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Review article            doi: https://doi.org/10.35469/ak.2019.162
received: 2018-07-29           UDC: 613.24:796.011

HOW DOES EXERCISE SUPPORT DIETARY APPROACHES 
TO WEIGHT LOSS AND BETTER HEALTH?

Katarina TOMLJENOVIĆ BORER

School of Kinesiology, The University of Michigan, Ann Arbor, USA

Corresponding author:
Katarina T. BORER

School of Kinesiology, The University of Michigan, 1402 Washington Heights, Ann Arbor, MI 
48109-2013, USA

Tel. +1 734 249-8809
E-mail: katarina@umich.edu

ABSTRACT 

The rapid global rise of obesity incurs a heavy personal and healthcare burden due 
to obesity-associated morbidities and shortening of life. The purpose of this review is 
to provide evidence-based strategies for prevention, reversal, and mitigation of obesity 
and its sequelae. To that end, this review highlights the features of human physiology 
that favor fat accretion and interfere with fat loss. Strategies for prevention of obesity 
include understanding the basis for the strong motivating properties of palatable food, 
for human inability to consciously detect calories eaten or calories expended through 
exercise, for metabolic and hormonal adaptations to negative energy balance that drive 
weight regain, and for evolutionary natural selection which likely led to high human 
capacity for fat storage. Reversal of obesity is difficult primarily due to metabolic, 
hormonal, and behavioral reactions to body fat loss. Reduced resting metabolic rate 
presents a physiological challenge whether the weight loss is achieved through dietary 
restriction or energy expenditure of exercise. Increased insulin sensitivity after body fat 
loss drives resynthesis of storage substrates including triglycerides in the adipose tis-
sue, muscle glycogen, and proteins, thus contributing to weight regain. Reduced basal 
plasma leptin concentration elicits a strong hunger drive. Mitigation of obesity-asso-
ciated morbidities involves adding exercise energy expenditure to deliberate control 
of the quantity of food eaten, reducing postprandial hyperinsulinemia by lowering the 
carbohydrate load of the diet, and exercising after, rather than before, the meals to 
facilitate improved glucose tolerance.

Keywords: obesity morbidities exercise insulin leptin body weight



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KAKO GIBALNA VADBA DELUJE KOT PODPORA DIETI PRI 
ZNIŽEVANJU TELESNE MASE IN IZBOLJŠEVANJU ZDRAVJA?

IZVLEČEK

Hiter globalni razmah debelosti in prekomerne telesne mase zaradi številnih z njim 
povezanih bolezni in posledično krajšanja življenjske dobe, predstavlja vedno večje 
breme tako za posameznike kot tudi za zdravstvene sisteme. Namen preglednega članka 
je predstaviti na dokazih temelječe strategije za preprečevanje in ublažitev posledic 
prekomerne telesne mase. Izpostavili bomo fiziološka ozadja, ki imajo odločilno vlogo 
pri kopičenju maščobnega tkiva, ter tista, ki preprečujejo izgubo maščobe. Strategije za 
preprečevanje prekomerne telesne mase vključujejo tako razumevanje osnovnih vzvo-
dov, ki vodijo do močne navezanosti človeka na okusno hrano, kot tudi razumevanje 
osnov človekove nezmožnosti, da bi zavestno prepoznal količino kalorij, ki jih je prejel z 
zaužito hrano ali tistih, ki jih je s telesno aktivnostjo porabil. Izpostavili bomo presnov-
ne in hormonalne adaptacije na negativno energijsko bilanco, ki vodijo v pridobivanje 
telesne mase in evolucijsko naravno selekcijo, ki je verjetno vodila do visoke sposobno-
sti človeka, da v telesu kopiči zaloge maščobe. Spreminjanje trenda naraščanja preko-
merne telesne mase je težavno predvsem zaradi presnovnih, hormonalnih in vedenjskih 
odzivov na izgubo telesnih maščob. Pri zmanjšani stopnji presnove v mirovanju pred-
stavlja poseben fiziološki izziv vprašanje ali gre v teh primerih za zmanjšanje telesne 
mase zaradi restriktivne prehrane ali zaradi povečanja porabe energije, kot posledico 
gibalne aktivnosti. Povišana stopnja inzulinske rezistence po izgubi telesnih maščob 
vodi v resintezo skladiščenih substratov, vključno trigliceridov v maščobnem tkivu, 
mišični glikogen in proteine, kar prispeva k ponovnemu pridobivanju telesne mase. 
Zmanjšane koncentracije bazalnega leptina v plazmi sprožijo občutek lakote. Zmanjša-
nje posledic s prekomerno telesno maso povezanih bolezni, ob zavestnem nadzorovanju 
količine zaužite hrane, vključuje tudi dodatno porabo energije s pomočjo gibalne vad-
be, zniževanje postprandialne hiperinzulinemije z nižanjem količine ogljikovih hidratov 
v prehrani ter z izvajanjem gibalne/športne aktivnosti po zaužitem obroku, raje kot pred 
njim, saj to izboljšuje toleranco za glukozo.

