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HYPOTHESIS AND THEORY
published: 10 August 2018
doi: 10.3389/fphys.2018.01053
Cell-Specific “Competition for
Calories” Drives Asymmetric
Nutrient-Energy Partitioning,
Obesity, and Metabolic Diseases in
Human and Non-human Animals
Edward Archer1* , Gregory Pavela2, Samantha McDonald3, Carl J. Lavie4 and
James O. Hill5
1 EvolvingFX, Jupiter, FL, United States, 2 The University of Alabama at Birmingham, Birmingham, AL, United States,
3 East Carolina University, Greenville, NC, United States, 4 School of Medicine, John Ochsner Heart and Vascular Institute,
The University of Queensland, New Orleans, LA, United States, 5 Center for Human Nutrition, University of Colorado Health
Sciences Center, Denver, CO, United States
The mammalian body is a complex physiologic “ecosystem” in which cells compete
for calories (i.e., nutrient-energy). Axiomatically, cell-types with competitive advantages
Edited by: acquire a greater number of consumed calories, and when possible, increase in
Brian James Morris, size and/or number. Thus, it is logical and parsimonious to posit that obesity is the
University of Sydney, Australia
competitive advantages of fat-cells (adipocytes) driving a disproportionate acquisition
Reviewed by:
Daniel Donner, and storage of nutrient-energy. Accordingly, we introduce two conceptual frameworks.
Baker Heart and Diabetes Institute, Asymmetric Nutrient-Energy Partitioning describes the context-dependent, cell-specific
Australia
Andrew Wolfe, competition for calories that determines the partitioning of nutrient-energy to oxidation,
Johns Hopkins University, anabolism, and/or storage; and Effective Caloric Intake which describes the number
United States of calories available to constrain energy-intake via the inhibition of the sensorimotor
*Correspondence: appetitive cells in the liver and brain that govern ingestive behaviors. Inherent in
Edward Archer
archer.edwardc@gmail.com these frameworks is the independence and dissociation of the energetic demands
of metabolism and the neuro-muscular pathways that initiate ingestive behaviors and
Specialty section: energy intake. As we demonstrate, if the sensorimotor cells suffer relative caloric
This article was submitted to
Integrative Physiology, deprivation via asymmetric competition from other cell-types (e.g., skeletal muscle- or
a section of the journal fat-cells), energy-intake is increased to compensate for both real and merely apparent
Frontiers in Physiology
deficits in energy-homeostasis (i.e., true and false signals, respectively). Thus, we
Received: 30 March 2018
Accepted: 16 July 2018 posit that the chronic positive energy balance (i.e., over-nutrition) that leads to obesity
Published: 10 August 2018 and metabolic diseases is engendered by apparent deficits (i.e., false signals) driven
Citation: by the asymmetric inter-cellular competition for calories and concomitant differential
Archer E, Pavela G, McDonald S, partitioning of nutrient-energy to storage. These frameworks, in concert with our
Lavie CJ and Hill JO (2018)
Cell-Specific “Competition previous theoretic work, the Maternal Resources Hypothesis, provide a parsimonious
for Calories” Drives Asymmetric and rigorous explanation for the rapid rise in the global prevalence of increased body
Nutrient-Energy Partitioning, Obesity,
and Metabolic Diseases in Human and fat mass, and associated metabolic dysfunctions in humans and other mammals
and Non-human Animals. inclusive of companion, domesticated, laboratory, and feral animals.
Front. Physiol. 9:1053.
doi: 10.3389/fphys.2018.01053 Keywords: obesity, nutrition, physiology, non-genetic, evolution, competition
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Archer et al. Competition for Calories
INTRODUCTION consumed and stored than expended. This leads to diminished
insulin sensitivity, and increments in both body and fat mass,
“Frustra fit per plura, quod potest fieri per pauciora” [It is futile to and metabolic diseases. Thus, our frameworks in concert with
do with more that which can be done with less]. the Maternal Resources Hypothesis provide a parsimonious and
William of Occam (Thorburn, 1918) physiologically rigorous explanation for the rapid rise in the
global prevalence of increased body and fat mass, and/or
Although obesity is described as a complex phenomenon metabolic dysfunction in humans and other mammalian species,
of disputed etiology (Archer et al., 2018), the defining inclusive of companion, laboratory, farm, and feral animals
characteristic is an excess of body-fat mass (Schwartz et al., (Herberg and Coleman, 1977; Flather et al., 2009; Klimentidis
2017) attributable to a greater number and/or size of fat-cells et al., 2011; Ertelt et al., 2014; Hoenig, 2014; Sandoe et al., 2014;
(adipocytes) relative to other cell-types (Brook et al., 1972; NEHS, 2015).
Salans et al., 1973; Knittle et al., 1979; Sjostrom and William-
Olsson, 1981). Thus, it is logical and parsimonious to posit
that the etiology of obesity is simply the result of physiologic THE CONCEPTUAL FRAMEWORK OF
processes that increase fat-cell number, size, or both. Since ASYMMETRIC NUTRIENT-ENERGY
it is well-established that in utero development and positive
energy balance are two such processes (Greene, 1939; Ingle, PARTITIONING
1949; Mayer et al., 1954, 1956; Hill and Peters, 1998; Hill
et al., 2003; Hill, 2006; Sun et al., 2011; Archer et al., 2013b, Ecological Science
2018; Archer, 2015a,b,c, 2018; Shook et al., 2015; Archer and Competition is fundamental to the evolution of biological
McDonald, 2017), in this paper we extend our previous theoretic organisms (Darwin, 1859), and the asymmetric acquisition of
work, the Maternal Resources Hypothesis (Archer, 2015a,b,c,d; energy and other resources via exploitative and interference
Archer and McDonald, 2017), by introducing two conceptual competition are well-established phenomena (Case and Gilpin,
frameworks. The first, Asymmetric Nutrient-Energy Partitioning 1974; Weiner, 1990; Bourlot et al., 2014). For example, in
describes the context-dependent, cell-specific competition for exploitation competition, organisms acquire and use (i.e., exploit)
calories that determines the partitioning of nutrient-energy resources directly so that they are no longer available for use by
to oxidation, anabolism, and/or storage. The second, Effective other organisms. Thus, competitive advantages allow “individuals
Caloric Intake describes the quantity of calories (i.e., nutrient- [to] obtain a disproportionate share of the resources. . .and
energy) available to constrain energy-intake via the inhibition suppress the growth of smaller individuals” (Weiner, 1990, p. 360).
of the sensorimotor cells that initiate ingestive behaviors (i.e., Given this foundation, our framework of asymmetric nutrient-
energy-sensing appetitive neuro-muscular networks in the liver energy partitioning extends the ecologic concept of resource
and brain) (Langhans, 1996; Schwartz et al., 2000; Friedman, competition from individual organisms to the inter-cellular
2008; Allen et al., 2009; Woods, 2009). These frameworks are competition for calories within the mammalian body.
extensions of the ecological principles of exploitative and/or To be precise, we do not use the competitive acquisition and
interference competition (Case and Gilpin, 1974; Weiner, 1990; exploitation of resources in the natural world as a mere analogy;
Bourlot et al., 2014), and are founded upon well-established rather, we posit that the cell-specific asymmetric competition and
physiologic principles. concomitant partitioning of nutrient-energy resources is central
Briefly, we posit that the context-dependent inter-cellular to understanding the rapid rise in global prevalence of obesity
competition for calories results in an asymmetric nutrient-energy and metabolic disease in human and non-human animals. The
partitioning that reduces the effective caloric intake of each meal. essential element of this framework is the characterization of the
The relative lack of calories available to the energy-sensing, mammalian body as an “ecosystem” in which disparate cell-types
sensorimotor cells in the liver and brain initiates ingestive employ a diverse set of context-dependent competitive strategies
behaviors and energy intake. Inherent in this conceptualization to meet their unique demands for nutrient-energy.
is the independence and dissociation of the energetic demands
of metabolism and the neuro-muscular networks that initiate Body-as-Ecosystem and the
ingestive behaviors and concomitant energy intake. The de- Competition for Calories
coupling of the initiation of ingestive behaviors from metabolic We posit that the mammalian body is a complex, physiologic
demands explains why individuals with substantial amounts of “ecosystem” in which survival and health are determined by
stored energy continue to chronically consume calories in excess metabolic-flux (i.e., the flow of energy through living cells)
of metabolic demands (i.e., over-nutrition). (Archer, 2015c, 2018; Archer and McDonald, 2017; Archer et al.,
While there are numerous phenomena that reduce effective 2018). An organism’s metabolic-flux is determined primarily by
caloric intake and lead to chronic increments in energy intake the energetic demands of the constituent populations of cells,
(e.g., exercise, puberty, and pregnancy), we posit that excessive energy-intake behaviors, and the availability of nutrient-energy to
fat-cell hyperplasia and physical inactivity are unique in that meet metabolic demands. Significant disturbances to metabolic-
they unbalance metabolic-flux (i.e., the flow of nutrient-energy flux such as starvation (i.e., insufficient energy-intake relative
into and out cells) and by doing so, engender false signals of to metabolic demands), exhaustion (i.e., excessive metabolic
short-term energy homeostasis that cause more energy to be demands relative to energy intake), and physical inactivity
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Archer et al. Competition for Calories
(i.e., insufficient metabolic demands relative to energy intake) neuro-muscular) networks linking energy-sensing cells in the
increase morbidity and mortality (Mayer, 1953; Mayer et al., liver and brain to the musculoskeletal system. These networks
1954, 1956; Archer and Blair, 2011; Shook et al., 2015; Archer maintain adequate levels of metabolic-flux by initiating energy-
et al., 2017a, 2018; Archer, 2018). intake behaviors to meet chronic whole-body metabolic demands
Within each mammalian body, each cell must compete for (i.e., the sum of cell-specific energy expenditures over time).
