Eur J Appl Physiol (2008) 102:381–390
DOI 10.1007/s00421-007-0606-5
INV ITED R EVIEW
Reduced physical activity and risk of chronic disease:
the biology behind the consequences
Frank W. Booth · Matthew J. Laye · Simon J. Lees ·
R. Scott Rector · John P. Thyfault
Accepted: 22 October 2007 / Published online: 7 November 2007
© Springer-Verlag 2007
Abstract This review focuses on three preserved,
ancient, biological mechanisms (physical activity, insulin
sensitivity, and fat storage). Genes in humans and rodents
were selected in an environment of high physical activity
that favored an optimization of aerobic metabolic pathways
to conserve energy for a potential, future food deWciency.
Today machines and other technologies have replaced
much of the physical activity that selected optimal gene
expression for energy metabolism. Distressingly, the nega-
F. W. Booth (&) · S. J. Lees
Department of Biomedical Sciences,
University of Missouri, 1600 East Rollins St,
Columbia, MO 65211, USA
e-mail: boothf@missouri.edu
F. W. Booth · M. J. Laye
Department of Medical Pharmacology and Physiology,
University of Missouri, Columbia, MO, USA
J. P. Thyfault
Department of Nutritional Sciences,
University of Missouri, Columbia, MO, USA
R. S. Rector · J. P. Thyfault
Department of Medicine,
University of Missouri, Columbia, MO, USA
F. W. Booth
Dalton Cardiovascular Institute,
University of Missouri, Columbia, MO, USA
J. P. Thyfault
Harry S. Truman Memorial VA Hospital, Columbia, MO, USA
F. W. Booth · M. J. Laye · S. J. Lees · R. S. Rector · J. P. Thyfault
Health Activity Center, University of Missouri,
Columbia, MO, USA
tive by-product of a lack of ancient physical activity levels
in our modern civilization is an increased risk of chronic
disease. We have been employing a rodent wheel-lock
model to approximate the reduction in physical activity in
humans from the level under which genes were selected to
a lower level observed in modern daily functioning. Thus
far, two major changes have been identiWed when rats
undertaking daily, natural voluntary running on wheels
experience an abrupt cessation of the running (wheel lock
model). First, insulin sensitivity in the epitrochlearis mus-
cle of rats falls to sedentary values after 2 days of the cessa-
tion of running, conWrming the decline to sedentary values
in whole-body insulin sensitivity when physically active
humans stop high levels of daily exercise. Second, visceral
fat increases within 1 week after rats cease daily running,
conWrming the plasticity of human visceral fat. This review
focuses on the supporting data for the aforementioned two
outcomes. Our primary goal is to better understand how a
physically inactive lifestyle initiates maladaptations that
cause chronic disease.
Keywords Exercise · Evolution · Metabolism ·
Adaptation · Insulin sensitivity · Adipose tissue
Introduction
Exercise is a treatment to prevent most chronic diseases
(Booth and Tseng 1995; US Department of Health and
Human Resources 1996). More importantly, the lack of
regular exercise or physical inactivity is an “actual” cause
of chronic diseases (Blair et al. 1993; Mokdad et al. 2004).
The CDC has deWned inactivity as “not engaging in any
regular pattern of physical activity beyond daily function-
ing” (Centers for Disease Control and Prevention 2007).
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A necessary tenet of medicine is to understand underly-
ing biological mechanism of a disease so that eVective
treatments are developed and preventive methods can be
deWned. Unfortunately, there is little scientiWc evidence
detailing the biological eVects of reduced physical activity
on the development of chronic disease. It is therefore,
imperative to better understand these mechanisms to
improve medical practice and therefore, improve both qual-
ity and length of life. This review will focus on three pre-
served, ancient, biological mechanisms (physical activity,
insulin sensitivity, and fat storage).