Ključne besede: debelost, slabotnost, gibalna vadba, inzulin, leptin, telesna masa



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INTRODUCTION

Obesity has risen rapidly over the past half a century in all of 200 sample countries 
of the world (NCD Risk Factor Collaboration, 2017). It increased from 3.2% in men 
and 6.4% in women in 1975 to 10.8% and 14.9%, respectively, in 2014. In 2014, 2.3% 
of world’s men and 5% of women were severely obese, and 0.64% men and 1.6% 
women were morbidly obese. By 2025, global obesity is projected to reach 18% in men 
and 21% in women, and 6 and 9% are, respectively, likely to become severely obese. 
In the US, 32.2% of men and 35.5% of women were obese in 2016 (Hales, Carrol, 
Fryar & Ogden, 2017). Their health care burdened the economy with 147 billion USD 
(Finkelstein, Trogdon, Cohen & Dietz, 2009). The corresponding health care costs of 
obesity in Europe in 2008 were 10.4 billion euros (Muller-Riemenschneider, Reinhold, 
Berghofer, & Willich, 2008).

Obesity-associated morbidities include hypertension (Vaněčková et al., 2014), ath-
erosclerosis (Lovren, Teoh, & Verma, 2015), hypercoagulability of blood (Samad & 
Ruf, 2013), endothelial dysfunction (Iantorno et al., 2014), coronary vascular (Ranki-
nen, Sarzynski, Ghosh, & Bouchard, 2015), kidney (Ritz, Rychlik, Locatelli, & Halimi, 
1999), and heart disease (Després et al., 1996), stroke (Field et al., 2001), and particu-
larly type 2 diabetes (T2D). These obesity-linked morbidities increase the risk of mor-
tality by two to three fold (Adams et al., 2006). The close association between obesity, 
peripheral tissue resistance to insulin action, and T2D is reflected in the frequently used 
descriptive term “diabesity” (Farag & Gaballa, 2011).

Since the driver of recent rapid increases in obesity is the interaction between be-
havioral choices and human physiological barriers, the purpose of this review is to 
describe behavioral strategies that could prevent or reduce obesity and mitigate its as-
sociated morbidities.

METHODS

The data for this review are based, in part, on PubMed search for the scientific 
reports on the behavioral and physiological controls of food intake and on the physi-
ological, psychological, and hormonal barriers to weight loss, as well as, in part, on the 
author’s research findings and views on the regulation of energy balance in humans 
(Borer, 2005; 2008; 2010; 2014; 2019; Borer, Wuorinen, Chao, & Burant, 2005; Borer, 
Wuorinen, Ku & Burant, 2009; Wuorinen & Borer, 2013; and Lin & Borer, 2016).

Five points will be interpreted from the evidence-based research:
(1) The endocrine basis of obesity-associated morbidities; (2) Physiological fea-

tures that facilitate overeating, (3) Evolutionary burden of high human capacity for 
obesity, (4) Failure of spontaneous physical activity to compensate for obesity; and (5) 
Dietary and exercise solutions to some obesity-associated morbidities. Integration of 
these points will guide the recommendation for behavioral strategies toward preven-
tion, reversal, or mitigation of obesity and its associated morbidities. 



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RESULTS

1. The endocrine basis of obesity-associated morbidities

Obesity leads to a disturbance in the endocrine regulation of body energy storage 
and its mobilization by reducing the effectiveness of its chief endocrine agent insulin. 
Circulating glucose and amino acids elicit insulin secretion, and activate its four chief 
actions, to increase uptake of these nutrients by muscle and other energy-depleted tis-
sues, to reduce the concentration of circulating glucose by increasing its metabolism, 
to further reduce circulating nutrients by promoting their storage in the form of muscle 
and liver glycogen, adipocyte triglyceride, and tissue protein, and finally, to block the 
breakdown, release, and metabolism of metabolic fuels from their inert storage form. It 
is less well-recognized that a second hormone, leptin, also plays a key role in the meal-
associated regulation of energy balance. While its release from the white adipose tissue 
(WAT) is universally recognized, it is less well known that leptin gets also released 
from the stomach during meal eating (Sobhani et al., 2000). Its secretion and actions are 
linked to that of insulin in a counter-regulatory fashion. Insulin stimulates leptin release 
during meal-eating, and leptin then restrains all four of the insulin’s actions as well as 
insulin release. It indirectly counter-regulates the energy storage actions of insulin by 
promoting lipolysis and stimulation of lipid metabolism (Borer, 2014). This endocrine 
counter-regulation of short-term energy balance is disrupted in obesity by the resistance 
of peripheral tissues to the actions of both insulin and leptin.