nutrient-energy, and cell-types with competitive advantages will Fifth, a large body of research demonstrates that chronic whole-
exploit (i.e., acquire, oxidize, and/or store) a greater percentage body energy expenditure, which is comprised chiefly of the
of consumed calories and serum energy substrates (e.g., glucose, energetic demands of basal metabolism and physical activity,
amino and fatty acids) at the expense of less advantaged cell- is the primary driver of habitual energy-intake (Mayer et al.,
types. As a result of the enhanced acquisition, advantaged 1954; Edholm et al., 1955; Blundell et al., 2003, 2015; Shook
cell-types (e.g., skeletal muscle- or fat-cells) will increase in et al., 2015). Therefore, because both basal and physical activity
size and/or number when possible. As discussed in subsequent energy expenditures are driven by cell-specific metabolic activity,
sections, competitive strategies are context-dependent and it is logical to conclude that habitual energy-intake is driven
therefore contingent upon inter- and extra-cellular environments primarily by the asymmetric, cell-specific competition for calories
[e.g., level of serum insulin and energy substrates, glycogen and the asymmetric partitioning of nutrient-energy to oxidation,
saturation and/or cellular 5? adenosine monophosphate-activated anabolism, and/or storage.
protein kinase (Baron et al., 1988; Claret et al., 2007; Jensen et al., Thus, we posit that in mammals there is an evolutionarily
2011; Friedrichsen et al., 2013; O’Neill, 2013)]. conserved relation between the sum of cell-specific metabolic
Furthermore, because the initial populations of the activity over time (i.e., chronic basal and physical activity energy
mammalian ecosystem (i.e., type, number, and quality of expenditure) and habitual energy intake. This relation was
cells) are established during gestation, we posit that early implied over two thousand years ago when Aristotle wrote that
development (e.g., in utero through puberty) is the critical period the defining characteristic of animals was the necessity of bodily
for the construction of the competitive milieu and concomitant movement (i.e., physical activity) in order to eat (i.e., energy
partitioning of nutrient-energy that determine body mass and intake), and contrasted the daily physical activity of animals with
metabolic health trajectories from infancy to senescence (Archer, that of plants, which have the luxury of energy acquisition and
2015c; Archer and McDonald, 2017). survival despite stasis (Aristotle, 1943).
Asymmetric Competition and Partitioning Cell-Specific Competitive Strategies
The asymmetric inter-cellular competition and concomitant While all living cells require and compete for nutrient-
partitioning of nutrient-energy in mammals are well-established energy, herein we focus primarily on fat- and skeletal muscle-
(Bauman and Currie, 1980; Bell et al., 1987; Ivy, 1987; Baron cells because these cell-types have the greatest influence
et al., 1988; Heymsfield et al., 2006; Halas et al., 2007; Thyfault on the competitive milieu and concomitant metabolic and
et al., 2007; Peters, 2011). Yet with notable exceptions [e.g., health trajectories of the mammalian body. First, the defining
see (Peters, 2011; Archer, 2015a,b,c,d; Archer and McDonald, characteristic of obesity is an excess of body-fat mass (Schwartz
2017)], energy metabolism is not recognized as a cell- and et al., 2017) attributable to a greater number and/or size
context-specific competitive process. We argue that because of fat-cells (adipocytes) relative to other cell-types (e.g.,
competition is an essential feature of all levels of biology (i.e., myocytes) (Brook et al., 1972; Salans et al., 1973; Knittle
from cells to societies), our conceptualization is essential for the et al., 1979; Sjostrom and William-Olsson, 1981). Second, unlike
understanding and treatment of obesity and energy-contingent other cell-types, the storage of nutrient-energy in fat-cells is
metabolic diseases (e.g., type 2 diabetes mellitus, T2DM). independent of their metabolic demands. Third, fat-cell plasticity
The asymmetric competition and partitioning of nutrient- (i.e., hypertrophic/hyperplastic potential) and capacity to store
energy in mammals follows from several physiologic facts. First, nutrient-energy is greater than other cell-types. Fourth, in healthy
all living cells exhibit metabolic-flux, and therefore require (i.e., physically active and insulin sensitive) individuals, the most
energy intake to meet metabolic demands. Second, because the successful competitors for serum glucose in the post-prandial
availability of nutrient-energy in the mammalian body is finite, period, and lipids in the post-absorptive period are skeletal
undulating, and zero-sum (i.e., only one cell can dispose of muscle-cells (Baron et al., 1988; Dube et al., 2008; DeFronzo
any given molecule of an energy substrate), all cells compete to and Tripathy, 2009; Rabøl et al., 2011). Fifth, the competitive
acquire the nutrient-energy necessary to meet their metabolic strategies and storage capacity of skeletal muscle-cells are variable
demands. Third, because cells differ in metabolic activity (Elia, and dependent on the chronic metabolic demands induced via
1992), context-dependent cell-specific strategies evolved to meet physical activity (Ivy and Holloszy, 1981; Ivy, 1987; Jensen
the unique energy demands of each cell type (e.g., insulin and et al., 2011). Sixth, skeletal muscles-cell metabolism is a major
contraction-mediated processes) (Ivy, 1987, 2004; Baron et al., determinant of resting energy expenditure (Zurlo et al., 1990)
1988; DeFronzo, 1988; Ivy and Kuo, 1998; Jensen, 2003; Aas and in confluence with cardiac myocytes, is responsible for
et al., 2005; Jensen and Richter, 2011; Peters, 2011). Fourth, nearly 100% of physical activity energy expenditure. Seventh,
because homeostasis and survival necessitated meeting the alterations in the competitive advantages in skeletal muscle-
energy demands of all cells, the evolution of complex organisms, cells (e.g., decrements in insulin sensitivity) are the major driver
such as mammals required the development of sensorimotor (i.e., of metabolic diseases (DeFronzo, 1988; DeFronzo et al., 1992;
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DeFronzo and Tripathy, 2009). Finally, we posit that socio- glycogenolysis to maintain blood sugar levels. These endogenous
environmental evolution over the past century induced the glucose-producing processes are metabolically costly and reduce
greatest phenotypic changes in fat- and skeletal muscle-cells hepatic nutrient-energy stores (e.g., glycogen and lipids). Note:
compared with other cell-types (Archer and Blair, 2011; Church the metabolic costs of gluconeogenesis explain the effects of
et al., 2011; Archer et al., 2013b,c, 2018; Archer, 2015a,b,c,d, 2018; exercise on non-alcoholic fatty liver disease (Magkos, 2010;
Archer and McDonald, 2017). Chalasani et al., 2012).
Thus, the reductions in stored nutrient-energy due to physical
Competitive Advantages of Skeletal activity lead to competitive advantages in both skeletal muscle-
Muscle-Cells (Myocytes) and hepatic-cells with concomitant increments in nutrient-
Insulin-Induced Competitive Advantages energy disposal in these cells during the post-prandial and post-
Numerous context-dependent competitive strategies exist for the absorptive periods (Ivy and Holloszy, 1981; Ivy, 1987, 1991, 2004;
acquisition and storage of nutrient-energy in mammalian skeletal Ren et al., 1994; Friedman, 1995; Perseghin et al., 1996; Boulé
muscle-cells (myocytes) (Ivy, 1987; Baron et al., 1988; Jensen, et al., 2001; Powell et al., 2002; Holloszy, 2005; Bergouignan
2003). For example, under hyperinsulinemia, the skeletal muscle- et al., 2006, 2009, 2010, 2013, 2014; Stewart-Hunt et al., 2006;
cells of insulin-sensitive individuals dispose of 70–90% of serum Thyfault et al., 2007; Dube et al., 2008; Krogh-Madsen et al.,
glucose at the expense of other tissues (Thiebaud et al., 1982; 2010; Jensen and Richter, 2011; Jensen et al., 2011; Thyfault
Baron et al., 1988; DeFronzo, 1988; Shulman et al., 1990). In and Krogh-Madsen, 2011; Davis et al., 2012; Friedrichsen et al.,
fact, supra-physiologic doses of insulin (i.e., overdoses) induce 2013; O’Neill, 2013). There is a great deal of heterogeneity
such extreme competitive advantages in skeletal muscle-cells in competitive strategies within skeletal muscle-cell sub-groups
that neurons in the central nervous system cannot compete and [e.g., glycolytic and oxidative (James et al., 1985)]; therefore, the
are deprived of serum glucose. This exploitation competition effects of physical activity on metabolic-flux and partitioning
results in neuroglycopenia, seizures, coma, and death (Cryer, of nutrient-energy to oxidation, anabolism, or storage will be
2007; Russell et al., 2009). Thus, insulin-dependent (i.e., context- dependent on the training status of the individual in concert with
specific) competitive advantages allow skeletal muscle-cells to the dose of physical activity (i.e., frequency, intensity, duration,
exploit serum glucose at a rate that can deprive non-insulin and mode).
dependent cells of nutrient-energy. In the context of starvation, All physical activity training protocols of sufficient dose
this competitive advantage increases substantially (Goodman and induce competitive advantages and attendant increments
Ruderman, 1979; Brady et al., 1981). in nutrient-energy disposal in both skeletal muscle- and
Conversely, the skeletal muscle-cells of insulin-resistant hepatic-cells (Krogh-Madsen et al., 2014). Furthermore,
individuals fail to gain competitive advantages under exercise protocols of sufficient intensity and volume in
hyperinsulinemia and dispose of significantly less serum concert with nutritional support (Phillips, 2011) (e.g.,
glucose (DeFronzo, 1988; DeFronzo and Tripathy, 2009), “bodybuilding” training) also induce skeletal muscle-cell
thereby increasing the availability of glucose to other cell-types. hypertrophy and satellite cell activation with significant
These results demonstrate that the competitive advantages increments in nutrient-energy (e.g., amino acids, lipids,
and partitioning of nutrient-energy to skeletal muscle-cells are and glucose) disposal and oxidation, and metabolic control
context-dependent (e.g., serum insulin levels or dose of physical (Frontera et al., 1988; Phillips et al., 2005; Phillips, 2014;
activity), and exemplify the ecological principles of exploitation Snijders et al., 2015). Thus, exercise training increases the
and interference applied to the intercellular competition for competitive advantages of skeletal muscle-cells via multiple
nutrient-energy. mechanisms (e.g., insulin, contraction, and hypertrophic related
processes). Therefore, both increased physical activity and
Physical Activity-Induced Competitive Advantages greater muscle mass induce competitive advantages (Borghouts
Physical activity is the major modifiable determinant of the and Keizer, 2000; Boulé et al., 2003; Van Der Heijden et al.,
competitiveness and concomitant asymmetric partitioning of 2010; Srikanthan and Karlamangla, 2011; Shih and Kwok,
nutrient-energy to both hepatic (liver) and skeletal muscle- 2018).