Selection for aerobic metabolism increased the yield of
ATP from 2 to 3 molecules of ATP by anaerobic means
from glucose to 36–38 molecules of ATP per molecule of
glucose (Brooks et al. 2005). The selective advantage of an
increased aerobic capacity for physical activity, according
to Bennett and Ruben (1979), are gathering food rather than
being the source of food, territorial defense or invasion, and
successful courtship and mating. Thus, through the course
of evolution, aerobic metabolic pathways must have been
selected to optimize fuel utilization during aerobic physical
activity (Booth and Lees 2007; Koch and Britton 2007;
Raymond and Segre 2006). The aim of this review is to
achieve two tasks. The Wrst aim is to discuss an animal
model that employs a sudden decrease in physical activity
to sedentary levels as a “systemic metabolic knockdown”
model. The purpose of the model is to understand which
genes might have been selected to maintain and support
physical activity throughout evolution. Our approach is also
based upon the notion that nature optimized fuel compart-
mentalization for survival by employing strategies for
energy partitioning, conservation, and utilization in physi-
cally active humans and animals. Sedentary lifestyles inter-
fere with the inherited metabolic expectancies of fuel
turnover caused by daily physical activity. The second aim
is to compare the animal model to the limited existing stud-
ies using human models of physical inactivity. The purpose
is to highlight metabolic alterations that are caused by our
new sedentary lifestyle.
Some of the contributors to our ideas on lack of physical
activity as a cause of many chronic diseases
In this section, we brieXy site the evolution of papers that
drive our quest for the mechanisms that underlie the tre-
mendous increase in many chronic diseases caused by a
sedentary lifestyle.
In 1970, Åstrand and Rodahl (1970) wrote, “…in
close to 100 percent of the biologic existence of our
species has been dominated by outdoor activity.
Hunting and foraging for food and other necessities in
the wilds have been a condition of human life for
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Eur J Appl Physiol (2008) 102:381–390
millions of years. We are adapted to that style of
life…we have ended up in an urbanized, highly tech-
nologic society. There is obviously no way to revert
to our natural way of life…But with insight into our
biologic heritage we may yet be able to modify our
current life style. Knowledge of the function of the
body at rest, as well as during exercise under various
conditions is important as a basis for an optimization
of our existence.”
In 1988, Eaton et al. (1988) extended Åstrand’s and
Rodahl’s tenet,
“From a genetic standpoint, humans living today are
Stone Age hunter-gatherers displaced through time to
a world that diVers from that for which our genetic
constitution was selected. Unlike evolutionary malad-
aptation, our current discordance has little eVect on
reproductive success; rather it acts as a potent pro-
moter of chronic illnesses: atherosclerosis, essential
hypertension, many cancers, diabetes mellitus, and
obesity among others. These diseases are the results
of interaction between genetically controlled bio-
chemical processes and a myriad of biocultural inXu-
ences-lifestyle factors-that include nutrition, exercise,
and exposure to noxious substances. Although our
genes have hardly changed, our culture has been
transformed almost beyond recognition during the
past 10,000 years, especially since the Industrial
Revolution. There is increasing evidence that the
resulting mismatch fosters “diseases of civilization”
that together cause 75 percent of all deaths in Western
nations, but that are rare among persons whose life-
ways reXect those of our preagricultural ancestors.”
From these ideas we wrote in 2000 (Booth et al. 2000),
“…we present the concept that the human genome
evolved within an environment of high physical activ-
ity. Accordingly, we propose that exercise biologists
do not study ‘the eVect of physical activity’ but in
reality study the eVect of reintroducing exercise into
an unhealthy sedentary population that is genetically
programmed to expect physical activity.”
Types of physical inactivity
For purposes of this paper, reductions in physical activity
can be subdivided into three categories: (1) elite athlete to
physically active lifestyle (2) physically active lifestyle to
sedentary, and (3) sedentary to bed rest. In this review we
will focus on the change from an active lifestyle to a seden-
tary lifestyle. We believe this shift best mimics the rapid
maladaptations resulting from the collision between a
genome selected on a background of physical activity and
Eur J Appl Physiol (2008) 102:381–390
a sedentary lifestyle produced by a rapidly changing
environment.
The rationale for our animal model designed to study
physical inactivity
In order to further our understanding of the above concepts
in humans, we applied an existing rodent exercise model.
Rats naturally will run in wheels, which we reasoned would
closely mimic the intermittent physical activity of hunting
and foraging for food (mentioned by Åstrand and Rodahl
1970) and Stone Age hunter-gatherers (referred to by Eaton
et al.). Cordain et al. (1998) estimate that recently studied
hunter-gatherers expended in their daily physical activity
the equivalent of 19 km walking (»24,000 steps) each day.