Increased insulin and leptin resistance in obesity (Samuel, Petersen, & Shulman, 
2010; Shulman, 2014a) is reflected in the proportional rise in fasted, basal and stimu-
lated concentration of both hormones as a function of increased body fat (Figure 1). 
The effect of obesity on the basal insulin concentration is expressed in a disposition 
index (DI) (Lorenzo et al., 2010). DI is a product of insulin sensitivity and the amount 
of insulin secreted in response to blood glucose level. Plotted as insulin response as a 
function of insulin sensitivity, the parabolic curve shows that little insulin is needed to 
stimulate the glucose uptake when insulin sensitivity is high, but a high insulin con-
centration is required when the peripheral tissues are insulin-resistant and when insulin 
sensitivity is low. Insulin-resistant peripheral tissues in obesity thus require high basal 
and stimulated insulin concentrations. 
 The rise in the basal or fasted concentrations of insulin and leptin are a con-
sequence of a fundamental relationship between prevailing hormone concentration and 
the number of specific hormone receptors on the cell membrane. The number of recep-
tors on energy-storing cells (like WAT, liver, or muscle) varies with the state of energy 
depletion or repletion. Energy depleted adipocytes are smaller and have a higher den-
sity of insulin receptors on their membranes than lipid-packed adipocytes in over-fed 
or obese state (Olefsky & Reaven, 1975). This relationship is explained in Figure 2 
(Mendelson, 1996). In this hypothetical example, a biological response is possible when 
insulin binds to 5000 receptors. Any time the cell has in excess of 5000 insulin receptors 
(called “spare receptors”), the cell sensitivity to insulin, and the affinity of the hormone 



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Figure 1. The positive correlation between fasting serum insulin (top) and fasting se-
rum leptin (bottom) as a function of percentage body weight or body fat. Data for insu-
lin from Bagdade, 1968 and for leptin from Considine et al., 1996.



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Figure 2. The sensitivity of peripheral tissues to fasting concentration of a hormone 
declines in parallel with the number of receptors on the target cell surface and the 
repletion of target cells with storage fuels. As the amount of storage fuel and the cell 
size increase, the number of receptors on the surface membrane declines. At the same 
Km (A), tissue sensitivity to a hormone increases in proportion to the number of “spare 
receptors above the threshold number required to elicit a biological response (5000 
receptors in this example). With the smaller number of receptors in energy-replete cells, 
resistance to a hormone manifests in the form of a higher hormone concentration re-
quired to elicit the biological response (B). From Mendelson, 1996.



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for the cell are increased, and the biological effect is achieved with lower insulin con-
centration (Figure 2A). The figure also shows the way to express hormone-receptor 
affinity or hormone sensitivity as half-maximal concentration of the hormone producing 
the biological effect (Kd or dissociation constant). When the cell is more energy replete 
and has fewer (about 5,000 to 10,000) membrane receptors, hormone concentration 
required to produce full (100%) biological response will have to be higher (Figure 2 B). 

This fundamental rule of hormone interaction with the number of its receptors in the 
context of cellular energy depletion or repletion explains why obese tissues become 
more resistant to insulin and why the basal concentration of insulin and leptin rise with 
obesity. So, postprandial hyperglycemia and hyperinsulinemia are the consequence, 
respectively, of reduced effectiveness of insulin to stimulate glucose uptake by pe-
ripheral tissues and to inhibit glucose mobilization from the liver and free fatty acid 
mobilization from WAT because of insulin resistance. Hyperglycemia and compensa-
tory hyperinsulinemia (Taylor, 2013) lead to glycation of circulating proteins and the 
formation of advanced glycation products associated with pathological oxidative stress 
(Nowotny, Jung, Höhn, Weber & Grune, 2015). High fasting concentrations of FFAs 
resulting from diminished insulin suppression of their mobilization from storage fat 
(Yazıcı & Sezer, 2017) directly interfere with insulin signaling in the muscle (Schenk 
& Horowitz, 2007).