cells across mammalian species (Ivy and Holloszy, 1981; Ivy, Conversely, physical inactivity (i.e., low whole-body
1987, 2004; Ivy and Kuo, 1998; Galassetti et al., 1999; Powell metabolic-flux) causes dose-dependent decrements in hepatic-
et al., 2002; Stewart-Hunt et al., 2006; Pratt et al., 2007; Krogh- and skeletal muscle-cell metabolic-flux that drive decrements
Madsen et al., 2014). Specifically, physical activity induces in the competitiveness of these cells via reductions in insulin
contractions of skeletal muscle-cells that are metabolically costly sensitivity and total glycogen storage capacity (Ivy, 1991;
and deplete stored nutrient-energy (e.g., glycogen and lipids) in Ren et al., 1994; Dube et al., 2008; Bergouignan et al., 2009,
a dose-dependent manner (i.e., frequency, intensity, duration, 2013; Krogh-Madsen et al., 2010; Jensen and Richter, 2011;
and mode/type of activity). The decrement in stored nutrient- Thyfault and Krogh-Madsen, 2011). Nevertheless, increases
energy causes increments in the uptake of serum glucose and in physical activity restore the competitiveness of insulin
lipids by skeletal muscle-cells via insulin-dependent and insulin- resistant skeletal muscle cells (Devlin et al., 1987; Thyfault et al.,
independent (e.g., contraction-induced) mechanisms (Ivy, 1987; 2007). Even a single bout of exercise is sufficient to enhance
Jensen, 2003). The increased disposal of serum glucose by insulin sensitivity and the resultant competitiveness of skeletal
skeletal muscle-cells stimulates hepatic-cell gluconeogenesis and muscle-cells while limiting the fuel available for increments
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in fat mass, hepatic and adipose tissue de novo lipogenesis, and obesity (Spalding et al., 2008; Chandler-Laney et al., 2011;
and ectopic fat deposition (Maehlum et al., 1978; Devlin et al., Adamo et al., 2012); and fifth, monozygotic twins concordant
1987; Larson-Meyer et al., 2006; Thyfault et al., 2007; Dube for birth weight exhibit similar fat-cell numbers, while in
et al., 2008; Rabøl et al., 2011; Krogh-Madsen et al., 2014). those discordant for birth weight, the smaller twin displays
Thus, the glycogen and lipid depletion-repletion cycles (i.e., both lower body mass and fat-cell number (Ginsberg-Fellner,
metabolic-flux) induced via physical activity are essential for 1981).
the maintenance of insulin sensitivity, metabolic flexibility [i.e., Yet, the strongest evidence for the cellularity-based
the ability to alter substrate oxidation as substrate availability competitive strategy of adipocytes comes from experimental
changes (Galgani et al., 2008)], and concomitant metabolic studies across species (Häger et al., 1978; Yukimura and
health across species (Devlin et al., 1987; Ivy, 1987; Perseghin Bray, 1978; Jackman et al., 2008). For example, after a dietary
et al., 1996; Brooks, 1998; Ivy and Kuo, 1998; Powell et al., 2002; intervention in prepubescent girls, Häger et al. (1978) found
Stewart-Hunt et al., 2006; Pratt et al., 2007; Dube et al., 2008; that “obese girls who were most successfully treated had the
Bergouignan et al., 2009, 2013; Jensen et al., 2011; Thyfault and lowest increase in fat-cell number.” In other words, greater
Krogh-Madsen, 2011; Egan and Zierath, 2013; Friedrichsen et al., increments in the number of fat-cells (i.e., hyperplasia) resulted
2013; O’Neill, 2013; Hawley et al., 2014; Goodpaster and Sparks, in asymmetric competition and an increase in the partitioning
2017). of nutrient-energy to fat-cells with concomitant decrements in
In summary, the ability of hepatic and skeletal muscle-cells treatment success. Häger et al.’s (1978) findings were consistently
to compete for nutrient-energy is dependent on metabolic-flux replicated, and in a review of the literature, Arner and Spalding
(i.e., substrate depletion-repletion cycles). Increments in physical (2010) stated, “hyperplastic obese individuals have a poorer
activity induce dose-dependent competitive advantages, whereas treatment outcome following diet-induced weight loss than
physical inactivity decreases metabolic-flux, and concomitant hypertrophic individuals. . ..” Similarly, in rodents Jackman
nutrient-energy disposal. Thus, our framework of asymmetric et al. (2008) found that fat-cell “hyperplasia occurring early in
nutrient-energy partitioning suggests that physical activity is the relapse persists throughout the regain process and that the small,
key to the prevention and treatment of metabolic dysfunction, presumably new, adipocytes preferentially accumulate fat relative
and offers a comprehensive answer to the question of why to their large adipocyte counterparts.”
physically active individuals exhibit a reduced risk of T2DM and
other energy-contingent chronic non-communicable diseases Mechanisms of Fat-Cell Hyperplasia
(e.g., cardiovascular disease and non-alcoholic fatty liver disease) While a detailed discussion of the mechanisms of fat-cell
compared to inactive individuals (Irwin et al., 2003; Sigal et al., hyperplasia is beyond the scope of this paper, it plays a pivotal
2006; Hallsworth et al., 2011; Davis et al., 2012; Keating et al., role in the development of obesity and metabolic diseases.
2012; Archer et al., 2013a; Fedewa et al., 2014; Krogh-Madsen Hyperplasia results from the recruitment and differentiation
et al., 2014). of mesenchymal/progenitor cells and mitotic clonal expansion
(Asakura et al., 2001; Tang et al., 2003; Laharrague and Casteilla,
Competitive Strategies of Fat-Cells 2010; Shoham and Gefen, 2012; Tang and Lane, 2012; Gavin
(Adipocytes) et al., 2016). Hyperplasia is both a normal component of fetal
The primary role of fat-cells in the mammalian “ecosystem” is to development (Archer, 2015c; Archer and McDonald, 2017), and a
acquire and store nutrient-energy. While both fat- and skeletal compensatory mechanism in response to chronic positive energy
muscle-cells use context-dependent competitive strategies such balance (i.e., overnutrition) (Archer et al., 2018). As described
as insulin and gain substantial competitive advantages in the in subsequent sections, excessive fat-cell hyperplasia during
context of negative energy balance (Goodman and Ruderman, gestation is principal phenomena leading to inherited obesity
1979; Arner et al., 1981; Brady et al., 1981), hyperplasia (Archer, 2015c; Archer and McDonald, 2017; Archer et al., 2018),
(i.e., increments in the number of a cell-type) is the main whereas the hyperplasia induced via physical inactivity-induced
competitive strategy of fat-cells. Thus, ceteris paribus, the amount positive energy balance (i.e., low metabolic-flux) is responsible for
of energy partitioned to fat-cells will increase as a function of acquired obesity, increments in visceral adiposity, and ectopic fat
the number of fat-cells. This argument is supported by several deposition (Archer et al., 2018).
facts. First, adipocyte number is the primary distinguishing In our frameworks, ectopic fat deposition is a compensatory
feature of obesity across species (Brook et al., 1972; Salans mechanism in response to the inability of skeletal muscle-
et al., 1973; Knittle et al., 1979; Hager, 1981; Sjostrom and cells and adipocytes within adipose tissue to dispose of excess
William-Olsson, 1981; Bjorntorp, 1996; Spalding et al., 2008; serum lipids at the rate at which they are supplied via
McLaughlin et al., 2014; Archer, 2015c). Second, a strong inverse dietary fat consumption or de novo lipogenesis. As we posited
relationship exists between the partitioning of dietary fat in previously, chronic positive energy balance at any point from
obese versus lean humans and other mammals (Hocquette et al., gestation through senescence leads to a “training effect for fat
1999, 2007; Jackman et al., 2006; Westerterp, 2009). Third, cell development” (Archer, 2015b) because as existing fat-cells
increments and decrements in fat mass are functions of existing reach their hypertrophic potential (or maximum), hyperplasia is
adiposity (i.e., fat-cell number and size) (Bell et al., 1987; induced (Shoham and Gefen, 2012; Tang and Lane, 2012). Ectopic
Elia et al., 1999; Forbes, 2000; Kozusko, 2002). Fourth, early fat deposition is a serious manifestation because it exacerbates
development is a major determinant of both fat-cell number the competitive dominance of fat-cells by limiting the number of
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Archer et al. Competition for Calories
stem cells available for differentiation to muscle or bone while the evolutionary benefits of this cooperative strategy in the
simultaneously increasing the number of fat-cells in non-adipose mammalian ecosystem. Nevertheless, in the context of elevated
tissues. and incomplete fatty-acid oxidation due to obesity (Jensen et al.,
In summary, a large body of prior research into hyperplastic 1989; Kelley et al., 1999) or physical inactivity (Bergouignan et al.,
obesity across species (Häger et al., 1978; Jackman et al., 2008) 2010, 2013, 2014), hepatic-insulin resistance leads to a decrement
supports the hypothesis that increased adipocyte cellularity is in metabolic flexibility with subsequent declines in metabolic
the main competitive strategy of fat-cells, and that increments health over time (Galgani et al., 2008; Goodpaster and Sparks,
in adipocyte cellularity result in increasingly asymmetric and 2017).
adipogenic nutrient-energy partitioning (Archer, 2015c,d; Archer With respect to fat-cell specific cooperative strategies, the
and McDonald, 2017; Archer et al., 2018). Thus, for any given nutrient-energy stored in fat-cells (e.g., glycerol and fatty-acids)
level of caloric intake, a larger number of fat-cells will acquire is sequestered and not available to other cell-type until conditions
and sequester a larger percentage of total energy intake, leading of negative energy balance (e.g., fasting or elevated physical
to increments in both adiposity and body mass. activity), hypoinsulinemia, and/or beta-adrenergic stimulation.