A current human model of our ancestor’s putative level of
physical activity might be the US Amish, who have not
adopted most of the technological changes occurring during
the 20th century. Amish men and women walk 18,000 and
14,000 steps per day, respectively, (Bassett et al. 2004). In
Colorado, the US state with the lowest obesity prevalence,
the average man and woman walk 6,700 and 6,400 steps
per day, respectively, (Wyatt et al. 2005). These data dem-
onstrate that machines and technology have replaced
human labor and largely reduced our daily physical activity
levels. We contend that voluntary (natural) running closely
approximates the daily living environment that generated
the human genome. We next reasoned that a sudden termi-
nation of natural physical activity by locking the running
wheels would allow us to approximate the loss of physical
activity from the level of our ancestors to the level of sed-
entary adults in the US Investigating this loss of activity is
extremely important as the Centers for Disease Control and
Prevention (Centers for Disease Control and Prevention
2007) report that 25% of US adults are not active at all in
their leisure time.
It is important to note that the animals when wheel
locked retain ambulatory cage activity and do not become
completely immobile like studies using hindlimb unloading
in animals and bed rest in humans as we reasoned that the
inactivity in those models is more extreme than in modern
lifestyle and do not appropriately mimic the loss of activity
levels over the last 100–200 years.
In addition while the term “detraining” is commonly
associated with athletes to describe the end of high-inten-
sity training, we use the term “reduced natural physical
activity” to specify the cessation of natural physical activity
which is diVerent than ceasing endurance exercise training.
We have previously shown biochemical diVerences when
rats continuously run daily for 2 h (forced treadmill run-
ning) or by intermittent, voluntary wheel running for 2 h/
day. Mitochondrial markers in a predominantly type II
muscle »doubled with daily, continuous 2–h treadmill
383
running (Winder et al. 1974), but only increased 26% with
2 h of intermittent voluntary running (Kump and Booth
2005a, b). Further in type I muscle, forced running for two
continuous hours »doubles mitochondria (Winder et al.
1974), but daily 2-h running produces no change in mito-
chondrial concentration (unpublished observation). The
intermittency of running closely approximates the animals
scurrying around Welds in search for food, thus serving as a
model to study natural physical activity.
In summary the underlying basis for our model mimics
that pattern of physical activity for which genes were
selected to optimize metabolism to support that activity pat-
tern (Booth et al. 2002a, b; Booth and Lees 2007; Chakra-
varthy and Booth 2004); and we are employing the rodent
wheel lock model to determine what happens to gene
expression (protein levels) and their biological function
when physical activity is not engaged beyond daily func-
tioning. The primary goal is to better understand how a
physically inactivity lifestyle initiates maladaptations that
cause chronic disease.
Results of the rodent wheel lock model
We have published four papers using the rodent wheel lock
model. Two of the major biological consequences of the
shift from high physical activity to a sedentary condition
are: a rapid decrease in skeletal muscle insulin sensitivity
and a rapid expansion of intra-abdominal fat storage, fac-
tors that also play a part in obesity, the metabolic syn-
drome, and type 2 diabetes.
Reduction in insulin sensitivity
Rapid reductions in insulin sensitivity upon ceasing
a physically active lifestyle
The major purpose of our study (Kump and Booth 2005a)
was to elucidate some of the mechanisms by which
decreasing the natural physical activity causes decreased
insulin sensitivity in skeletal muscle. Four-week-old, Fis-
cher-Brown Norway F1-generation male rats had access to
running wheels for 3 weeks, running »5 km/day in the
third week. Wheels were locked for 5 (WL5), 29 (WL29),
or 53 h (WL53); a separate group of rats never had wheel
access (sedentary, SED). In this paradigm, WL5 rats repre-
sent the healthy control while rats who have their wheel
locked for longer periods of time (WL29 and WL53) or
who never run (SED) represent the “experimental” groups.
Relative to WL5, submaximal, insulin-stimulated 2-deoxy-
glucose uptake into the epitrochlearis muscle was lower in
WL53 and SED (Kump and Booth 2005a), demonstrating a
rapid reduction in insulin sensitivity of the predominantly
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type II epitrochlearis muscle in only 2 days. Along with
these Wndings we witnessed reduced insulin binding, insu-
lin receptor beta-subunit (IRbeta) protein level, submaxi-
mal insulin-stimulated IRbeta tyrosine phosphorylation,
and glucose transporter-4 protein level in both the WL53
and SED rats when compared to the WL5 and WL29
(Kump and Booth 2005a). In addition, Akt/protein kinase B
Ser(473) phosphorylation was lower in WL53 and SED
than in WL5 demonstrating that both upstream and down-
stream insulin signaling was reduced following the cessa-
tion of daily running (Kump and Booth 2005a).
