as well as effects that may
induce rapid, phenotypic alterations in offspring, be in direct contrast to traits favored by natural
independent of the genotype.24-28 As such, ME selection (ie, nonadaptive).7,25,27,45 Maternal ef-
represent a mechanism by which the environ- fects occur in 2 developmental contextsdthe
mental exposures that generated the phenotype prenatal (ie, intrauterine) and postnatal environ-
of the mother are translated directly (via mentsdand are a major driver of other evolu-
developmental plasticity34) into the phenotype tionary processesdPE and SEE.
of the offspring.24 Maternal effects may be
induced via direct physiological effects on the Phenotypic Evolution
fetus in utero35,36 and/or the transmission of Phenotypic evolution is a unidirectional, pro-
behavior25,28 from mothers to infants and chil- gressive alteration in ontogeny that is propa-
dren via social learning, imitation, and operant gated over multiple successive generations
and/or classical conditioning.37-40 Maternal ef- and may be quantified as the change over
fects are ubiquitous in nature25,26 and contribute time in the population mean for the trait under
to the variation in phenotypes derived from any examination (eg, height and obesity). As will
given genotype.24-28,41,42 Maternal effects are be presented in detail in a later section, PE is
causal elements in ontogeny and phenotypic neither mere phenotypic plasticity nor acute
plasticity in response to environmental heteroge- adaptations to environmental heterogeneity
neity24 and are of evolutionary significance19,42 but the progressive intergenerational trans-
because they are an essential component in mission of acquired characteristics over mul-
generating the substrate on which natural selec- tiple successive generations. Phenotypic
tion acts (ie, the phenotype).19,24,25,32,42 Within evolution may occur in anatomic and/or phys-
a permissive environment, ME may be cumula- iologic traits (eg, height, weight, size at birth,
tive43,44 and can produce a progressive accelera- age at menarche, hyperplastic adiposity, and
tion or regression of both phenotypic and organ mass and function) or behavioral traits
Mayo Clin Proc. n XXX 2014;nn(n):1-16 n http://dx.doi.org/10.1016/j.mayocp.2014.08.006 3
www.mayoclinicproceedings.orgMAYO CLINIC PROCEEDINGS
(eg, inactivity and sedentarism). Because natu- that obviated the need for deliberate exercise.49
ral selection acts directly at the level of the Nevertheless, over the past few centuries,
phenotype, PE has direct evolutionary conse- humans have become extremely adept at altering
quences and may be induced via genetic, the environments in which they exist, and the
epigenetic, or nongenetic pathways of evolution of their physical, social, and cultural
inheritance.32 milieus (ie, SEE) has proceeded much more
rapidly than has genetic evolution.22 Socioenvir-
Socioenvironmental Evolution onmental evolution has altered the evolution of
Socioenvironmental evolution is a progres- human energy metabolism by inducing substan-
sion of social and/or cultural practices that tial decrements in EE imposed by daily life50
significantly alters behavior and/or the phys- while improving both the quality and the quan-
ical environments in which humans tity of nutrient-energy availability.51 For example,
exist.21,22 It has been posited that SEE can as thermoneutral environments became ubiqui-
be measured by a population’s “ability to uti- tous,52 the energy cost of thermoregulation
lize energy for human advancement or declined, and improved sanitation (eg, clean wa-
needs.”46 Socioenvironmental evolution oc- ter and safer food)53 and vaccinations54
curs in multiple contexts such as social prac- decreased the energy cost of supporting parasites
tices (eg, health care) or changes in the (eg, fleas)55 and resisting pathogens (eg, commu-
physical environment (eg, sanitation, food nicable diseases and diarrheal infections).56
supply, labor and time-saving technologies, Together, these changes not only decreased EE
heating, and air conditioning). Socioenviron- but also dramatically curtailed periods of low-
mental evolution may be considered both a energy consumption via reductions in both
process and a product of numerous factors illness-induced hypophagia and declines in appe-
including both technological innovation21 tite from elevated ambient temperatures.57
and social learning and imitation (eg, By gradually reducing the energy costs of
memes).47 Because SEE may affect the devel- survival and increasing nutrient-energy avail-
opment of a phenotype and substantially ability,53 SEE increased the energy available
alter the environmental context and conse- for development, growth, and reproduction.