Thus, akin to the competitive strategies, the cooperative strategies
Cooperative Strategies of fat-cells are also context-specific. Conversely, the nutrient-
The survival of complex social organisms (e.g., humans, energy stored in skeletal muscle-cells as glycogen is never
canines, and rodents) required the evolution of both cooperative available to other cell-types due to the lack of glucose-6-
and competitive strategies at all levels of socio-biological phosphatase (i.e., the glycogen molecule is too large to leave the
organization (i.e., from cells to societies). In contrast to cell). Thus, the nutrient-energy partitioned to “selfish” skeletal
competitive strategies, cooperative mechanisms increase muscle-cells is “lost” to other cells in the body and is not
the availability of nutrient-energy to other cells, or at the available to constrain ingestive behaviors. From an evolutionary
societal level, conspecifics. For example, societal-level strategies perspective, the sequestering of nutrient-energy in mammalian
allow the survival of the group by constraining dominant skeletal muscle-cells is adaptive given the necessity of physical
individuals from monopolizing nutrient-energy resources to activity for the survival of both the individual and the species
the exclusion of conspecifics (e.g., preventing alpha males from (e.g., fight-flight and mating behaviors, acquisition of nutrient-
consuming all available food). These cooperative strategies energy).
include both long and short term physiological signals (e.g., In the following section, we introduce the conceptual
satiety hormones) such as leptin, cholecystokinin, and pancreatic framework of effective caloric intake to explain how the
poly-peptides (Austin and Marks, 2009) that cause decrements asymmetric inter-cellular competition and partitioning of
in ingestive behaviors as energy intake and energy storage nutrient-energy drives increments in ingestive behaviors and
increase. energy intake.
At the cellular level, we posit that insulin resistance is the
predominant cooperative strategy and operates by increasing
the availability of serum glucose to other cells. For example, as THE CONCEPTUAL FRAMEWORK OF
the level of stored energy within hepatic- and skeletal muscle- EFFECTIVE CALORIC INTAKE
cells increases (e.g., glycogen saturation and lipid accumulation),
insulin sensitivity and the ability to store serum glucose as The framework of effective caloric intake describes the amount
glycogen decline (Devlin et al., 1987; Ivy, 1987, 2004; Roden of nutrient-energy available to constrain energy-intake via
et al., 1996; Thyfault et al., 2007; Dube et al., 2008; Jensen the inhibition of the sensorimotor cells that govern ingestive
et al., 2011). The concomitant reduction in the competitiveness of behaviors (i.e., energy-sensing appetitive neuro-muscular
insulin-resistant cells increases the availability of nutrient-energy networks in the liver and brain) (Langhans, 1996; Schwartz et al.,
substrates to other cells, especially those that remain insulin 2000; Friedman, 2008; Allen et al., 2009; Woods, 2009). We posit
sensitive. that the availability of nutrient-energy to each cell is constrained
Hepatic- and skeletal muscle-cell insulin resistance is induced not only by ingestive behaviors and total energy-intake, but also
in numerous contexts including the elevated levels of fatty-acid by the context-dependent, asymmetric competition between
oxidation induced via hypo-caloric feeding, fasting, or starvation individual cells. Thus, when energy-sensing, appetitive cells
(Newman and Brodows, 1983; Björkman and Eriksson, 1985; in the liver and brain are “outcompeted” by other cell-types
Cigolini et al., 1985; Svanfeldt et al., 2003). This cooperative (e.g., fat and/or muscle-cells), the effective caloric intake of a
strategy diverts nutrient-energy substrates to other cells (e.g., meal is diminished, and total energy-intake will be increased
neurons), and allows for the survival of all cells in the body. As to compensate for the deficit (Archer, 2015c, 2018; Archer and
we posited previously, the naturally occurring insulin resistance McDonald, 2017; Archer et al., 2018).
of pregnancy is a cooperative strategy that drives nutrient-energy Inherent in this framework is the independence and
to the fetus (Archer, 2015c; Archer and McDonald, 2017; Archer dissociation of the energetic demands of metabolism and the
et al., 2018). Thus, in contrast to the current consensus on the sensorimotor (i.e., neuro-muscular) pathways that initiate
pathological nature of insulin resistance, we posit that insulin ingestive behaviors. We posit that eating and drinking
resistance is an essential feature of mammalian metabolism, and can be stimulated by either real or apparent deficits in
our frameworks of competitive and cooperative strategies explain energy homeostasis (i.e., true or false signals). Thus, when
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ingestive behaviors are stimulated by real deficits, such as Conversely, increments in fat-cell hyperplasia lead to
those induced by starvation or increments in physical activity, reductions in effective caloric intake and increments in energy-
energy-intake will be increased to maintain homeostasis and intake that are not matched by parallel increases in energy
ensure survival. In contrast, when ingestive behaviors are expenditure. This occurs because, in contrast to muscle-cells,
chronically initiated via merely apparent deficits in energy the competitive advantages and storage capacity of fat-cells are
homeostasis (i.e., false signals) induced via excessive fat- driven by number and size, and not their metabolic demands.
cell hyperplasia or physical inactivity (i.e., low metabolic As stated, a larger number of fat-cells will acquire and store a
flux), energy-intake is increased above metabolic demands, larger percentage of total energy-intake independent of their
leading to positive energy balance, acquired obesity, metabolic demands. Therefore, in contrast to physical activity,
and/or metabolic diseases (Archer, 2015c, 2018; Shook increments in fat-cell hyperplasia lead to apparent deficits (i.e.,
et al., 2015; Archer and McDonald, 2017; Archer et al., false signals) in short-term energy homeostasis that cause more
2018). energy to be consumed and stored than expended. This leads to
The independence and dissociation of deficits in energy increments in both body and fat mass with concomitant weight-
homeostasis and the initiation of ingestive behaviors can be dependent decrements in physical activity and insulin sensitivity.
illustrated by a simple example. If after fasting for 48 h, you Our arguments are supported by research demonstrating
find several large insects crawling in your food, your ingestive that appetitive processes are more sensitive to stimuli from
behaviors and energy intake will be diminished while your body’s nutrient-energy metabolism and related hormones and cytokines
metabolic demand for nutrient-energy is unaffected. In time, the than total fat mass per se (e.g., serum glucose, insulin, leptin,
deficit in nutrient-energy sensed by the sensorimotor appetitive hepatic metabolic-flux and adenosine triphosphate/adenosine
cells in the liver and brain will result in renewed eating and diphosphate ratio, gut peptides) (Woods et al., 1985; Langhans,
drinking. There is a large body of literature delineating the 1996; Friedman et al., 1999; Schwartz et al., 2000; Friedman,
dissociation of ingestive behaviors and nutrient-energy surpluses 2008; Allen et al., 2009; Woods, 2009).
and deficits (Leibowitz et al., 1981; Elmquist et al., 1999). We In summary, physical activity and fat-cell hyperplasia lead
think the failure to distinguish these processes and speculations to the asymmetric competition and partitioning of nutrient-
based of non-observable phenomena (i.e., mental states; e.g., energy to skeletal muscle- and fat-cells, respectively. The
appetites, perceptions, drives, needs, wants, etc.) contributes to disproportionate disposal of nutrient-energy reduces the effective
the current confusion and lack of progress surrounding obesity caloric intake of each meal by lessening the absolute amount of
and metabolic diseases (Archer et al., 2018). nutrient-energy available to inhibit the sensorimotor cells in the
liver and brain that govern ingestive behaviors. This reduction in
available energy leads to compensatory increases in energy-intake
Physical Activity, Fat-Cell Hyperplasia, to overcome real or merely apparent deficits. While physical
and Effective Caloric Intake activity engenders a real perturbation in energy homeostasis
Physical activity and fat-cell hyperplasia reduce the effective (i.e., a true signal) that necessitates an increase in total energy-
caloric intake of meals because both lead to a reduction intake to ensure survival, excessive fat-cell hyperplasia leads
in the nutrient-energy available to inhibit the sensorimotor to an apparent deficit (i.e., false signal) that drives increments
appetitive cells in the liver and brain that govern ingestive in ingestive behaviors and the overconsumption of calories.
behaviors. For example, as explained previously, physical activity This leads to chronic positive energy balance and subsequent
induces skeletal muscle-cells to exploit (i.e., acquire and use) increments in body and fat mass, and metabolic diseases. Thus,
nutrient-energy at the expense of other less-advantaged tissues an individual’s nutrient-energy consumption over time will equal
(e.g., adipocytes, neurons, and hepatocytes). Thus, because or exceed the sum of chronic cell-specific metabolic activity (i.e.,
the nutrient-energy partitioned to skeletal muscle-cells is not basal and physical activity energy expenditure) plus the nutrient-
available to constrain ingestive behaviors, total energy-intake energy sequestered in fat-cells and other low metabolically active
will be increased to compensate for the real deficit in energy tissues.
homeostasis. Therefore, reductions in effective caloric intake from To be precise, we do not argue that decrements in effective
physical activity lead to an increase in eating and drinking and a caloric intake are the only mechanism that drives energy intake.
necessary increment in total energy-intake over time. However, we argue that the asymmetric competition for nutrient-
Thus, decrements in effective caloric intake from physical energy and concomitant reductions in the inhibition of energy-
activity provide a true signal of deficits in energy homeostasis; sensing appetitive cells in the liver and brain are the primary
and because physical activity induced increments in energy- drivers of habitual energy-intake above basal metabolic energy
intake are driven in parallel with dose-dependent increases in requirements.