These Wndings conWrm two human studies that found the
loss of whole-body insulin sensitivity at 38 and 60 h after
cessation of endurance training. In a study by Burstein et al.
(1985) of highly trained athletes; the metabolic clearance
rate of glucose during euglycemic clamps was 15.6, 10.1,
and 8.5 ml/kg/min at 12, 60, and 168 h, respectively, of no
exercise after their last workout. Metabolic clearance rates
reached the values of the sedentary group (not athletically
active; 7.8 ml/kg/min) at 60 and 168 h of inactivity. Insulin
receptor binding to insulin in young erythrocytes also fell
60-h post-exercise (Burstein et al. 1985). In a later study
(Oshida et al. 1991), the rate of insulin-mediated glucose
uptake (glucose disposal) in a euglycemic clamp was 9.40,
7.78, 6.82, 7.11 ml/kg/min for athletes at 14, 38, 86, and
144 h after their last exercise bout; no diVerences existed
from non-trained subjects (6.80 ml/kg/min) at 38, 86 or
144 h. Our studies extend the human studies by showing
rapid declines in insulin sensitivity in rat epitrochlearis
muscle upon cessation of habitual exercise (Kump and
Booth 2005a).
The rapid decrease in insulin sensitivity by the cessation
of a physically active lifestyle initiates metabolic chronic
diseases
Our ideas are based upon extensions of earlier papers. In
1972, Lipman et al. (1972) published that the area under
the insulin curve during an oral glucose tolerance test sig-
niWcantly increased on the third day of continuous bed
rest in humans. Ten years later, we showed that insulin
resistance develops in the mouse soleus muscle after
1 day of hindlimb immobilization (Seider et al. 1982). In
1991, Wendorf and GoldWne (1991) hypothesized, “selec-
tive insulin resistance in muscle would have the eVect of
blunting the hypoglycemia that occurs during fasting but
would allow energy storage in fat and liver during feed-
ing. Both of these features could allow hunter-gatherers to
have survival advantages during periods of food shortage.
However, in sedentary individuals allowed free access to
food, this genotype would be disadvantageous; these indi-
viduals would become obese with concomitant secondary
insulin resistance in fat and liver”. In 1999, Grundy
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Eur J Appl Physiol (2008) 102:381–390
(1999) wrote, “Certainly, obesity and physical inactivity
are the dominant causes of insulin resistance, although
genetic factors undoubtedly aVect its severity.” Obesity
and the level of habitual physical activity each accounted
for »25% of the variance in modulation of insulin-medi-
ated glucose disposal in normal volunteers (Bogardus
et al. 1985). Given his data, Reaven in 2001 concluded:
“…the importance of habitual physical activity, as distinct
from exercise training, in modifying the ability of insulin
to mediate glucose disposal should no longer be mini-
mized” (Reaven 2001).
In recent years we have emphasized the issues:
• The presence of physical inactivity during states of con-
tinuous feeding results in a downregulation of the activ-
ity phenotype leading to insulin resistance, which is an
underlying part of metabolic syndrome (Booth et al.
2002a).
• Reduced physical activity is associated with a rapid
development of insulin resistance (Booth et al. 2002b).
• Physical activity deWciency plays a key role in the rapid
development of insulin resistance (Chakravarthy and
Booth 2004).
• Lower mitochondrial densities in skeletal muscle
because of physical inactivity may play a role in trigger-
ing metabolic dysfunction (Booth and Lees 2007).
As early as 1988, Reaven (1988) proposed that insulin
resistance was the primary defect associated with com-
pensatory hyperinsulinemia in a syndrome he called
“Syndrome X” that today is known as the metabolic syn-
drome. He further indicated, “it seems reasonable to sug-
gest that the various facets of Syndrome X are involved
to a substantial degree in the cause and course of the
major diseases of civilization” (Reaven 1988). In 2006,
Willet et al. (2006) identiWed overweight and inactivity
as “the most direct causes” of the insulin resistance syn-
drome. In 2007, Shulman’s groups reported data support-
ing the concept that insulin resistance in skeletal muscle
likely preludes any other maladaptation(s) like visceral
adiposity and alterations in circulating cytokines thought
to cause type 2 diabetes. Petersen et al. (2007) concluded
that their data support the hypothesis that insulin resis-
tance in skeletal muscle is due to decreased muscle gly-
cogen synthesis, diverting energy away from muscle
glycogen synthesis into increased hepatic de novo lipo-
genesis. They further contend, “…reversing defects in
insulin-stimulated glucose transport in skeletal muscle to
reverse insulin resistance in this organ might be the best
way to prevent the development of the metabolic syn-
drome at its earliest stages of development.” (Petersen
et al. 2007).