Obesity-associated pathologies also result from excess fat deposition in ectopic 
sites when the capacity of adipocytes to hypertrophy exceeds the capacity of fat stor-
age in the WAT. Excess fat storage in the liver (van der Zijl et al., 2011; Taira et al., 
2013; Shulman, 2014b), the pancreas (van der Zijl et al., 2011), the muscle (Taira et 
al., 2013), and the kidney (Guebre-Egziabher et al., 2013) cause lipotoxicity in addition 
to insulin resistance. Non-alcoholic fatty liver disease (Than & Newsome, 2015) and 
steatohepatitis (Neuman et al., 2014) result from lipotoxic fat accumulation in the liver. 
Obesity drives the progression from insulin resistance, reduced glucose tolerance, and 
pre-diabetes to T2D. The incidence of T2D has increased from 4.4 million or 2.4% of 
US population in 1970s (Fox et al. 2006) to 29.1 million or 9.3% of the population in 
2014 (National Diabetes Statistics Report, 2017). Globally, in 2010, there were 284 
million diabetics representing 6.4% of the world population. If the increases continue, 
there will be 490 billion of diabetics in 2030 (Farag & Gaballa, 2011). 

2. Physiological features that facilitate overeating

Overwhelming evidence indicates that excessive food intake, rather than insuffi-
cient physical activity, is the primary cause of weight gain and obesity. Why is this 
behavior not subject to negative feedback to counteract the excessive energy gain? This 
question is often either overlooked or incorrectly attributed. The incorrect attribution is 
due to the hypothesis which posits that changes in the quantity of body fat control hun-
ger, meal eating, and motivation for physical activity in a way that maintains healthy 



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Figure 3. Energy content of diets (35-30% fat open circles, 20-25% fat solid circles) 
did not affect the amount of food eaten over 11 weeks (top). Instead, a similar volume 
of food was eaten over 11 weeks unaffected by dietary energy density (bottom). From 
Kendall, Levitsky, Strupp, & Lissner, 1991.



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body fat content (Schwartz, Woods, Porte, Seeley, & Baskin, 2000). This hypothesis is 
not supported by facts. The simple and convincing answer to the feedback question is 
that humans (and probably most animals) cannot directly detect calories eaten in meals 
or calories expended in physical activity. This flaw in our physiological design, com-
pounded by the strong motivating properties of palatable food, allow environmental 
influences such as portion size, easy availability of meals, and social facilitation, to 
drive food overconsumption. How good is the evidence that humans cannot track meal-
associated intake of calories and exercise-associated expenditure of calories? That the 
volume of food eaten rather than the nutrient energy is the critical determinant of nutri-
ent intake was demonstrated almost 30 years ago (Kendall, Levitsky, Strupp, & Lissner, 
1991). Lower energy low-fat (20-25% fat) or higher energy high-fat diets (35-40% fat 
diet) were available for 11 weeks. The volunteers spontaneously ate a constant volume 
of food per day regardless of the 1.1 KJ daily energy difference in the two diets (Figure 
3) and ended up with a different weight change. 

A more relevant demonstration of human inability to track calories eaten in a meal 
or expended in exercise was done 18 years later in a study demonstrating that only a 
variable quantity of food taken by mouth and processed by gastrointestinal tract af-
fected the sensation of hunger and fullness, while intravenous infusion of nutrients and 
substantial pre-meal exercise expenditure had no such effect (Borer, Wuorinen, Ku, & 
Burant, 2009, Figure 4). 

Furthermore, changes in plasma concentrations of both insulin and leptin correctly 
tracked calories gained or lost, but exerted no influence on the perception of hunger 
or satiation in contradiction to the homeostatic hypothesis of Schwartz et al. (2000). 
(Figure 5). 

These data show that our perception of satiation is based on gastrointestinal full-
ness, a signal that can easily be overlooked, and that insulin and leptin, postulated to 
affect appetite in response to changes in the size of WAT (Schwartz et al., 2000), do not 
operate during regular meal-to meal eating as such meal-associated changes in body fat 
are exceedingly small.

The second flaw in our physiological design is that food provides a powerful posi-
tive motivation to eat whether or not we are experiencing energy deprivation (Ber-
ridge, 2009). Food activates the same brain centers of reward as the various pleasurable 
events like sex, stimulating drugs, and direct electrical or pharmacological stimulation 
by neurotransmitters such as dopamine (Berridge, 2009), morphine-like endogenous 
opiates, and endocannabinoids (Kirkham & Williams, 2001). That palatable food alone 
and in the absence of deprivation can powerfully increase weight gain and obesity 
was demonstrated four decades ago with the cafeteria-diet experiment by Sclafani and 
Springer (1976, Figure 6). 