skeletal muscle-cell energy expenditure, the overall effect on
whole body energy-balance is neutral. As such, and as explained
in detail in a later section, increments in exercise or physical THE ETIOLOGIES OF INHERITED AND
activity in active (i.e., non-sedentary) individuals will not lead ACQUIRED OBESITY
to significant long-term weight-loss because body mass will be
maintained at a higher level of metabolic-flux (i.e., greater caloric In the following sections, we provide empirical support for our
intake and energy expenditure). hypothesis that the habitual overconsumption of nutrient-energy
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and concomitant elevated serum energy substrates (e.g., glucose, number of fat-cells acquiring and storing a larger percentage of
fatty-acids, and cholesterol) characteristic of both inherited total energy intake). The asymmetric partitioning of nutrient-
and acquired obesity and metabolic diseases (e.g., T2DM) are energy to storage in fat-cells reduced the effective caloric intake of
caused by the asymmetric nutrient-energy partitioning driven meals and drove increased energy intake, positive energy balance,
primarily via in utero engendered increments in fat- and beta- and increments in both body mass and adiposity. The increased
cell hyperplasia and/or physical inactivity induced decrements in body mass further reduced physical activity via diminished
metabolic-flux. strength-to-weight ratio [i.e., bigger or weaker individuals
move less than smaller or stronger (Chirico and Stunkard,
Inherited Obesity: Accumulative 1960; Archer et al., 2013a)] with additional decrements in thecompetitiveness of skeletal muscle-cells. These permanent and
Maternal Effects and the Maternal irreversible allometric, physiologic, and behavioral alterations
Resources Hypothesis were critical to the etiology of the inherited (i.e., childhood)
In the Maternal Resources Hypothesis (Archer, 2015a,b,c,d; obesity epidemic (Archer, 2015c; Archer and McDonald, 2017;
Archer and McDonald, 2017), we posited that inherited obesity Archer et al., 2018).
was the result of the irreversible competitive dominance of fat-
cells engendered during gestation via non-genetic evolutionary Racial and Socio-Economic Disparities in Obesity
processes known as accumulative maternal effects (Archer, 2015c; The Maternal Resources Hypothesis suggests that disparities in
Archer and McDonald, 2017). Briefly, we argued that the rapid obesity in the US that vary by race and socio-economic status
rise in the population prevalence of increased body and fat are in fact driven by differences in matrilineal pre-conception
mass, and metabolic dysfunction in the latter half of the 20th and pre-natal physical activity, body cellularity, and metabolic-
century were engendered by the effects of socio-environmental flux (Archer, 2015c,d; Archer and McDonald, 2017; Archer et al.,
evolution over the past century (e.g., reduced pathogenic load, 2018). For example, black girls decrease their physical activity to
decreased physical activity, and improved nutrition) (Church a greater degree than white girls during adolescence (Kimm et al.,
et al., 2011; Archer et al., 2013b,c). These phenomena led to 2002) and black mothers as a group are less physically active,
cumulative increments in maternal energy resources (i.e., body less affluent, less well-educated (Evenson et al., 2004; Schmidt
mass and adiposity) and decrements in maternal physical activity. et al., 2006; Haakstad et al., 2007; Archer et al., 2013b,c; Most
When a mother’s physical activity fell below her “Metabolic et al., 2018), and have children with greater adiposity and risk of
Tipping Point” (Archer et al., 2018), the competitive advantages metabolic diseases (Archer, 2015c; Archer and McDonald, 2017).
of her skeletal muscle-cells were reduced. This decrement altered Thus, what appears to be genetic or socially mediated processes,
the competitive relation between mother and conceptus thereby are in fact driven by non-genetic evolutionary processes induced
increasing the availability of nutrient-energy to the fetus. This via low levels of matrilineal/maternal physical activity and
fetal “over-nutrition” induced several allometric, physiologic, concomitant loss of metabolic control and overconsumption.
and behavioral inheritances that irreversibly engendered a
competitive dominance of fat-cells for the lifespan of the offspring Other Developmental Pathologies Related to
(Archer, 2015c). Maternal Effects
First, the excess nutrient-energy caused increments in fetal There are numerous developmental pathologies (e.g., increased
cellularity (Szabo and Szabo, 1974; Kalkhoff, 1991; Catalano and fetal mortality, congenital deformities, low birth-weight, and
Hauguel-De Mouzon, 2011), with disproportionate increments reduced neonate survival) that we posit are caused by the negative
in fetal fat- and pancreatic beta-cells (Szabo and Szabo, 1974; effects of excessive fat-cell mass and the overconsumption of
Kervran et al., 1978; Kalkhoff, 1991; Herrera and Amusquivar, nutrient-energy induced by low-levels of physical activity and
2000; Martens and Pipeleers, 2009; Chandler-Laney et al., 2011; concomitant low skeletal muscle- and hepatic-cell metabolic-
Portha et al., 2011; Long et al., 2012) while negatively altering flux (Archer et al., 2018). For example, the physical space
skeletal muscle-cell development (e.g., decreased contractile constraints and increments in intrathoracic pressure engendered
proteins with increased collagen accumulation and crosslinking) via excessive fat-cell mass (i.e., fat mass compressing the
(Tong et al., 2009; Huang et al., 2012). These latter alterations uterus, placenta, and/or supporting vasculature) and sedentary
permanently reduced the competitiveness of skeletal muscle- behavior reduce blood flow to both the placenta and fetus
cells by altering the quality of fetal skeletal muscle-cells (e.g., (i.e., placental and fetal ischemia). It was demonstrated
force production), leading to decrements in physical activity and that both higher body mass and sitting generated greater
cardio-respiratory fitness from infancy to adulthood. These latter intraabdominal pressure (Cobb et al., 2005) and increased
arguments have strong support (Tomkinson et al., 2003, 2012; pressure correlated with comorbidities (Sugerman et al., 1997).
Olds et al., 2006; Malina and Little, 2008; Archer and Blair, 2011; Thus, we posit that a portion of obese, sedentary mothers
Church et al., 2011; Archer et al., 2013b,c, 2017a). risk “starving” their fetuses of both oxygen and nutrient-
Second, the intensified insulin response (via enhanced beta- energy.
cell mass and function) and fat-cell hyperplasia in concert with Similarly, if pregnancy fails to induce sufficient increments
reduced competition from inactive and dysfunctional skeletal in nutrient-energy intake, the fetus may be spontaneously
muscle-cells exponentially increased the asymmetric partitioning aborted, exhibit intrauterine growth restriction and/or
and sequestering of nutrient-energy in fat-cells (i.e., a larger developmental defects. The mechanism is simple; if the
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naturally occurring insulin resistance of pregnancy is over- Accumulative Maternal Effects in Non-human
whelmed by the preexisting insulin resistance and poor Animals
metabolic control induced via low physical activity, low While the Maternal Resources Hypothesis focused principally on
metabolic-flux, and excessive fatty acid oxidation (Archer, 2015c; the inheritance of obesity in humans (Archer, 2015c; Archer
Archer and McDonald, 2017; Archer et al., 2018), ingestive and McDonald, 2017), the non-genetic evolutionary mechanisms
behaviors and energy intake will not be stimulated in parallel with of accumulative maternal effects are applicable to all mammals
the increased nutrient-energy demands of fetal development. that experienced a recent, rapid rise in the prevalence of
Thus, the fetus receives an inadequate nutrient supply because increased body mass, adiposity, and/or metabolic dysfunction
the mother’s cells outcompete the placenta and fetus’ ability to (Archer and McDonald, 2017; Archer et al., 2018) [e.g., dogs,
compensate. This conceptualization is supported by a large body cats, horses, rodents, monkeys, deer, and elk (Herberg and
of experimental evidence demonstrating that restrictions of the Coleman, 1977; Flather et al., 2009; Klimentidis et al., 2011;
nutrient supply to the intrauterine milieu induce numerous Ertelt et al., 2014; Hoenig, 2014; Sandoe et al., 2014; NEHS,
fetal pathologies (Wallace, 2000; Hay, 2006; Long et al., 2012; 2015; Montoya-Alonso et al., 2017)]. Accumulative maternal
Limesand et al., 2013). effects in mammals for body cellularity (e.g., adiposity), body
Thus, alterations in the competitive milieu (e.g., over- mass, behavior (e.g., physical activity), and/or risk of disease
nourished or restricted) may explain the high rate of negative were demonstrated consistently over the last century. In the
birth outcomes in populations that experience low physical 1930s, Walton and Hammond (1938) demonstrated unequivocal
activity, low metabolic flux, and high levels of obesity (e.g., “maternal effects” for growth and body mass in horses and
African-American women) (Hogue and Hargraves, 1995; Lu and ponies, and in the 1950s Falconer demonstrated accumulative
Halfon, 2003). Evidence suggest that these pathologies occur maternal effects for cellularity, body mass, and disease in
in populations with similar socio-economic status (Schoendorf mice (Falconer, 1965, 1967, 1973; Falconer et al., 1978). These
et al., 1992), medical care (Barfield et al., 1996), and use of assisted non-genetic effects were replicated repeatedly across species
reproductive therapies (Feinberg et al., 2006; Seifer et al., 2008; (Rossiter, 1996; Fox and Mousseau, 1998; Mousseau and Fox,
Mukherjee et al., 2013). Therefore, we contend that disparities in 1998; Bonduriansky and Day, 2009; Mousseau et al., 2009)
obesity, metabolic diseases, and birth outcomes are not driven inclusive of rodents (Garg et al., 2013), chickens (Liu et al.,
primarily by genetic or socio-economic factors (Archer et al., 1993), sheep (Maria et al., 1993), free-ranging cervids (Freeman
2018). et al., 2013), horses (Allen et al., 2002, 2004), and humans
(Brooks et al., 1995; Archer, 2015c; Archer and McDonald,
Iatrogenic Artificial Selection 2017).