quent phenotype-environment interactions, The positive energy balance facilitated by SEE
it has direct evolutionary consequences. In led to the evolution of many human character-
social species, conspecifics and the environ- istics (ie, PE). For example, improvements in
mental context may have a greater impact health and nutrition over the past century
on an individual’s survival than on his or have led to progressive and cumulative in-
her genetic inheritance. Socioenvironmental creases in height,1 body stature and mass,58
evolution, PE, and ME can have reciprocal re- birthweight,59-61 organ mass,2,62 head circum-
lationships as phenotype-environment inter- ference,3,63 and fat mass/adiposity.64 In concert
actions drive developmental dynamics, with these increments has been a progressive
which, in turn, drive the evolution of social global decline in the age at which adolescents
and environmental milieus. Figure 1 is a con- attain sexual maturity, with breast development
ceptual depiction of the MRH. (ie, thelarche) and menses (ie, menarche) in
girls and testicular development in boys begin-
THE MATERNAL RESOURCES HYPOTHESIS ning a year earlier in many populations.4 This
PE has been ubiquitous and significant. A
The Recent Evolution of Human Energy recent examination of the validity of the 1975
Metabolism “Reference Man”65 for determining the safety
Human metabolic, cardiovascular, and musculo- of medication doses and occupational radiation
skeletal systems evolved in environments in exposure found that men and women in 2010
which survival necessitated prodigious amounts were heavier, taller, and had more fat and skel-
of physical exertion and high levels of energy etal muscle (SM) mass and larger organ masses.
expenditure (EE).48 Evading predators, the hunt- Given that reproductive capacity is an
ing and gathering of food, and the literal “chop- essential facet of evolution, and in humans
ping wood and carrying water” of daily reproduction cannot occur without sufficient
existence provided a wholesome dose of PA maternal resources (ie, body mass and
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Mayo Clin Proc. n XXX 2014;nn(n):1-16
MATERNAL RESOURCES HYPOTHESIS
FIGURE 1. Conceptual depiction of the maternal resources hypothesis.
Socioenvironmental changes Legend: Adipocyte hyperplasia,
hypertrophy, and weight gain
Generation 1
Led to increases in
Decreased
Generation 2
Maternal inactivity, Generations 3+ Accelerated
Decreased sedentary behavior Reduced Strength to weight ratio
and adiposity
Led to
n
Reduced
Energy expenditure Lipidemic control
http://dx.doi.org/10.1016/j.mayocp.2014.08.006
Reduced Inactivity Reduced
Reduced Reduced
Increased
Adipogenic
Lipidemic control Glycemic control
Increased Glycemic control Increased nutrient-energy
partitioning from
Increased infancy to adolescence Led to Pregravid adiposity Led to
Survival of large fetuses in females
and mothers
who produced them Led to
Energy substrate
(glucose and fatty acids) Allowed
availability to Led to High-risk/obese children
intrauterine environment Increased Rate of
and fetus ceasarian sections Led to
Engendered
Increased Increased
Increased Phenotypic evolution:
Fetal pancreatic intensified insulin response,
Fetal adipocyte
β-cell mass adipocyte hyperplasia and
hyperplasia Prevalence
and function severe adipogenic
of dystocia
nutrient-energy partitioning
Increased Led to Initiated
Led to
Led to
Increased
Anatomic and physiologic
Fetal insulin production
Perpetuated tipping point in which
Perpetuated obesity is inevitable
Altered fetal Led to
body composition, Positive feedback loop
Led to
fetal size,
and/or adiposity The obesity pandemic
5MAYO CLINIC PROCEEDINGS
adiposity), these alterations in the phenotype sedentary behaviors in children, women, and
have nongenetic evolutionary consequences mothers.66-68 From the 1960s to 2010, esti-
(ie, they alter survival and reproductive success mated maternal household PAEE decreased
independent of changes in gene or allele fre- approximately 1200 to 1500 kcal/wk as the
quency). Logically, these results are representa- time spent in sedentary leisure (eg, watching
tive of PE because each of the aforementioned TV) increased to more than 2.5 h/d.68 Most
characteristics developed with a progressive, pregnant women currently spend more than
unidirectional linearity that was transmitted to 50% of their waking hours in sedentary
successive generations. For example, from behavior, and more than 15% of pregnant
1900 to 2000, the median height for Japanese women spend more than 5 h/d in leisure-time
boys and girls increased by 20 and 19 cm at screen-based media use.72 Recent work suggests
the age of 13 and 11, respectively.1 These that by the 1990s, women and mothers allocated
changes were neither mere developmental plas- more time to screen-based media use (eg, watch-
ticity nor acute adaptations to improved nutri- ing TV) than to all forms of PA combined.68 In
tion and/or decreased EE via reductions in concert with progressive increments in sedentar-
pathogen load. These changes in the phenotype ism, inactivity, and PAEE were progressive
were indicative of a gradual, progressive, and decrements in population-level metabolic con-
enduring intergenerational transmission of trol73-75 and substantial increases in maternal
greater stature over many generations that pregravid obesity,76 gestational weight gain,77
was robust to acute variations in environmental and gestational diabetes.78
influences (eg, food shortages).