Just by making highly palatable fatty and sweet food items available in addition 
to the less palatable standard diet, the authors observed sustained increase in weight 
gain and adiposity of laboratory rats. It is certain that some of human overeating is a 
consequence of easy and convenient availability of fast foods commercially designed 
for high palatability.



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Figure 4. Hunger (top left) and fullness (bottom left) are affected only by variable-size 
meals that transit through the mouth and gastrointestinal tract (2,090 KJ meals=SED-
AL, 418 KJ meals=SED-R) but not by 1521 KJ of parenteral nutrition (SED-R-TPN) 
infused intravenously or by 2 hours of mid-morning moderate-intensity exercise ex-
pending 2315KJ (top and bottom, right). From Borer, Wuorinen, Ku, & Burant, 2009.



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Figure 5. Accurate quantitative responses of circulating insulin (top) and leptin (bot-
tom) concentrations to the changes in energy as a function of variable meal size (SED-
AL, SED-R), intravenous infusion of total parenteral nutrition (SED-R-TPN) or energy 
expenditure of exercise (EX-AL, EX-TPN). From Borer, Wuorinen, Ku, & Burant, 2009.



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Figure 6. Cafeteria-diet phenomenon. Rapid weight gain in rats during 65 days of free 
access to a variety of supermarket palatable foods in addition to laboratory chow in 
groups I-S (solid circles) and E-S (solid triangles), compared to lower weight trajecto-
ries in rats given lab chow (groups I-P, open circle, A-P,open rectangles, and E-P, open 
triangles). The same fast-food dietary access with activity wheel present led to slower 
fat accretion during 65 days but attained the same level of obesity as E-S group after 
the wheel access was removed (Group A-S, solid rectangles). Introduction of activity 
wheels on day 65 to group E-S stopped weight gain on the fast-food diet.



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3. Evolutionary burden of high human capacity for obesity

Given that humans are unable to directly track calories in meals or calories ex-
pended in exercise, easy access to palatable food, and reduced opportunity for physical 
exertion in the modern societies lead inexorably to obesity and its metabolic patholo-
gies. So, how did humans end up with the largest capacity to become obese among the 
primates (Stini, 1981)? Natural selection toward increased brain size and the capacity 
of the woman to bear numerous offspring may have driven the evolution of increased 
capacity to store body fat in humans. Evolution of larger brains in human ancestors be-
came exponential over the past two million years (Figure 7, top) and resulted in about 
three-fold greater brain mass compared to that in higher primates (Ruff, Trinkaus & 
Holliday, 1997, Figure 7, bottom.). 

As human brain consumes between 20 and 25% of resting energy metabolism, natu-
ral selection toward bigger brains required larger energy stores. Non-arboreal existence 
in human ancestors has favored the evolution of unusually large brains and fat depots 
but not in the arboreal primates (Heldstab, van Schaik, & Isler, 2016). Similarly, the 
natural selection for increased fat storage capacity has provided human ancestral fe-
males with the advantage of being able to support the energy cost of pregnancy (about 
18,828 KJ/day) and, with about 1,255 to 1,674 KJ/day, to feed additional children. It is 
therefore useful to be mindful of our large capacity for fat storage and of the fact that 
natural selection does not operate on post-reproductive portion of the life span when 
most metabolic pathologies develop. 

4. Failure of spontaneous physical activity to compensate for obesity

 Voluntary physical activity declines in both humans (Rising et al., 1994; Schulz & 
Schoeller, 1994, Figure 8) and animals as the body fat mass increases. This indicates 
that behavioral energy expenditure does not serve as a component of energy regulatory 
feedback to maintain stable healthy body weight. Instead of increasing as the body fat 
rises, spontaneous physical activity is non-homeostatic in that, the fatter the humans 
and animals become, the less motivated they are to be physically active (Borer, 2010). 

The decline in voluntary running in experimental obesity is due to reduced mo-
tivation rather than a physical difficulty to move a larger body mass. In support of 
this conclusion are data showing no performance deficit in obese animals if running 
is enforced with a negative reinforcement (Borer, Potter & Fileccia, 1983, Figure 9). 
Similarly, obese humans seeking publicity and financial incentives to lose weight in the 
televised “The Biggest Looser” program, clearly demonstrate that increased motiva-
tion can produce large increases in physical activity and decreases in food consumption 
in obese individuals (Fothergill et al., 2016; Knuth et al., 2014) that they do not show 
spontaneously (as shown in Figure 8).