All of the above taken together support our view that
a primary consequence of physical inactivity is the
Eur J Appl Physiol (2008) 102:381–390 385

Fig. 1 A hypothetical sequence

to type 2 diabetes is shown (see
text for description)

development of skeletal muscle insulin resistance, Gain in intra-abdominal fat

which can contribute to the development of the meta-
bolic syndrome, cardiovascular disease, and type 2 dia- Rapid gain in intra-abdominal fat upon ceasing a physically
betes, as shown in Fig. 1, and described next. Physical active lifestyle
inactivity is an actual cause of type 2 diabetes (Mokdad
et al. 2004). Primary events from physical inactivity are Rats no longer expend energy in daily running when it
hypothesized to be decreased utilization of energy-pro- ceases. One issue is what happens to the loss of daily
ducing substrates by skeletal muscle. As feed-forward energy expenditure? We estimate an excess of 373 kJ
events, we hypothesize that skeletal muscle “senses” an (80 and 293 kJ from excess food intake and cessation of
underutilization of stored energy in its cells and signals daily running) as compared to age-matched cohorts
a reduced need for additional uptake of blood glucose, never having access to wheels for running (unpublished
thereby, diminishing insulin sensitivity for glucose
uptake. We believe that the aforementioned sequence of
events is a remnant of a selected survival mechanism to
conserve the limited whole-body stores of carbon atoms
for glucose in case a food shortage were to develop
(Chakravarthy and Booth 2004; Neel 1962). Such a
mechanism would have to be rapid (hours to days) to
conserve glucose since body stores of glucose are very
limited to <1,000 kcal and can be depleted in less than
1 day. However, in modern humans who live a sedentary
lifestyle throughout their lifespan, overt insulin
resistance develops contributing to the development of
type 2 diabetes. Diabetes has become pandemic, increas-
ing worldwide by Wvefold from 1985 to 2000 and the
International Diabetes Federation (2007) predicts diabe-
Fig. 2 Values taken from the International Diabetes Federation where
tes to increase another 2.5-fold to 380 million in 2025 the year 2025 is their prediction (International Diabetes Federation
(Fig. 2). 2007)

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estimation) The estimate is the caloric equivalent of
11.5 grams of fat. In our studies of cessation of daily
running, we subjectively observed an increase in intra-
abdominal fat after 53 h of no running, so we began
weighing the fat pads. Cessation of wheel running
for 53 h after 21 days of natural running resulted in a 25
and 48% increase in epididymal and omental fat pad
weights, respectively (Kump and Booth 2005b).
When humans reduce the number of daily steps from
»10,000/day to 1,500/day for 2 weeks, intra-abdominal fat
mass, as measured by MR-scan, was increased by 7%
(Pedersen, unpublished observation). Thus, Wndings in our
experimental animal model of reduced physical activity
from naturally high levels to that in a sedentary cage are
directionally similar to that in humans decreasing daily
stepping to an inactive level.
In another model of inactivity performed in humans
where the sedentary group was compared to exercising
groups, Slentz et al. (2005) observed a 9% increase in
visceral fat over a 6-month period in 40-65 year-old,
sedentary (exercise <2 times/week) subjects who were
already overweight or mildly obese at the onset of the
study (body mass index of 25–35 kg/m2). Two groups
exercising at an equivalent of running 12 miles/week at
moderate or vigorous intensity prevented the fat gain
and a third group exercising at an equivalent of vigorous
running 20 miles/week lost 7% abdominal fat (Slentz
et al. 2005). Thus, sedentary adults had 16%
more visceral fat after 6 months than cohorts who
expended calories at a rate equivalent to 20 miles of
running/week.
In other randomized controlled clinical trials using
imaging techniques to measure changes in visceral fat
with exercise (Kay and Fiatarone Singh 2006), the fall in
visceral fat ranged anywhere from a 6 to 49% reduction
in exercise studies ranging from 8 to 52 weeks in length
(Boudou et al. 2003; Irwin et al. 2003; Mourier et al.