The Necessity of PA for Metabolic Health
The Late 20th Century and Increments in Skeletal muscle activation via PA is an absolute
Maternal Resources requirement for metabolic health.79 Therefore,
Until the middle of the 20th century, SEE and as mothers spent more time in sedentary
PE were adaptive, given that in most species, behavior and the intensity, frequency, and vol-
mothers with greater energy resources (ie, ume of maternal PA decreased,67,68 there were
physiological or environmental) beget more marked reductions in SM activation and en-
robust offspring,41 and it is well established ergy flux. Because SM is the principal tissue
that human mothers with adequate or ample for both insulin-mediated glucose disposal17
physiological and environmental resources and fatty acid oxidation18 and an essential
produce healthier, more robust infants and element of energy metabolism,80 progressive
children than do women with fewer re- reductions in maternal PA and PAEE over
sources.51 Nevertheless, I posit that as the cen- the past century would result in progressive
tury drew to a close, sustained SEE and PE decrements in metabolic,17,29,31,81-83 glyce-
began driving ME that led to the childhood mic,83-85 and lipidemic86-88 control. This loss
obesity epidemic. of metabolic control led to both transient hy-
By the late 20th century, humans in indus- perglycemia (ie, glycemic excursions) and
trialized nations were immersed in environ- hyperlipidemia,74,89,90 the former driven by
ments explicitly engineered to reduce manual reductions in insulin signaling resulting from
labor,66-68 increase physical comfort (eg, the replete myocyte glycogen stores,91,92 and the
ubiquity of chairs and thermoneutral environ- latter from reduced SM energy demands and
ments52), and afford passive entertainment.69 consequent decrements in total fatty acid
As a result, physical inactivity and sedentary oxidation,86-88,93 increments in hepatic and
pastimes (eg, Web surfing and television [TV] adipocyte de novo lipogenesis,94-96 and lipid
viewing) became both ubiquitous features of accumulation in adipose tissue.97,98
the posteindustrial world51 and leading global
risk factors for mortality and morbidity.70 The ME of Inactivity and Insulin Resistance
Importantly, the confluence of passive trans- Although inactivity has dire effects on human
portation, spectator-based entertainment, and energy metabolism29,30,99,100 and health,70
decrements in occupational and household given the recent SEE and PE, it is substantially
PA66,68,71 led to significant declines in PA en- more pathologic to pregnant women and their
ergy expenditure (PAEE) and increments in fetuses. Human pregnancy is characterized by
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numerous metabolic changes that promote the lipid in fetal adipocytes.122 Second, maternal
accretion of adipose tissue in concert with glucose is the major substrate for fetal lipogen-
impaired insulin sensitivity and insulin resis- esis, is highly correlated with newborn body
tance.101 As explained previously, SM is the fat,123 and is a predictor of the fat mass of pre-
principal tissue for glucose disposal, and normal pubertal offspring.113 In the third trimester,
pregnancies will exhibit a hormone-induced maternal PA will be at its lowest point,124,125
40% to 60% reduction in insulin-mediated and, therefore, maternal glycemic control
glucose disposal.102 This decrement in insulin will be at its nadir. Consequently, fetal lipo-
sensitivity drives a 200% to 300% increase in in- genesis and adipocyte hyperplasia will be
sulin secretion to maintain maternal glycemic maximized as compared with metabolically
control.102 I posit that progressive reductions healthy (eg, lean and active) mothers because
in maternal PA and PAEE and consequent re- of a number of processes. First, maternal hy-
ductions in SM activation over the past half- perglycemic excursions will drive fetal hyper-
century act synergistically with the naturally glycemia, which, in turn, results in fetal
occurring metabolic sequelae of pregnancy (ie, hyperinsulinemia (via enhanced b-cell mass
hormone-induced insulin resistance and and function) and drives growth factors that
increased adiposity) to exacerbate the negative result in excessive fetal growth and
metabolic consequences of inactivity29,30,99,100 adiposity.126-129 Second, maternal inactivity
and drive fetal abnormalities. The reductions decreases maternal SM fatty acid oxidation
in insulin sensitivity and increments in transient and consequently promotes lipid transfer to
hyperglycemia and hyperlipidemia90 substan- the fetus by increasing the maternal-to-fetal
tially increase the availability of energy sub- fatty acid concentration gradient.114
strates to the intrauterine environment. Given the strong inverse relationship be-