This unfortunate non-homeostatic design for energy intake and motivation to move 
(Borer, 2010) may have been the result of evolutionary pressures to take advantage of 

https://www-ncbi-nlm-nih-gov.proxy.lib.umich.edu/pubmed/?term=van%20Schaik%20CP%5BAuthor%5D&cauthor=true&cauthor_uid=27765147
https://www-ncbi-nlm-nih-gov.proxy.lib.umich.edu/pubmed/?term=Isler%20K%5BAuthor%5D&cauthor=true&cauthor_uid=27765147


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Figure 7. Exponential evolution of human brain volume during the last three millennia 
(top) producing about 4-fold difference between human and primate brains (bottom). 
Data from Ruff, Trinkaus & Holliday, 1997, illustration from Lieberman, 2013, pages 
101 and 107.



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Figure 9. Obesifying septal lesions in golden hamsters (Mesocricetus auratus) pro-
duced 82% reduction in the level of spontaneous wheel running. However, when forced 
to run on a treadmill with electrified off-ramp grid as a negative reinforcement, obese 
hamsters showed no deficit in duration of running (left) or power production (right) 
compared to lean non-lesioned animals throughout the range of tested treadmill speeds.

Figure 8. Inverse relationship between non-basal daily energy expenditure as a func-
tion of human percent body fat. From Rising et al., 1994 and Schulz & Schoeller, 1994.



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uncertain food availability in human past by increasing the search for it when the food 
is scarce (Chakravarthy & Booth, 2004). Beyond the lower quantity of spontaneous 
physical activity with the rise in obesity, staying inactive or sedentary over several 
hours reduces cardiovascular health and increases risk of the morbidities associated 
with obesity (Després, 2016). The volumes of prescribed physical activity usually fall 
short of compensating for the ease with which excessive calories can be ingested and 
stored (Borer, 2008). Unless physical work is required for the procurement of food or 
some other life necessity, as was evident in Cuba during early 1990s when food em-
bargo led to food scarcity and population weight declines (Rodríguez-Ojea, Jiménez, 
Berdasco & Esquivel, 2002), human ingenuity to make voluntary physical work un-
necessary is likely to persist and obesity is likely to continue to rise. 

5. Dietary and exercise solutions to some obesity-associated morbidities

Obesity, and particularly T2D, are characterized with hyperglycemia, not only im-
mediately after the meals, but over postprandial periods spanning substantial periods of 
wakefulness (van Dijk et al., 2011). Persistent hyperglycemia, as reflected in elevated 
hemoglobin A1c, has been associated with coronary heart disease and increased mortal-
ity (Després et al., 1996). The association of hyperglycemia and hyperinsulinemia in 
T2D with obesity is firmly established as both can be reduced with weight loss (Tay-
lor, 2013). It is probable that the rapid rise in obesity and T2D in the US population 
since 1970’s (National Diabetes Statistics Report, 2017) may have been facilitated by a 
30.5% increase in daily carbohydrate consumption from 213 g per day in 1965 to 278 
g per day or 51% of daily calories in 2011 (Cohen et al., 2015). The currently high car-
bohydrate consumption in the US falls within the 45 to 65% of daily calorie range rec-
ommended in 2010 by US Departments of Agriculture and Health and Human Services 
(Dietary Guidelines for Americans, 2010). To test the hypothesis that the postprandial 
hyperglycemia is largely driven by the high insulin response to a high-carbohydrate 
diet, carbohydrate content of the isocaloric meals was reduced in a recent study (Lin & 
Borer, 2016) from 60% to 30% over a 24-hour period. 

The remarkable outcome of the study was that the postprandial insulin area under 
the curve was reduced by 39% by the third low-carbohydrate meal, after a 24-hour ex-
posure to the changed diet, but not after the high-carbohydrate meal (Figure 10). This 
reduced a homeostatic measure of insulin resistance by 37% (Figure 11). 

Another insight provided by the study was that exercising for 2 hours at moderate 
intensity before the meals aggravated carbohydrate intolerance rather than reducing 
plasma glucose as exercise is expected to do (Figure 12). 

The study provides helpful information that a simple dietary intervention consist-
ing of a decrease in dietary carbohydrate and increase in healthy dietary fat and protein 
could restrain hyperinsulinemia that may drive fat synthesis in WAT and ectopic sites. 
Also, that exercise before the meals, but not after the meals (Heden et al., 2015), exac-
erbates postprandial glucose intolerance.



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Figure 10. Reduction in postprandial insulin responses after the third low-carbohydrate 
meal in either (a) sedentary (LCS) or (b) exercise trials (LCX) but not in, respectively, 
high-carbohydrate sedentary (HCS) or exercise (HCX) trials. From Lin & Borer, 2016.



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Figure 11. Reduction in HOMA-IR measure of insulin resistance after the third low-
carbohydrate meal in either (a) sedentary (LCS) or (b) exercise trials (LCX) but not in, 
respectively, high-carbohydrate sedentary (HCS) or exercise (HCX) trials. From Lin & 
Borer, 2016.