1997; Ross et al. 2000, 2004; Weiss and Holloszy 2007).
Weight regain is a problem after virtually all dietary
and behavioral interventions for obesity (Wadden et al.
2004). The major challenge in the treatment of obesity is
maintenance of weight loss (Wing et al. 2006). Regular
physical activity has been found in many studies to be
associated with long-term weight loss maintenance
(Wing and Hill 2001). Most dieters regain about
one-third of the weight lost during the next year and
between 50 and 97% of individuals return to their
baseline in 4–5 years (Kramer et al. 1989; Wadden et al.
1989, 2004; Wing and Hill 2001). Taken together, vis-
ceral fat is very plastic in response to changes in the
amount of daily physical activity, increasing during
times of low activity and decreasing with enhancements
in activity.
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Eur J Appl Physiol (2008) 102:381–390
Cessation of daily running was associated with increased
palmitate incorporation into triacylglycerol
The rate of palmitate incorporation in epididymal fat was
4.2-fold greater in SED5 than in WL5, and increased 14-
fold between WL5 and WL10, being 79% lower in SED10
than in WL10 (Fig. 3). Palmitate incorporation (index of
triacylglycerol synthesis) remained at this elevated level (at
least 3.5-fold greater in WL29 and WL53 than SED5).
Thus, the rapid increase in epididymal fat mass with the
cessation of voluntary wheel running in our model was
associated with a prolonged overshoot in palmitate incorpo-
ration (Kump and Booth 2005b). The overshoot of palmi-
tate incorporation into triacylglycerol is a training eVect of
repeated days of running as overshoot did not occur after a
single day of running (Kump et al. 2006).
Mitochondrial glycerol-3-phosphate acyltransferase-1
(mtGPAT1) contributes to the overshoot in palmitate incor-
poration into triacylglycerol in adipose tissue upon the ces-
sation of daily, natural physical activity
In order to begin to understand the underlying basis for the
increased palmitate incorporation into triacylglycerol in
intra-abdominal fat upon the cessation of running, we
assayed some of the enzymatic steps in triacylglycerol syn-
thesis. Ten hours after 21 days of wheel running, activity of
mtGPAT1, a key regulator of triacylglycerol synthesis in
epididymal fat, overshot sedentary values by 48% and
remained higher than sedentary values at 29 and 53 h of
reduced physical activity (Kump et al. 2006). The over-
shoot in mtGPAT1 activity was accompanied by an
increase in mtGPAT protein level with no change in
mtGPAT1 mRNA. More than one bout of daily physical
activity is necessary to overshoot sedentary values for
palmitate incorporation into triacylglycerol in epididymal
fat (Kump et al. 2006), which suggests that repeated days
of physical activity (chronic eVect) are responsible for this
overshoot eVect. We conclude that an increase in mtGPAT
protein in epididymal fat associates with the overshoot in
palmitate incorporation in epididymal fat; this adaptation
would enhance restoration of fat stores after cessation of
daily physical activity, enhancing survival in case a food
deWciency were to occur.
Adipocyte hyperplasia is accentuated after the cessation
of daily wheel running
In order to determine if increased intra-abdominal fat is
solely due to increased food consumption, and not a cessation
of exercise, we tested the hypothesis that reduced physical
activity, independent of excessive caloric intake, would be
unable to induce an increase in fat pad mass. The experimental
Eur J Appl Physiol (2008) 102:381–390
Fig. 3 We hypothesize that the provision of wheels in cages allows
rats to express their intrinsic drive for natural daily running, exposing
the normal physiology of substrate utilization cycling. Removal of
daily running inhibits substrate cycling in the ensuing days. Thus, the
cessation of daily running stalls the up and down cycle of palmitate
incorporation into triacylglycerol in epididymal fat that occurs with
design was modiWed from our three studies (Kump and
Booth 2005a, b; Kump et al. 2006), above. 21-day-old rats
were given access to voluntary running wheels for 42–
43 days, thus starting the rats running at a younger age and
having them run twice as long before locking the wheels.