Because the human placenta evolved in a tween the oxidation of dietary fat in SM and
context of intense competition between obesity (ie, obese individuals partition more
maternal resources and fetal demands (ie, low fatty acids to storage as lipid in adipocytes,
to moderate maternal body mass and adiposity whereas lean individuals oxidize a greater rela-
in concert with moderate to high levels of tive amount130), the cumulative effect of alter-
maternal EE, PA, and PAEE103-105), the current ations in fetal myogenesis and impaired SM
context of high maternal resources in combina- morphology in concert with a greater number
tion with low PA represents an evolutionary of adipocytes and increased pancreatic b-cell
mismatch. Given that the partitioning of function (ie, enhanced insulin secretion) pro-
nutrient energy between the mother and the duce metabolically compromised infants pre-
conceptus is a major determinant of fetal out- disposed to lifelong inactivity, metabolic
comes,106 the perturbation of the intrauterine dysfunction, and obesity owing to the compet-
milieu via the mismatch of increased maternal itive dominance of adipocytes in the acquisi-
metabolic resources (eg, body mass and tion and sequestering of nutrient energy.
adiposity) and inactivity-driven decrements in In addition, although SEE led to large and
PAEE has significant metabolic consequences significant decrements in maternal activity
for the offspring.107 and glycemic control, it led to substantial de-
Excess intrauterine energy substrates clines in maternal smoking.131 Unfortunately,
stimulate the hypertrophy and hyperplasia of despite the maternal and fetal health benefits
both pancreatic b cells35,108-112 and adipo- associated with reductions in tobacco use, the
cytes,113-117 up-regulate fetal fatty acid and mild fetal hypoxia induced via smoking132
glucose transporters,116 increase the direct may have played a role in delaying the negative
free fatty acid uptake and storage as triglycer- effects of inactivity on maternal glycemic con-
ide in fetal adipocytes,118,119 alter myogenesis trol and consequent mother-conceptus energy
and increase collagen accumulation and cross- partitioning by altering fetal glucose trans-
linking in fetal SM,120,121 and increase the porter regulation133 and growth.134
expression of enzymes mediating de novo Figures 2 and 3 depict the hypothesized
lipogenesis.116 These points are critical. First, consequences of the perturbation of
fetal adipose de novo fatty acid synthesis is a maternal-conceptus energy partitioning and
primary mechanism for the accumulation of fetal outcomes.
Mayo Clin Proc. n XXX 2014;nn(n):1-16 n http://dx.doi.org/10.1016/j.mayocp.2014.08.006 7
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have relatively high levels of PA in concert with
Uncontrolled maternal
diabetes low energy resources (ie, low body mass,
adiposity, and nutrient-energy intake).135 Given
Fetal pancreatic β-cell mass and functiona
↑ Risk of
that the evolutionary forces that induced incre-
obesity ments in maternal energy resources and decre-
ments in PA are not present, the net result is a
decrease in the energy available to the intrauter-
↑ Lifetime risk of
T2DM in fetusb ine milieu. In the absence of maternal resources
to buffer fetal demands,135 the competition be-
tween fetal energy requirements and maternal
↑ Lifetime
energy needs results in intrauterine growth
risk of restriction106 and associated pathologies.136 In
T2DM in fetusb congruence with the thrifty phenotype (ie,
Barker) hypothesis,137,138 the MRH posits that
Restricted (Low) Normal Excess (hyperglycemic)c in the context of high levels of PA and low
Maternal glucose availability to fetus nutrient-energy intake, maternal myocytes and
other metabolically active tissues (eg, organs)
FIGURE 2. Hypothesized consequences of excess maternal glucose on fetal outcompete both maternal adipocytes and fetal
pancreatic b-cell function. aHypertrophy and hyperplasia of fetal pancreatic tissues for nutrient energy. This results in the
b cells.108-110 bAn inactive lifestyle as a child and adolescent is a necessary loss of maternal body mass and permanently al-
condition for risk to be actualized. cHyperglycemia may be transient (eg,
ters fetal development and consequent energy
acute excursions induced via mild insulin resistance) or chronic (frank dia-
betes). T2DM ¼ type 2 diabetes mellitus.
metabolism while predisposing offspring to
chronic noncommunicable diseases (eg, type 2
diabetes mellitus [T2DM] and cardiovascular
The Counterfactual Support for the MRH disease [CVD]) when the postnatal environment
The aforementioned results are in direct contrast permits low levels of PA in combination with
to those obtained for women in nonindustrial- adequate nutrition. Figure 4 depicts fetal out-
ized nations who have not experienced similar comes as maternal resources and PA vary.