In the Maternal Resources Hypothesis, we posited that the Given the parallel increases in body mass, adiposity, and/or
increased use of Cesarean sections over multiple generations metabolic disease across diverse species existing in disparate
led to the artificial selection for progressively larger, increasingly environments, current anthropocentric theories positing diet-
physically inactive, and metabolically compromised offspring centric influences (Bray et al., 2004; Swinburn et al., 2011),
predisposed to obesity and metabolic diseases (Archer, thrifty genes (Neel, 1962) and predation release (Speakman,
2015c; Archer and McDonald, 2017). Prior to the 20th 2007) in the etiology of obesity and metabolic disease are
century, morbid and super-morbid obese individuals were inadequate. Thus, our frameworks in confluence with the
extremely rare, in part because macrosomic fetuses and Maternal Resources Hypothesis subsume or refute dietary
their metabolically compromised mothers were subject to and genetic speculations and provide a comprehensive and
greater selection pressures (e.g., suffocation and hemorrhage) mechanistic evolutionary theory that explains the inheritance and
from cephalo-pelvic disproportion (i.e., incongruity of fetal familial resemblance for body mass, adiposity, physical activity,
head size and birth canal capacity) (Wells et al., 2012). and metabolic dysfunction in both human and non-human
Stated simply, the fetuses were too large to exit the birth animals.
canal. Thus, advances in obstetric care over the past century
were a primary driver of increments in the frequency of Obesity: A Homeorhetic Condition
larger humans in general but especially obese, inactive, Our frameworks in concert with the Maternal Resources
metabolically compromised phenotypes in populations Hypothesis explain why inherited obesity is a homeorhetic and
that had access to medicalized childbirth over multiple not a homeostatic condition. As depicted in Figure 1, after a
generations. dietary or “lifestyle” intervention the body and fat mass quickly
The strongest evidence for this iatrogenic artificial selection return to the initial trajectory engendered via the fat-cellularity
is the extremely rapid and disproportionate increases in severe created during gestation and early development (i.e., in utero
and morbid obesity (i.e., Class II and III) among children and through puberty) (Archer, 2015c; Archer and McDonald, 2017).
adolescents (Skelton et al., 2009), and adults varying by race, Thus, body and fat mass trajectories are neither a set-point,
sex, and socio-environmental contexts (Sturm, 2007; Skelton nor a settling point and the slope will be determined by the
et al., 2009). The Maternal Resources Hypothesis is the only initial populations of cell-types (e.g., ratio of fat-cells to skeletal
theory that offers a mechanistic and physiologically rigorous muscle cells) and physical activity. Importantly, our frameworks
explanation for the population shifts in both body and fat mass explain the often-insurmountable physiological barriers to long-
distribution. term weight loss in those suffering from morbid or severe obesity.
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First, the negative energy balance induced via hypocaloric dieting and energy-intake parallel physical activity energy expenditure
and/or exercise merely reduces the stored energy and size of such that body mass is maintained (Mayer, 1953; Mayer et al.,
fat-cells without altering the competitive advantage of increased 1954, 1956; Shook et al., 2015). For example, as Beaulieu et al.
fat-cell number. Second, smaller fat-cells have a competitive (2017) found, “higher habitual PA [physical activity] improves
advantage over larger fat-cells (e.g., greater surface area to acute homeostatic appetite control.” Our frameworks render
volume ratio). Third, as depicted in Figure 2, exercise merely the underlying mechanisms of these results unambiguous. As
decreases the slope of body and fat mass trajectories (i.e., rate explained previously, increments in physical activity induce
of gain). Therefore, greater adipocyte cellularity increases the dose-dependent competitive advantages that allow skeletal
rate of both weight gain and regain (as per Figure 1), and muscle-cells to exploit nutrient-energy resources at the expense
increases the effort required to achieve and maintain weight of less advantaged cells. This asymmetric partitioning leads to
loss (as per Figure 2). Thus, both fat-cell number and the reductions in the effective caloric intake of subsequent meals
physical activity-induced metabolic demands of skeletal muscle- with concomitant increments in energy-intake via reductions
cells determine the percentage of calories partitioned to fat- in inter-meal periods and/or increased energy density per meal.
and muscle-cells, respectively. The reduction in the slope is Yet, despite the increased energy intake, body mass remains
why exercise ameliorates the regain of both fat and body stable across a wide-range of doses of physical activity because
mass after hypo-caloric interventions when compared to diet- the increased skeletal muscle-cell energy expenditures are
alone. compensated by parallel increments in energy intake. Thus,
Thus, our frameworks explain why the majority of obese increments in physical activity merely lead to greater metabolic-
children become obese adolescents and adults, and why greater flux with no changes in body mass. Importantly, if the increment
than 95% of individuals suffering from inherited obesity fail to in physical activity is large, basal energy expenditures will
achieve and maintain a body-mass index (BMI) under 30 (Fildes decrease because less energy is available to non-skeletal muscles
et al., 2015), despite extreme interventions (Fothergill et al., cells (e.g., neurons in the central nervous system) inducing
2016). reductions in basal metabolic demands. These decrements in
In summary, we posited that the fat and body mass trajectories basal energy expenditures reduce the increment in energy-intake
of inherited obesity were engendered by accumulative maternal necessary to maintain energy homeostasis and body mass
effects leading to metabolically compromised human (and non- (Westerterp, 1998; Speakman and Selman, 2003; Westerterp and
human) infants with intensified insulin secretion, excessive Plasqui, 2004).
adipocyte cellularity, and dysfunctional muscle-cell development Nevertheless, as depicted on the left side of Figure 3 when an
predisposing to physical inactivity. These alterations irreversibly individual’s physical activity falls below their “Metabolic Tipping
altered the competitive milieu of the body and permanently Point” (Archer, 2015c, 2018; Archer and McDonald, 2017; Archer
established the dominance of fat-cells in the acquisition, storage, et al., 2018) (denoted as “Sedentary”), energy-intake becomes
and sequestering of nutrient-energy. dissociated from energy expenditure (Mayer, 1953; Mayer et al.,
1954, 1956; Stubbs et al., 2004; Shook et al., 2015; Beaulieu et al.,
The Etiology of Acquired Obesity 2017). As Westerterp and Plasqui (2009) stated, “The change
Acquired obesity is the excessive hypertrophy of existing fat- from a physically active to a more sedentary routine does not
cells and recruitment of new fat-cells (hyperplasia) driven by the induce an equivalent reduction of energy intake.” Over time,
chronic positive energy balance induced by physical inactivity. small increments in energy-intake coupled with low physical
This differs from inherited obesity in which the disturbance in activity lead to gains in fat mass and concomitant decrements
metabolic-flux is driven primarily by fat and beta-cell hyperplasia in insulin sensitivity. The increased body and fat mass lead
and dysfunctional skeletal muscle-cells engendered in utero to further declines in physical activity from reduced strength-
via non-genetic evolutionary forces (i.e., accumulative maternal to-weight ratio [i.e., bigger or weaker individuals move less
effects) (Archer, 2015a,b,c; Archer and McDonald, 2017; Archer than smaller or stronger (Chirico and Stunkard, 1960; Archer
et al., 2018). As explained below, in contrast to the rapidity with et al., 2013a)]. The lack of hepatic- and skeletal muscle-
which inherited obesity develops (i.e., 9 months of gestation), cell metabolic-flux induced via physical inactivity initiates a
acquired obesity is incrementally instantiated over years and cascade of metabolic dysfunction that drives both peripheral
decades. and central insulin resistance, positive energy balance, and
increments in both fat-cell number and size. Over time, these
Physical Inactivity, Low Metabolic-Flux, and the physical inactivity-induced phenomena lead to acquired obesity
“Metabolic Tipping Point” and/or metabolic disease (e.g., T2DM) (Archer, 2015c; Archer
In the 1950s, it was established experimentally and et al., 2017a, 2018; Archer and McDonald, 2017). Thus, there
observationally in rodents and humans (Mayer, 1953; Mayer is a minimum amount of physical activity-induced hepatic
et al., 1954, 1956), that the inter-relations between changes in and skeletal muscle-cell metabolic-flux (i.e., substrate depletion-
body mass, energy intake, and physical activity were curvilinear. repletion cycles) necessary to maintain energy homeostasis and
These results were replicated in a variety of settings (Stubbs metabolic health.
et al., 2004; Shook et al., 2015). As shown in the center of It is important to note that if the chronic positive
Figure 3, there is a range of physical activity (denoted as energy balance and reduced metabolic-flux characteristic of
“Physically Active”), in which habitual appetitive processes acquired obesity continues over time, existing fat-cells eventually
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FIGURE 1 | Body and fat mass trajectories of individuals varying in adipocyte cellularity. Body and fat mass trajectories return to the initial slope (i.e., rate of gain)
after diet-induced weight loss. The initial slope was determined by fat-cell number.
FIGURE 2 | Body and fat mass trajectories (i.e., rate of gain) differ as a function of both fat-cell number and exercise.
reach their hypertrophic potential (or maximum) and there humans, as body-cell mass is increased, males gain a greater
will be a “training effect for fat cell development” (Archer, proportion of skeletal muscle-cell mass relative to fat-cell mass,
2015b) via the enhanced recruitment of mesenchymal cells whereas females exhibit the converse (Butte et al., 2007). In
(Sjostrom and William-Olsson, 1981; Archer and McDonald, adulthood, it is well-established that increments in fat mass
2017). The resulting fat-cell hyperplasia renders the distinction are a function of the individual’s existing adiposity (Bell et al.,
between inherited and acquired obesity after sexual maturity 1987; Elia et al., 1999; Forbes, 2000; Kozusko, 2002). Thus, the
equivocal. amount of physical activity necessary to inhibit chronic positive
energy balance and the asymmetric partitioning of nutrient-
Individual Differences energy to storage in fat-cells varies. Individuals with low fat-
Individuals vary in both inherited and acquired ratios of cell numbers or high skeletal muscle- to fat-cell ratio (e.g.,
skeletal muscle-cells to fat-cells. For example, during pubescence, lean muscular males) require less physical activity to maintain
sexual dimorphism in adipogenesis and shifts in the ratio of metabolic-flux and offset adipogenic nutrient partitioning and
skeletal muscle-cell to fat-cell mass are well established. In weight gain (see Figure 2). Individuals born with an excessive
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FIGURE 3 | Relations between physical activity (PA), body mass, and energy intake (adapted from Archer, 2018). As physical activity declines below the “Metabolic
Tipping Point” (i.e., into the “Sedentary” range), energy intake and energy expenditure become dissociated due to insufficient metabolic-flux, and as a result, body
mass will begin to increase as energy balance becomes positive.
number of fat cells relative to skeletal muscle-cells will need and partitioning of nutrient-energy. The ensuing “high storage
a dose of physical activity that may be beyond their capacity. but low triglyceride removal promotes fat tissue accumulation and
For these individuals, increments in body and fat mass are obesity” (Arner et al., 2011).