Rats were running approximately 9 km/day in the last week,
after which wheels were locked for 5, 53, or 173 h (WL5,
WL53, WL173) before sacriWce. During the 53 and 173 h of
inactivity, one group of animals was pair fed (PF) to match
sedentary controls, whereas the other continued to eat ad
libitum (AL). Epididymal and retroperitoneal fat masses
were signiWcantly increased in the WL173-PF versus the
WL5 group, whereas epididymal, perirenal, and retroperito-
neal fat masses were all signiWcantly increased in the
WL173-AL group compared with the WL5 group (Laye
et al. 2007). The demonstrated increase in intra-abdominal
fat stores after the cessation of running in the absence of
hyperphagia demonstrates that physical inactivity induced
fat storage is independent of food intake. Additionally,
hyperplasia of adipocytes in epididymal fat mass occurred in
WL173-AL but no change in mean adipocyte size was noted.
Interim summary of our animal model of reduced physical
activity
Two major changes have been identiWed when 21- or
28-day-old rats undertake 3 or 6 weeks of daily, natural
voluntary running on wheels, followed by an abrupt cessa-
387
daily activity and assumedly leads to an accumulation of adipose tis-
sue. The gray horizontal bar represents their range for palmitate incor-
poration into triacylaglycerol of age-matched cohorts that never ran;
the range of the bar is from 11 am (395 § 71 pmol per mg homogenate
protein per min) to 4 pm (226 § 35). For more detail, see references
(Chakravarthy and Booth 2004; Kump and Booth 2005b)
tion of the running. First, insulin sensitivity in the epit-
rochlearis muscle of rats falls to sedentary values with
2 days of the cessation of running (Kump and Booth
2005a), conWrming the decline to sedentary values in
whole-body insulin sensitivity when physically active
humans stop daily exercise (Burstein et al. 1985; Oshida
et al. 1991). Second, visceral fat increases within 1 week
when rats cease daily running (Laye et al. 2007), conWrm-
ing the plasticity of human visceral fat. A fundamental
question in biology then becomes, why were rats and
humans built this way?
Speculated bases for the inactivity-induced changes
Why is the body so plastic to decreases in physical activity?
One answer to the question was popularized by Neel (1962)
who in 1962 introduced the concept of “thrifty” genotype.
Neel (1962) proposed that certain genotypes were selected
into the human genome because of their selective advan-
tage over the less “thrifty” ones. Neel (1962) deWned a
“thrifty” genotype as “being exceptionally eYcient in the
intake and/or utilization of food”. The rationale is that dur-
ing periods of food deprivation, animals and humans with
the “thrifty” genotype would have a survival advantage
because they could rely on larger, previously stored energy
to maintain homeostasis, whereas those without “thrifty”
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genotypes would be at a disadvantage by having smaller
fuel stores at the start of the food deprivation, and therefore,
would be less likely to survive (Neel 1962). Chakravarthy
and Booth (2004) extended Neel’s thrifty genotype by pos-
tulating that survival during the feast-food deprivation
cycle of the hunter-gatherer also selected genes to support a
“physical activity cycle” in which cycling of metabolic pro-
cesses was triggered by the reduction of skeletal muscle
glycogen and triglyceride stores. Indeed, our recent work
provides an example of such speculation.
Cessation of daily, natural physical activity is associated
with a disappearance of the natural cycling of palmitate
incorporation (an index of triacylglycerol synthesis) into
triacylglycerol of epididymal fat (Fig. 3). To speculate on
the potential biological signiWcance of triacylglycerol
cycling, we will apply concepts of evolutionary or Darwin-
ian medicine (Williams and Nesse 1991; Eaton et al. 2002)
to understand from an evolutionary perspective why the
human body is not better designed for physical inactivity.
We suggest that increased fat storage upon initiating physi-
cal inactivity is an inherited survival mechanism to store
energy as fat in anticipation of a future food deWciency; it
accomplishes this feat by imposing decreased insulin sensi-
tivity to repartition glucose from inactive skeletal muscle to
adipocytes, where energy storage occurs. The phenotype
becomes maladaptive when physical inactivity continues
unabated for months/years.
To sum up our beliefs as to why natural selection
resulted in energy partitioning from inactive skeletal mus-
cle to fat is energy conservation so that fuels not needed for
work are stored for survival in the next food deWciency.