It would be remiss not to emphasize the advantage of combining exercise with the 
recommended caution in selection of quantities and quality of food. This emphasis 
should mitigate the problems of the two already-mentioned weaknesses of physical ac-
tivity in preventing or reversing obesity, its non-homeostatic nature, and its low power 
to overcome the ease of ingesting palatable food calories. The benefits of exercise are 
so impressive that since at least 2009 (Salis, 2009), the term “exercise is medicine” has 
been applied to the American College of Sports Medicine position stand on the benefits 
of exercise (Garber et al., 2011) and to the standing category of scientific presenta-
tions at the annual meeting of the American College of Sports Medicine. These sources 
document strong scientific evidence that regular exercise contributes to primary and 
secondary prevention of diabetes, hypertension, cancer (particularly breast and colon 
cancer), depression, osteoporosis and dementia, and while it is not very effective in 
weight loss, it helps maintain healthy body weight, and reduces all-cause mortality. 
Furthermore, it benefits human health regardless of ethnicity or age. Finally, exercise 
also assists weight control through temporary suppression of hunger (King, Burley & 
Blundell, 1994).



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Figure 12. Exacerbation of postprandial glucose intolerance in exercise trials (bot-
tom) but not in sedentary trials (top) after the third low-carbohydrate as well as high-
carbohydrate meals high-carbohydrate meals. From Lin & Borer, 2016. 



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DISCUSSION

The reviewed data were selected to help formulate some inferences, and provide 
guidance, regarding behavioral prevention, reversal, or mitigation of obesity and its 
associated morbidities. Prevention of obesity should entail the awareness that humans 
are unable to track calories eaten or calories expended in exercise, elaborated in the 
second section on The Physiological Features that Facilitate Overeating. This fact and 
the evidence for the powerful motivational draw to eat palatable food, discussed in the 
same section, should provide a cautionary note to individuals with healthy weight to 
exercise vigilance and restraint about quantities of food eaten and monitor and respond 
to their gastrointestinal signals of fullness. Preferential selection of naturally nutritious 
food rather than “fast food” that is commercially manipulated for maximal palatability 
should help counteract our innate motivation to seek palatability. Selecting a diet that 
is rich in healthy fats and protein and avoiding over-indulging in high-carbohydrate 
diet should control postprandial insulin response and the property of the high circulat-
ing concentrations of this hormone to engage in excessive energy storage. Conscious 
avoidance of long sedentary periods and introducing opportunities for physical work 
should, along with prudent eating pattern, help establish a stable and healthy body 
weight level. 

Reversal of obesity presents a more formidable challenge. Three powerful obstacles 
to maintenance of weight loss include physiological defense responses to any weight 
reduction, be it from obese level or a healthy level. The first one is a persistent reduction 
in resting metabolism, the second is increased hunger, and the third is heightened ef-
ficiency of energy storage. For this reason, most of the deliberately lost weight through 
food restriction, with or without additional exercise, is regained in the matter or months 
or years (Wing et al., 2016, Figure 13). 

The effect of deliberate weight loss on resting metabolic rate (RMR) was studied by 
Kevin Hall in individuals responding to the challenge of large weight losses seeking to 
win “The Biggest Loser” televised competition and compared to weight loss produced 
by Roux-en-Y gastric bypass surgery (Knuth et al., 2014). Both approaches produced 
between 40 and 49 kg weight loss with a smaller lean body mass loss in the television 
competition (16%) than in gastric-surgery patients (30%). However, in both groups, 
the reduction in RMR (characterized as the metabolic adaptation) was similarly pro-
portional to, and associated with, a reduction in plasma leptin (Knuth et al., 2016). This 
metabolic adaptation in the form of reduced metabolic rate occurs in response to nega-
tive energy balance caused either by fasting or by energy expenditure of exercise. It is 
currently viewed as an evolutionary defense response against deviations in total daily 
energy expenditure (Pontzer, 2015). In this view, higher energy expenditure due to in-
creased body mass is sustained with high energy intake, but any reduction in intake and 
exercise energy expenditure is compensated by a reduction in resting metabolism. This 
therefore means that once the increased body mass is acquired, attempts to reduce its 
lipid component will trigger downward adjustments in RMR. It also appears that a lack 
of change in gastro-intestinal scaling during weight loss does not affect the outcome, as 

https://www-ncbi-nlm-nih-gov.proxy.lib.umich.edu/pubmed/?term=Wing%20RR%5BAuthor%5D&cauthor=true&cauthor_uid=27271190