SEE and PE over the past century. These women The MRH and the extant evidence suggest a
continuum of metabolic control and mother-
conceptus energy partitioning with both
High restricted135 and excess maternal resources,139
pathologically altering the metabolic health of
offspring.140 As such, the ideas presented here-
in subsume and extend both the Barker138 and
Relative adipocyte number
Pedersen139 hypotheses and offer a nongenetic
mechanism for the intergenerational transmis-
sion of obese and other high-risk phenotypes.
↑ Lifetime risk
of obesityb Stated simply, the MRH posits that the risk of
obesity, T2DM, and CVD is propagated pro-
↑ Lifetime gressively via the interplay between maternal
risk of ↓ Risk of energy resources, maternal patterns of PA,
visceral obesityb
and the ensuing metabolic sequelae of
adiposity
pregnancy.
Low
Postnatal ME
Restricted (Low) Normal Excess (hyperglycemic)
The intergenerational transmission of behavior
Energy availability to fetusa
is well accepted in social animals such as
humans.40,141 Because the primary ecological
FIGURE 3. Hypothesized consequences of excess intrauterine energy on
fetal adipocyte development. aDetermined by maternal adiposity, energy niche of an infant is the social environment
intake, physical activity, and total daily energy expenditure. bObesity as that caregivers create, the processes of postnatal
categorized by body mass index >30 kg/m2. ME provide nongenetic mechanisms by which
the environmental exposures generated by the
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8 Mayo Clin Proc. XXX 2014;nn(n):1-16 http://dx.doi.org/10.1016/j.mayocp.2014.08.006
www.mayoclinicproceedings.orgMATERNAL RESOURCES HYPOTHESIS
behavioral phenotype of the mother (or care-
giver) directly alters the behavioral phenotype
High
of infants and children. Numerous potential
mechanisms have been posited, including social SGAb
learning and modeling (ie, observational, oper-
Physical activity
ant, and/or classical conditioning).37-40,142-144
Metabolically
It is well established that a mother’s TV viewing healthy
behavior affect her progeny’s TV behavior37;
therefore, as with the intergenerational transmis-
sion of smoking behavior,143 children who grow LGAc
up with an inactive, sedentary caregiver may be
more likely to be sedentary, inactive, and obese Low
as adults.142,145 For example, if a woman de-
velops the habit of breast-feeding while watch- Restricted (Low) Normal Excess
ing TV, her infant may associate the sights and Maternal energy resourcesa
sounds of the TV with feeding behavior. Given
that maternal attention and feeding are powerful FIGURE 4. Hypothesized consequences of maternal energy balance on fetal
reinforcers,146 the process of classical condition- development. aMaternal resources determined by socioenvironmental
ing may (metaphorically speaking) turn the TV evolution and phenotypic evolution of familial line, prenatal body mass,
into Pavlov’s dinner bell.144 The conjoined be- adiposity, and energy intake. bSmall for gestational age (SGA): predisposed
haviors of feeding and TV viewing will be to visceral adiposity type 2 diabetes mellitus and cardiovascular disease.
c
continuously reinforced when TV and food are Large for gestational age (LGA): predisposed to obesity, type 2 diabetes
used to control infant behavior (ie, used as a mellitus, and cardiovascular disease.