Rationale for rapidity of changes to reductions
in enhanced physical activity
Genes that regulate PDK4 mRNA/protein degradation
were selected into the human genome
As the onset of food deWciency is rapid, adaptations for
energy storage and utilization to enhance the probability of
survival had to be rapid, leading to the need to have a rapid
turnover proteins involved in energy metabolism. Important
regulatory processes must, therefore be very plastic. Natu-
ral selection is based upon the concept that those organisms
that can adapt to a new environment best are more likely to
pass their gene pools on to the next generation as compared
to those with slower adaptations to the new environment.
Therefore, one criterion for selection of genes to study
function when reduced inactivity ensues would be to con-
sider whether their half life was short. Goldberg and Dice
(1974) has commented that of the 40 liver proteins that
have the shortest half lives [determined by (Berlin and
123
Eur J Appl Physiol (2008) 102:381–390
Schimke 1965)] were either rate limiting or Wrst steps in
pathways. Whereas, the twelve proteins that had the longest
half lives did not function as rate limiting. Thus, principles
of protein turnover will be brieXy described.
The importance of short half lives (t½) is that the time
course between steady state levels of protein is determined
solely by the Wrst-order rate constant for degradation (kd),
where t½ = ln 2/Kd (Schimke 1970). Thus, proteins with
shorter half lives adapt to new steady state levels faster than
proteins with longer half lives challenged by an environ-
mental perturbation (Schimke 1970). Natural selection is
based upon the concept that those organisms that can adapt
to a new environment best are more likely pass their gene
pools on to the next generation as compared to those with
slower adaptations to the new environment. Therefore, one
criterion for selection of genes to study when reduced inac-
tivity ensues would be to consider whether the half life of
the protein they encoded for was short.
One such example of a key regulatory protein is pyruvate
dehydrogenase kinase 4 (PDK4). PDK4, when activated,
phosphorylates and inactivates the pyruvate dehydrogenase
complex (PDC). As PDC is switched between glucose-
derived pyruvate and long chain fatty acid entry into the
TCA cycle, increased PDK4 activity would inhibit glycoly-
sis, conserving glucose carbon chains from oxidation. PDK4
has a very short half life of 1.3 h in Morris heptoma 7800 C1
cells (Huang et al. 2002). Two hours following an endurance
exercise bout, PDK4 mRNA increases »fourfold (Pilegaard
et al. 2005). Further at 8 h post-exercise, PDK4 mRNA had
returned to pre-exercise values in muscles having high car-
bohydrate levels before exercise as opposed to muscles with
low carbohydrate at the start of exercise (Pilegaard et al.
2005), demonstrating the importance of local energy status
in regulating its expression. Regulation of PDK4 mRNA has
been shown at the transcriptional level; no data is yet avail-
able that shows regulation by its mRNA stability (Sugden
and Holness 2006). However, since the rise in PDK4 mRNA
and protein is very transient after a single bout of exercise,
speciWc mechanisms, yet unknown, must have been selected
to regulate the rapid increase in its transcription and its rapid
decrease in mRNA and/or protein. In conclusion, the puta-
tive function of high PDK4 protein (inferred from its high
mRNA) during exercise would be to conserve the limited
stores of whole-body glucose carbons for the central nervous
system and red blood cells, which do not oxidize fatty acids.
Further, fast turnover of molecules allows rapid adaptive
changes to meet new metabolic challenges.
Concluding remarks
Current human biology is a prisoner of the metabolic path-
ways designed by our evolution. Without knowledge of
Eur J Appl Physiol (2008) 102:381–390
selected genes and their functions for which they evolved, a
precise deWnition of normal function is impossible. Less
than adequate knowledge leads to incorrect interpretations
and less than optimal preventative measures and therapies
to improve health. The selection of genes for survival over
hundreds of thousands of years includes those metabolic
processes that were optimized for energy partitioning, con-
servation, and utilization. Genes were selected to allow aer-
obic metabolism and to orchestrate the complex integration
needed for physical activity for survival in food acquisition,
defense, and reproduction. Imposition of minimal daily
physical activity on a system primed for aerobic activity
initially results in fuel redistribution to minimize glucose
uptake into skeletal muscle and to maximize fat storage and
eventually progresses to obesity and type 2 diabetes.
Acknowledgments The authors thank the University of Missouri
Research Board (FB), the College of Veterinary Medicine Research
Fund (FB), and the Life Sciences Predoctoral Fellowship Program
(ML) for support of the reported research. The review was written
while supported by Department of Veterans AVairs Career
Development Grant—CDA-2 (JPT) and Department of Internal
Medicine at University of Missouri (RSR).
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