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voluntary-effort and gastrectomy weight losers displayed similar metabolic adaptation 
(Knuth et al., 2014; 2016). While this metabolic adaptation was shown to persist for up 
to 30 weeks post weight loss, it is not yet known whether moderate food restriction and 
at least 1 hour of exercise that are practiced by successful weight-loss maintainers (Mc-
Guire, Wing, Klem, Seagle, & Hill, 1998) can, over much longer periods of time, lead 
to reduced total energy expenditure setpoint through proportional reductions in all com-
ponents of body mass, as well as in gastrointestinal remodeling. This is suggested by 
a study in which an individual totally abstained from eating for 382 days and lost 125 
kg or 60.4% of initial weight. Five years after returning to ad-libitum eating, his weight 
increased to only 89 kg from the post-fasting level of 82 kg (Stewart & Fleming, 1973).

The other two variables that interfere with weight-loss maintenance and promote 
weight regain are a significant increase in insulin sensitivity as a result of weight loss 
which powerfully drives fat and glycogen re-synthesis and blocks triglyceride break-
down, and reduction of fasted plasma leptin to very low concentration (Figure 1). As 
most of leptin is released from the subcutaneous WAT, its role in weight-reduced state is 
to reduce satiation and increase hunger. This was demonstrated in powerful suppression 
of hunger by leptin administration to individuals who were experimentally undergo-
ing a 10% weight loss (Rosenbaum & Leibel, 2014) and in persons with genetic in-
ability to produce leptin in whom hormone administration suppressed both the hunger 
and reduced obesity (Farooqi & O’Rahilly, 2014). The appetite-suppressing effects of 
increases in basal leptin act on the previously-mentioned brain substrates of reward 
(Berridge, 2009). 

Figure 13. Patterns of weight loss and regain as percent difference from the start dur-
ing 4 years of an intensive lifestyle diet-and-exercise intervention in the Look AHEAD 
Clinical Trial. From  Wing et al., 2016.



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While there are no highly effective behavioral strategies for rapid weight loss, it 
is possible to sustain weight loss through deliberate control over the quantity of food 
eaten, daily exercise, and frequent monitoring of the weight balance (McGuire, et al., 
1998). In 750 individuals tracked by the National Weight Control Registry, a 13.5-kg 
weight loss was maintained for about 6 years by eating a low-calorie diet (5,792.3 kJ/d 
and 25% of daily calories from fat) and by engaging in high levels of physical activity 
(11,847.3 kJ/week). 

The strategies for the mitigation of morbidities associated with obesity include re-
ducing the carbohydrate content of the diet to lower postprandial insulinemia and gly-
cemia (Lin & Borer, 2016), exercising shortly after eating a meal (Heden et al, 2015) 
rather than before the meals (Lin & Borer, 2016) because the former reduces postpran-
dial glycemia while the latter exacerbates it. In addition, controlling the quantity of 
food eaten and changes in body weight with daily or at least weekly weighing provides 
helpful feedback for adjustments in energy balance, and engaging in about an hour of 
moderate daily physical activity contributes to a negative energy balance. Increased 
exercise energy expenditure and negative energy balance may, due to reduction in total 
metabolic rate, be responsible for the many health benefits of exercise including lower 
inflammatory responses leading to reduced cardiovascular disease risk, and lower stress 
levels contributing to endocrine and psychological health as a consequence of the re-
duction in non-exercise energy expenditure (Pontzer, 2015).

CONCLUSIONS

The rapid global rise of obesity incurs a heavy personal and healthcare burden due 
to obesity-associated morbidities and shortening of life. We explain the features of 
human physiology that favor fat accretion and interfere with fat loss for the benefit 
of individuals who use this survey of evidence on strategies for prevention, reversal, 
and mitigation of obesity and its sequelae. Obesifying features of human physiology 
include strong motivating properties of palatable food, inability to consciously detect 
calories eaten or expended through exercise, and hormonal and metabolic adaptations 
to negative energy balance that drive weight regain. We also point to the evolutionary 
burdens of high human capacity for fat storage and absence of a compensatory role 
for spontaneous physical exertion in counteracting the weight gain. Adding exercise 
energy expenditure to deliberate control of the quantity of food eaten will reduce the 
incidence of some obesity-linked risk factors that lead to cardiovascular disease despite 
the metabolic adaptation of reduced resting metabolism. Deleterious concomitants of 
obesity can also be mitigated by reducing postprandial hyperinsulinemia, namely by 
lowering the carbohydrate load of the diet and by exercising after, rather than before, 
the meals to facilitate greater glucose tolerance.

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