inevitable because as energy-intake is stimulated by physical
activity induced decrements in effective caloric intake, the larger
number of fat-cells “outcompete” other cell-types and sequester
a larger amount of total energy intake. This conceptualization TYPE-II DIABETES MELLITUS:
provides a rigorous, mechanistic explanation for the ubiquitous DIMINISHED METABOLIC-FLUX AND
failure of non-surgical treatments of obesity. Nevertheless, THE COMPETITIVE FAILURES OF
at some point, the absolute caloric intake is sufficient to SKELETAL MUSCLE AND FAT-CELLS
inhibit the sensorimotor appetitive cells and constrain energy
intake so that body and fat mass stabilize at a new, higher A large body of research over the past 50 years demonstrates
level. that the “primary defect” (DeFronzo and Tripathy, 2009) driving
In summary, as individuals reduce their physical activity below T2DM is a decrement in skeletal muscle-cell insulin sensitivity
their “Metabolic Tipping Point” (Archer et al., 2018), reductions leading to both peripheral and central insulin resistance
in both hepatic and skeletal muscle-cell metabolic-flux engender (DeFronzo, 1988; Shulman et al., 1990; DeFronzo et al., 1992;
positive feedback loops that lead to increments in energy intake, Holloszy, 2005; DeFronzo and Tripathy, 2009). While these
chronic positive energy balance, and the asymmetric competition findings suggest that T2DM is simply the result of the inability
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of skeletal muscle-cells to dispose of excess serum glucose, our for the reduced disposal of serum glucose declines. Over
frameworks instruct otherwise. Since all cell-types compete for time, this leads to T2DM as pancreatic-beta cells become
nutrient-energy and the main function of fat-cells is the storage of overloaded/exhausted and/or lose their sensitivity to serum
excess energy, T2DM can be most precisely characterized as the glucose (DeFronzo, 1988; DeFronzo et al., 1992; DeFronzo and
failure of both skeletal muscle- and fat-cells to compete for and Tripathy, 2009).
dispose of the nutrient-energy consumed in excess of metabolic In summary, our frameworks and existing evidence suggest
demands. that there is a minimum amount of physical activity metabolic-
When physical activity falls below the “Sedentary” metabolic flux (e.g., glycogen and lipid depletion-repletion cycles) that
tipping point (as per Figure 3), energy intake begins to is necessary to maintain energy homeostasis and prevent
increase despite the decreasing energy expenditure (Mayer, 1953; acquired obesity and metabolic diseases (Colberg et al., 2016). In
Mayer et al., 1954, 1956; Shook et al., 2015). We posit this conclusion, T2DM is caused by habitual physical inactivity (i.e.,
occurs because as hepatic-cell metabolic-flux declines, these cells low metabolic-flux) driving decrements in the competitiveness of
become saturated with glycogen and metabolites from fatty- hepatic and skeletal muscle-cells in concert with the long-term
acid oxidation (Koves et al., 2008). This leads to decrements failure of fat-cell plasticity and beta-cell function (DeFronzo,
in insulin sensitivity and metabolic flexibility [i.e., the ability to 1988; DeFronzo et al., 1992; Heilbronn et al., 2004; Galgani et al.,
alter substrate oxidation as substrate availability changes (Kelley 2008; DeFronzo and Tripathy, 2009).
et al., 1999; Galgani et al., 2008; Bergouignan et al., 2011;
Goodpaster and Sparks, 2017)]. As discussed previously, the only
contexts in mammalian evolutionary history in which hepatic- THE LACK OF EXPLANATORY AND
cells experienced elevated levels of fatty-acid oxidation would PREDICTIVE POWER OF GENE- AND
be starvation and/or chronic elevated physical activity. Given
the fact that these contexts induce the initiation of ingestive DIET-CENTRIC PARADIGMS
behaviors and energy intake and a reduction in basal energy
expenditure to ensure survival, we posit that physical inactivity Science can be defined as the discovery of valid knowledge of the
(i.e., low metabolic-flux) provides a false signal that drives observable world. In contrast to other domains (e.g., philosophy
increments in energy intake with concomitant decrements in and religion), science is distinguished by the capacity to explain,
energy expenditure (Mayer, 1953; Mayer et al., 1954; Stubbs et al., predict, and (where possible) control natural phenomena. Thus,
2004; Shook et al., 2015). The positive energy balance increases the true test of scientific theories is how well they explain
the availability of serum energy substrates for hepatic and adipose extant evidence. In this section we demonstrate that because the
tissue de novo lipogenesis, increments in fat-cell mass, and ectopic processes that lead to mammalian obesity and metabolic diseases
fat deposition (Strawford et al., 2004; Larson-Meyer et al., 2006; are in fact well-established, anthropocentric speculations based
Dube et al., 2008; Rabøl et al., 2011). on dietary and genetic correlations are inadequate [e.g., gene- and
Nevertheless, as long as the capacity to expand fat-cell mass diet-centric models; see (Neel, 1962; Bray et al., 2004; Speakman,
and/or recruit new, smaller adipocytes from the mesenchymal 2007; Swinburn et al., 2011)].
stem-cell pool is maintained, whole body insulin sensitivity
will not decline significantly. Thus, fat-cell hyperplasia and Gene-Centric Paradigms Versus
hypertrophy allow for the disposal of excess serum glucose Non-genetic Evolutionary Processes
and lipids (Heilbronn et al., 2004; Roberts et al., 2009). We posit that accumulative maternal effects are causal to variance
This compensatory mechanism allows individuals to remain in obesity and metabolic diseases independent of genotype
metabolically healthy despite increasing body and fat mass. (Archer, 2015c; Archer and McDonald, 2017). And because these
This conceptualization suggests that skeletal muscle- and fat- non-genetic evolutionary processes mimic the alleged genetic
cells act as energy “sinks” that prevent the increase in serum effects, they provide a rigorous, mechanistic explanation for
energy substrates that lead to metabolic diseases such as familial resemblance in metabolic and behavioral phenotypes
T2DM. Nevertheless, because increments in body mass reduce (Archer, 2015a,b,c; Archer and McDonald, 2017; Archer et al.,
physical activity [i.e., heavier individuals move less than lighter 2018). We previously commented on the lack of explanatory
individuals (Chirico and Stunkard, 1960; Archer et al., 2013a; and predictive power of gene-centric paradigms (Archer et al.,
Archer and McDonald, 2017)], many “metabolically healthy 2018), inclusive of epigenetics (Archer, 2015a,b,c). We stated
but obese” individuals (Mathew et al., 2016) will progress that the “missing heritability. . .will not be found in the genome”
toward metabolic disease (Short and Joyner, 2002; Soriguer (Archer, 2015c) but is explained almost entirely by accumulative
et al., 2013) as physical activity declines over time. This is maternal effects in the pre- and post-natal periods (Archer, 2015c;
especially true with older individuals whose strength-to-weight Archer and McDonald, 2017). These non-genetic evolutionary
ratio is already in decline (McGlory et al., 2017). Thus, when processes have significant and unequivocal effects on body and
individuals are physically inactive and have limited fat-cell fat mass, and metabolic and behavioral phenotypes in offspring
plasticity, serum energy substrates rise over time. This occurs across species (Walton and Hammond, 1938; Falconer, 1965,
because as physical inactivity drives increased energy-intake 1967, 1973; Falconer et al., 1978; Liu et al., 1993; Maria et al.,
in concert with decrements in skeletal muscle-cell insulin 1993; Brooks et al., 1995; Rossiter, 1996; Fox and Mousseau,
sensitivity, the ability of pancreatic beta-cells to compensate 1998; Mousseau and Fox, 1998; Allen et al., 2002, 2004;
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Bonduriansky and Day, 2009; Mousseau et al., 2009; Freeman (Freinkel and Goodner, 1962; Pedersen, 1967/1977; Whitelaw,
et al., 2013; Garg et al., 2013; Archer, 2015c; Archer and 1977; Kervran et al., 1978; Catalano et al., 1998, 2003; Aerts
McDonald, 2017). and Van Assche, 2006; Egeland and Meltzer, 2010; Catalano
To extend our previous commentaries (Archer, 2015a,b,c; and Hauguel-De Mouzon, 2011; Adamo et al., 2012; Cisse
Archer and McDonald, 2017; Archer et al., 2018), we present et al., 2013; Ferraro, 2013). For example, in siblings discordant
several arguments. First, while the presence and initial location for intrauterine exposure to T2DM, Dabelea et al. (2000,
of mammalian fat-cells is clearly genetic (Raff, 2012), variation p. 22208) demonstrated that exposure “conveys a high risk for
in the initial population of fat-cells (i.e., body cellularity) is the development of diabetes and obesity in offspring in excess of
determined almost exclusively by the amount of nutrient-energy risk attributable to genetic factors alone”. Similarly, Kral et al.
reaching the placenta, intrauterine milieu, and fetus; which (2006) showed that maternal weight-loss surgery reduced the
is controlled by the competition between maternal and fetal prevalence of obesity and severe obesity in offspring by 52 and
metabolic demands (Archer, 2015a,b,c,d; Archer and McDonald, 45%, respectively. These studies show that maternal effects via
2017). A large body of observational and experimental research altered maternal metabolism (i.e., altered metabolic-flux and
supports this argument. For example, monozygotic twins inter-cellular competition) are causal to both obesity and T2DM.
concordant for birth weight exhibit similar fat-cell numbers, There are no similar studies demonstrating causal genetic effects.
while in those discordant for birth weight, the smaller twin Finally, there is “a great deal of biology” between a nucleotide
displays both lower body mass and fat-cell number (Ginsberg- sequence and a phenotype, and there are myriad processes that
Fellner, 1981). Clearly, this effect is not genetic and is explained render the associations between any given DNA sequence and
by chorionic status (Ramos-Arroyo et al., 1988; Cordero et al., a phenotype irrelevant [please see our prior work for a review
2005) and the intra-uterine competition for calories between the (Archer et al., 2018)]. For example, alternative splicing and post-
twins. The effect of intrauterine competition for energy substrates translational mechanisms can produce peptides with opposing
on fetal body and fat mass is extremely well-established in non- physiological properties [e.g., the “Ghrelin Gene” (Zhang et al.,
human animals, and inter-fetus competition due to litter size 2005)].