babysitter).14,69
This conceptualization of the intergenera-
tional transmission of inactivity and sedentary predispositions are permanently entrenched by
behavior is supported by research reporting the infant’s and child’s early social environ-
strong relationships between mother-daughter ments. Over the past 50 years, the use of
body mass index and obesogenic behaviors screen-based media has increased consider-
(eg, eating in front of the TV).147 Maternal TV ably,151 and by the late 1990s, mothers and
viewing and obesity are associated with greater children were spending the vast majority of
infant TV exposure,145 with infants as young as their leisure time watching TV.67,151 Screen-
3 months old exposed to an average of more based media (eg, TV) is often used as a surro-
than 2.5 hours of TV and/or videos daily and gate caregiver (ie, “babysitter”)69 for precisely
nearly 40% of infants exposed to more than 3 the same reason that it is detrimental to infants
hours of TV daily before the age of 12 and children: it captures their attention and
months.145 Having a TV in the bedroom is keeps them relatively immobile. In a none
one of the most powerful predictors of child- media-enhanced world, the child will stimulate
hood obesity,148 and large-scale epidemiolog- his or her nervous system via movement and
ical studies have found that one of the “exploration” facilitated by the activation of
strongest determinants of obesity and cardio- SM. Because osteocytes, myocytes, and adipo-
metabolic risk factors in later life was TV cytes share a common pool of progenitor cells,
viewing in early life.149 In addition to the meta- reduced PA leads to a reduction in the physio-
bolic effects of postnatal ME, there are cognitive logical resources (eg, muscle development,
effects. TV viewing before the age of 3 is associ- strength, and coordination) necessary for life-
ated with cognitive delays, decrements in lan- long PA, and every kilocalorie of energy that
guage development, attention issues, and is not used to build muscle and bone may be
sleep disorders.150 used to further increase adipocyte size and/or
number.87,88,152 As such, the predisposition
Screen-Based Media as a Caregiver (ie, TV to obesity would be instantiated via accelerated
as a Babysitter) hyperplastic adiposity, inactivity, decrements
I posit that current obese phenotypes are pre- in the physiological resources necessary for
disposed at birth via prenatal ME and that these movement (eg, strength and coordination),
Mayo Clin Proc. n XXX 2014;nn(n):1-16 n http://dx.doi.org/10.1016/j.mayocp.2014.08.006 9
www.mayoclinicproceedings.orgMAYO CLINIC PROCEEDINGS
and the initiation of a positive feedback loop and behavioral trajectories induced by the previ-
that negatively alters health trajectories over ous generation’s phenotype (ie, the ME) were
successive generations via mother-daughter propagated progressively as the ontogeny of
transmission. their offspring was initiated at a point further
along the continuum of phenotypic plasticity
IATROGENIC ARTIFICIAL SELECTION (ie, advanced baseline). This evolutionary pro-
The excessive fetal growth induced via evolu- cess of accumulative ME19 was facilitated by
tionary processes has resulted in larger and fatter medicalized childbirth and led to anatomic,
infants over the past few generations (eg, physiologic, metabolic, and behavioral tipping
increased neonatal organ mass, head circumfer- points that ensured an escalating competitive
ence, fat mass, and birthweight2,3,60,63). Because dominance of adipocytes in the acquisition
the evolution of infant head circumference155 and sequestering of nutrient energy in many hu-
has progressed more quickly than the evolution man subpopulations (eg, African Americans).
of the birth canal,154 the prevalence of dystocia- Within a few generations, the postprandial insu-
related cesarean sections (ie, surgically assisted lin response was so intense (via enhanced b-cell
births) has increased substantially.15,153,155 This mass and function and inactivity-induced insu-
SEE (ie, progression of medical technology and lin resistance), the relative number of adipocytes
practice) allowed both larger fetuses and the so large, and inactivity so pervasive that the
mothers who produced them to survive and competitive dominance of adipocytes in the
reproduce, thereby increasing the frequency of acquisition and sequestering of nutrient energy
metabolically compromised, obese phenotypes was inevitable and obesity was unavoidable.
in the global population. As such, “natural selec-
tion” was iatrogenically and unintentionally CONSEQUENCES OF THE MRH FOR OBESITY
rendered “artificial selection.” The artificial selec- RESEARCH
tion of metabolically compromised infants is Most obesity research is based on the concep-
clearly supported by numerous facts: familial tual framework of energy balance derived
line is a major predictor of both dystocia156 and from the first law of thermodynamics.162
cesarean birth,157 childhood obesity has a strong The fundamental a priori assumption is that
relationship with cesarean birth,158 and, most relative imbalances between nutrient-energy
importantly, the frequency of cesarean births is consumption and EE cause the excessive stor-
greatest in the population that is most inactive, age and sequestering of energy as lipid in
sedentary, and obese (ie, non-Hispanic black)13- adipocytes. This paradigm assumes a tempo-
15
and has had the largest increments in TV rality that has no empirical foundation and
viewing over the past 50 years.159 merely provides a valid description of the in-
crease in the storage and sequestering of en-
METABOLIC TIPPING POINT ergy (ie, an analytic truth). As such, these
The greatest declines in maternal activity (via paradigms offer no insight into the causal
our data67,68) occurred from the 1960s to the mechanisms or the temporal nature of the
1970s, although prior research suggests that increase. I argue that because all tissues
the declines began earlier.160 This suggests compete for energy, obesity is the result of ad-
that the female children of the increasingly inac- ipocytes outcompeting other cells, tissues,
tive mothers of the 1950s through the 1970s and organs in postprandial periods. The
would themselves be having metabolically initial trajectory that engenders this competi-
compromised children and grandchildren 20 tive dominance of adipocytes (and conse-
to 50 years later (ie, from the early 1970s to quent obesity) is initiated in utero because
late 2000s). As these metabolically compro- of ME induced via reduced metabolic control,
mised female children matured and transitioned leading to the confluence of an intensified in-
through puberty, adipocyte number and mass sulin response (via enhanced b-cell mass and
were further exacerbated via the hormonal function), decreased fatty acid oxidation via
milieu161 and obesogenic environment (eg, decrements in myogenesis and myocyte
inactive caregivers producing inactive children morphology, and the law of mass action (ie,
and adolescents). When these women repro- a larger relative number of fat cells disposing
duced, the anatomic, physiologic, metabolic, of a larger percentage of energy intake).
n n
10 Mayo Clin Proc. XXX 2014;nn(n):1-16 http://dx.doi.org/10.1016/j.mayocp.2014.08.006
www.mayoclinicproceedings.orgMATERNAL RESOURCES HYPOTHESIS
This conceptualization is strongly sup- muscle mass and parallel decrease in relative
ported by extant research, given that incre- body fat as exhibited by bodybuilders would
ments in fat mass are a function of be impossible. As such, the genesis of obesity
adiposity,163 adipocyte number is a primary is predicated on a greater allocation, storage,
determinant of obesity,164,165 and early devel- and sequestering of lipid in adipocytes as a
opment is a major determinant of adipocyte function of adipocyte number, pancreatic
number.164,165,167 As such, the infant born b-cell function (ie, insulin secretion), and SM
to an inactive mother would be metabolically energy metabolism (ie, glucose and fatty acid
compromised via the confluence of the prena- oxidation and glycogen synthesis).
tal ME (eg, adipocyte hyperplasia and reduced
myogenesis) and the postnatal ME (eg, learned Obesity as an Inherited, Chronic Condition
inactivity). This hypothesis is strongly sup- The MRH suggests that the energy meta-
ported by the facts that the adipose tissue of bolism of affected individuals is permanently
young obese children differs both qualitatively altered in utero, and strategies such as reduc-
and quantitatively from the adipose tissue of tions in energy intake (ie, “dieting”) and other
lean children166 and that adipocyte number energy manipulations (eg, exercise) will be
increases throughout early development.167 offset, not by a regulatory mechanism per
In addition, monozygotic twins concordant se, but by the fact that the nature of the
for birthweight exhibit similar adipocyte nutrient-energy partitioning will not be
numbers, whereas in those discordant for altered via the loss of lipid content in adipo-
birthweight, the smaller twin displays both cytes or an increase in fatty acid oxidation
lower body weight and adipocyte number.168 by other tissues. Because it can be assumed
I posit that these results suggest an in utero that human energy metabolism evolved under
“training effect” in which the chronic parti- intense selective pressures, it will be robust to
tioning of energy to storage in adipose tissue acute perturbations. In other words, as long as
induces numerous metabolic sequelae that the predisposing metabolic impairments
lead to obesity via adipogenic nutrient parti- exist, the individual will continue to store a
tioning and an exacerbated recruitment and greater amount of energy as lipid in adipo-
differentiation of mesenchymal cells to mature cytes than does an individual with normal
adipocytes.169 SM metabolism, pancreatic b-cell function,
Importantly, the increase in the storage and and adipocyte number. Hence, for most indi-
sequestering of nutrient energy in adipocytes viduals, obesity is a chronic condition of
reduces the substrates and metabolic stimuli adipocyte dominance in the acquisition and
that inhibit hunger and appetitive processes sequestering of nutrient energy that cannot
(eg, adenosine triphosphate/adenosine diphos- be “cured” via “moving more and eating less.”