is the “single greatest influence on birth weight” (Gardner et al., In summary, these results support our contention that with
2007). respect to obesity and T2DM, genetic/epigenetic research is an
Second, as presented herein, obesity, and insulin resistance incongruous level of analysis because “genes” are the “tools of
result from positive energy balance driven by fat-cell hyperplasia the [species-specific cell], and their use (i.e., expression) is strictly
and/or physical inactivity (i.e., low metabolic-flux). Thus, we environment-dependent” (Archer, 2015b, p. 556). Thus, we posit
contend that the genes associated with obesity and metabolic that obesity and adult-onset metabolic diseases are exclusively
disease are necessary but are not causal or predisposing factors. environmentally induced phenotypes. These phenotypes have
Association studies support our argument. For example, trends evolutionary consequences because in females, accumulative
in physical activity over the past 50 years (Church et al., 2011; maternal effects induce the progressive inheritance of acquired
Archer et al., 2013b,c) explain cohort-specific associations of characteristics, independent of changes to the genome.
the FTO gene and obesity (Kilpelainen et al., 2011; Ahmad
et al., 2013). Third, association studies are merely descriptive Diet-Centric Paradigms
and provide no evidence of causality, whereas numerous Diet-centrism is the tendency to attribute a wide-range of
experimental studies demonstrated the unequivocal and large negative health outcomes exclusively to dietary factors while
consequences of accumulative maternal effects on metabolic neglecting the essential role of individual differences (Archer,
outcomes (e.g., body and fat mass) and physical activity across 2018; Archer et al., 2018). The fundamental error of “diet-
species (Walton and Hammond, 1938; Falconer, 1965, 1967, centrism” is the conflation of “diet” with nutritional status and
1973; Falconer et al., 1978; Liu et al., 1993; Maria et al., 1993; health, in concert with the failure to acknowledge that identical
Brooks et al., 1995; Rossiter, 1996; Fox and Mousseau, 1998; diets consumed by different individuals result in divergent
Mousseau and Fox, 1998; Allen et al., 2002, 2004; Bonduriansky metabolic effects (Krogh-Madsen et al., 2014; Zeevi et al.,
and Day, 2009; Mousseau et al., 2009; Freeman et al., 2013; Garg 2015). The explicit conflation of diet with nutritional status
et al., 2013; Archer, 2015c; Archer and McDonald, 2017). For and health contravenes the fact that the mammalian body is a
example, ovum transfer, animal breeding, and cross-fostering complex ecosystem in which the effects of dietary factors are
studies clearly demonstrated that the intrauterine milieu and wholly dependent on the current state and compensatory fluxes
early post-natal periods can induce obesity and metabolic of that ecosystem (e.g., metabolic phenotype and nutritional
dysfunction in a single generation, independent of genotype. status). For clarity, an individual’s metabolic phenotype is
Embryo transfer studies demonstrate that the inheritance influenced by factors, such as body cellularity and composition,
of pathological metabolic phenotypes can be ameliorated or nutritional status, physical activity and fitness levels, age, sex,
potentially abolished when the embryo is transferred and reproductive, and disease status, and the state of the cellular
“gestated in a normal metabolic environment” (Garg et al., 2013). systems responsible for metabolic control (i.e., skeletal muscle-,
There are no studies that demonstrate similar genetic effects. hepatic-, and pancreatic beta-cells) (DeFronzo, 1988; Archer,
Fourth, as demonstrated over the past century, intrauterine 2018).
exposure to reduced maternal metabolic control has significant Thus, it is not what is eaten (i.e., diet) that engenders
effects on the health and metabolic trajectories of offspring health or disease, but what one’s body does with what
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was eaten (i.e., nutrient metabolism). Therefore, macro- and century that vary by race, sex, and socio-environmental contexts
micronutrients cannot have health-effects independent of the (Sturm, 2007; Skelton et al., 2009). Conversely, the Maternal
metabolic phenotype of the consuming individual, and dietary Resources Hypothesis and our frameworks provide a detailed,
components per se cannot be the determining factor in obesity mechanistic, and parsimonious explanation for these population-
and metabolic health (Archer, 2018). Thus, obesity and T2DM are specific trends.
not dietary concerns but are metabolic ones. Evidence in support
of our argument is found across disciplines. Unfounded and Unchallenged
First, most diet-centric speculations are based on associations Conjecture Impede Progress
derived from data and methods previously demonstrated to Scientific progress necessitates bold conjectures coupled with
be wholly invalid and scientifically “inadmissible” for the rigorous supporting evidence and comprehensive attempts
purposes of establishing causal relationships between dietary at refutation. Nevertheless, within the domains of obesity
intake and health (Archer et al., 2015a,c, 2017b). Second, simple and metabolic diseases, the sheer volume of unfounded and
carbohydrates (e.g., dietary sugars and starches) and fats are often unchallenged conjecture threatens to obscure well-established
presumed to be causal factors, yet there are populations that evidence. Recently, we presented a review of the evidence
consume substantial amounts of these macro-nutrients with very that is contrary to the major etiologic paradigms and stated
low prevalence of obesity and metabolic diseases (Ichikawa, 1981; “that progress in the understanding, prevention, and treatment
Hill et al., 1984; WHO, 1995; Matsumura, 2001; Onywera et al., of obesity and metabolic diseases requires moving beyond the
2004; Marlowe et al., 2014). Therefore, “diet” is merely necessary, epidemiologic ‘association-game’ in which mere correlations are
but not sufficient. Third, the prevalence of human obesity cited as rigorous support for conjectures on causation” (Archer
increased significantly across the globe in populations displaying et al., 2018). Nevertheless, there are hundreds of published
dietary patterns differing in nutrient composition. Thus, dietary speculations on the etiology of obesity and metabolic diseases
patterns are not causal. Fourth, there is no evidence that chronic ranging from air conditioning and vending machines, to
positive energy balance is driven by the widespread availability viruses, mosquitos, and microbiota (Downey, 2015). These
of inexpensive, highly palatable foods and beverages. If this published putative “causes” rarely demonstrate any predictive or
speculation was true, all humans in high income nations would explanatory value, and none offer biologically plausible and non-
be obese because these foods and beverages were ubiquitous trivial mechanisms in conjunction with rigorous experimental
for multiple generations. As such, fat-cell hyperplasia and/or support. In fact, many speculations rely upon “prescientific
physical inactivity (i.e., low metabolic-flux) induced increments thought” (Olesen and Alm, 2016) or tenuous correlations
in energy-intake behaviors provide a more rigorous, mechanistic generated from “pseudoscientific methods” (Archer et al., 2015a,c,
explanation for over-nutrition. 2018), and are often demonstrative of “physiologic illiteracy”
Fifth, some of the strongest evidence to support our (Archer, 2018). Thus, we think the failure to distinguish between
contention that dietary patterns and dietary components have no established causal mechanisms and mere speculations based on
causal effect on the prevalence of obesity and metabolic diseases statistical associations continues to engender the proliferation of
is inferential. Human dietary patterns cannot have caused the misleading and demonstrably false research programs and failed
parallel increases in body and fat mass, obesity, and metabolic public health initiatives (Archer et al., 2017b, 2018; Archer, 2018).
diseases in feral, laboratory, farm, and companion animals (i.e., In contrast, our novel frameworks in concert with our
rodents, horses, cats, and dogs) over the last half of the 20th prior theoretical work represent a detailed, mechanistic,
century. Given the disparate environments and dietary patterns and comprehensive synthesis of rigorous experimental and
of these species, and the fact that all are placental mammals, observational results that spans the continuum from proximate
accumulative maternal effects provides a more mechanistically to ultimate causation (i.e., physiologic and evolutionary,
rigorous explanation than diet-centric speculations based on respectively). As such, this paper is a productive, albeit
mere associations. controversial step forward in constraining conjecture to
Sixth, the strongest evidence supporting our contention that hypotheses supported by well-established mechanisms.
the diet-centric paradigm is mistaken is the well-established
finding that over several generations, both obesity and metabolic
diseases (e.g., T2DM, gestational diabetes) developed in non- FUTURE DIRECTIONS
human primates living in highly controlled environments with
“little to no change in diet, particularly in the rhesus and Our Maternal Resources Hypothesis and frameworks of
cynomolgus macaque species” (Bauer et al., 2010). The “close asymmetric nutrient-energy partitioning and effective caloric
genetic relatedness to humans” (Bauer et al., 2011), make these intake are both retrodictive and predictive. Thus, unlike most
species “excellent models for [obesity] in humans” (Bauer et al., conjectures, the ideas presented herein can be used to re-interpret
2011). These results provide an unequivocal refutation of the diet- and/or “predict” prior results while providing fodder for future
centric paradigm with respect to obesity and metabolic diseases investigations across myriad domains. Since all theories should
(Archer et al., 2018). be tested and have their foundational assumptions, background
Finally, diet-centric speculations cannot explain the rapid knowledge, and predictions challenged, we are currently
and differential increases in severe and morbid obesity (i.e., planning a number of in vivo and in silico experiments to test
Class II and III) in adults and offspring during the late 20th our “body-as-an-ecosystem” and “cell-centric” approaches.
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Furthermore, given that our work spans multiple levels of global prevalence of obesity and metabolic diseases in human and
analysis, we think empirical ventures targeting the evolutionary other mammalian species.
consequences of accumulative maternal effects on offspring
cellularity and body mass over multiple generations are
warranted. Additionally, we think examinations of the effects AUTHOR CONTRIBUTIONS
of body cellularity (e.g., ratio of high to low metabolically
active cells) on cell-specific partitioning of lipids and glucose are Each author contributed to the intellectual content and
potentially productive avenues for future research efforts. organization of this paper. EA wrote the paper with assistance
from each of the co-authors.
CONCLUSION
ACKNOWLEDGMENTS
In this paper we presented the conceptual frameworks of
asymmetric nutrient-energy partitioning and effective caloric The authors wish to thank Dr. Michael Joyner for his critiques
intake. These frameworks, in concert with our previous theoretic and comments on earlier drafts of this manuscript and the
work, the Maternal Resources Hypothesis, provide a parsimonious reviewers who provided accurate, insightful, and productive
and physiologically rigorous explanation for the rapid rise of the suggestions. Our paper was greatly improved as a result.
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Frontiers in Physiology | www.frontiersin.org 22 August 2018 | Volume 9 | Article 1053