phate ratio, hepatic energy flux, and glucose
and fatty acid oxidation).170,171 As such, this Practical Implications of the MRH
sequestration engenders a perception of fa- Given the breadth, scope, and strength of the
tigue172 (and consequent inactivity and evidence that supports the MRH, there are a
inactivity-induced decrements in metabolic number of practical implications. First, the
control), depression,173 decreased energy,172 acknowledgment that obesity is the result of
and an accelerated development of hunger nongenetic evolutionary forces and not glut-
and consequent shorter intermeal interval tony and sloth174 may help to alter the moral-
and/or increased energy density per meal. izing and demoralizing social and scientific
These phenomena result in a positive feedback discourse that pervades both public and
loop that leads to excessive food and beverage clinical settings. Second, the conceptual frame-
consumption, which exacerbates the vicious work of tissues competing for nutrient-energy
cycle of adipogenic nutrient-energy partition- substrates has consequences for both the
ing, increasing adiposity, decreased metabolic research community and clinicians. Future
control, and obesity. research may be most productive if funding is
Logically, people do not develop excessive directed away from naive examinations of en-
adiposity simply by being in positive energy ergy balance per se and redirected to investiga-
balance; if this were true, the increase in tions of interventions that alter the competitive
Mayo Clin Proc. n XXX 2014;nn(n):1-16 n http://dx.doi.org/10.1016/j.mayocp.2014.08.006 11
www.mayoclinicproceedings.orgMAYO CLINIC PROCEEDINGS
strategies of various tissues. From the stand- interplay between maternal energy resources,
point of the clinician, accurate patient pheno- maternal patterns of PA, and the ensuing meta-
typing (inclusive of family obstetric history bolic sequelae of pregnancy over multiple gener-
and metabolic profiling) may allow the target- ations. Given that maternal metabolic control is a
ing of women most likely to be a part of popu- strong determinant of fetal metabolic outcomes
lations that have evolved beyond the metabolic and health (eg, risk of obesity, T2DM, and
tipping point and therefore require significant CVD), the health and well-being of future gener-
preconception intervention. ations depend on policies and preconception in-
terventions that can ameliorate the effects of more
SUMMARY OF THE MRH than a century of nongenetic evolutionary pro-
The MRH posits that the childhood obesity cesses and overcome the current competitive
epidemic is the result of the evolutionary pro- dominance of adipocytes.
cesses of ME, PE, and SEE, leading to a metabolic
tipping point in human energy metabolism at
ACKNOWLEDGMENTS
which adipocytes outcompete other cell types
The author would like to thank his esteemed
in the acquisition and sequestering of nutrient
colleagues and critics for the conversations and
energy. The recent competitive dominance of feedback that led to this paper, especially Saman-
adipocytes was achieved via the confluence of
tha McDonald, Chip Lavie, John Sievenpiper,
multiple evolutionary processes. Over the past
Chris Kuzawa, Diana Thomas, Michael Dweck,
century, SEE and PE facilitated increments
Wendy Kohrt, Bob Malina, Tonia Schwartz,
in maternal resources (eg, body mass and
Steve Heymsfield, Russ Pate, Mike Pratt, Gregory
adiposity), inactivity, and sedentarism that
Pavela, Emily Dhurandhar, Kathryn Kaiser,
induced decrements in maternal metabolic
Krista Casazza, and finally my mentors David
control (eg, insulin sensitivity). This PE path-
B. Allison and Steven N. Blair.
ologically increased the energy substrates
available to fetuses, causing mothers to pro-
Abbreviations and Acronyms: CVD = cardiovascular
duce progressively larger, fatter, more inac- disease; EE = energy expenditure; ME = maternal effects;
tive, and consequently more metabolically MRH = maternal resources hypothesis; PA = physical ac-
compromised and less physically fit175 off- tivity; PAEE = physical activity energy expenditure; PE =
spring predisposed to chronic noncommuni- phenotypic evolution; SEE = socioenvironmental evolu-
cable diseases.176 Increments in the use of tion; SM = skeletal muscle; T2DM = type 2 diabetes mel-
litus; TV = television
cesarean sections allowed the frequency of
metabolically compromised female offspring Grant Support: The work was supported by the National
in the population to increase. When these Institute of Diabetes and Digestive and Kidney Diseases of
women reproduced, the ME of hyperplastic the National Institutes of Health under award number
T32DK062710.
adiposity, intensified pancreatic b-cell function,
altered SM myogenesis, and inactivity were pro- The content is solely the responsibility of the author and
gressively propagated to successive generations, does not necessarily represent the official views of the Na-
thereby making obesity inevitable in many tional Institutes of Health.
human familial lines. The consequences of the Correspondence: Address to Edward Archer, PhD, MS,
MRH suggest that recent evolutionary trends Office of Energetics, Nutrition Obesity Research Center, Uni-
have not been adaptive177 and that the evolu- versity of Alabama at Birmingham, 1675 University Blvd, Webb
tionary fitness (ie, survival177 and reproduc- 568, Birmingham, AL 35294 (archer1@uab.edu).
tion178) of some human familial lines is in decline.
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