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Am J Physiol Regul Integr Comp Physiol 301: R581–R600, 2011.

First published June 15, 2011; doi:10.1152/ajpregu.00755.2010. Review

Biology’s response to dieting: the impetus for weight regain


Paul S. MacLean, Audrey Bergouignan, Marc-Andre Cornier, and Matthew R. Jackman
University of Colorado Anschutz Medical Campus, Department of Medicine, Division of Endocrinology, Metabolism,
and Diabetes, Center for Human Nutrition, Denver, Colorado
Submitted 15 November 2010; accepted in final form 8 June 2011

MacLean PS, Bergouignan A, Cornier M, Jackman MR. Biology’s response to


dieting: the impetus for weight regain. Am J Physiol Regul Integr Comp Physiol 301:
R581–R600, 2011. First published June 15, 2011; doi:10.1152/ajpregu.00755.2010.—
Dieting is the most common approach to losing weight for the majority of obese
and overweight individuals. Restricting intake leads to weight loss in the short term,
but, by itself, dieting has a relatively poor success rate for long-term weight
reduction. Most obese people eventually regain the weight they have worked so
hard to lose. Weight regain has emerged as one of the most significant obstacles for
obesity therapeutics, undoubtedly perpetuating the epidemic of excess weight that
now affects more than 60% of U.S. adults. In this review, we summarize the
evidence of biology’s role in the problem of weight regain. Biology’s impact is first
placed in context with other pressures known to affect body weight. Then, the
biological adaptations to an energy-restricted, low-fat diet that are known to occur
in the overweight and obese are reviewed, and an integrative picture of energy
homeostasis after long-term weight reduction and during weight regain is pre-
sented. Finally, a novel model is proposed to explain the persistence of the “energy
depletion” signal during the dynamic metabolic state of weight regain, when
traditional adiposity signals no longer reflect stored energy in the periphery. The
preponderance of evidence would suggest that the biological response to weight
loss involves comprehensive, persistent, and redundant adaptations in energy
homeostasis and that these adaptations underlie the high recidivism rate in obesity
therapeutics. To be successful in the long term, our strategies for preventing weight
regain may need to be just as comprehensive, persistent, and redundant, as the
biological adaptations they are attempting to counter.
energy restriction; diet-induced obesity; obesity prone; weight loss; energy balance

IN THE UNITED STATES, OVER 60% of adults and close to 20% of obese. Because there are unique features of the adaptive response
children are overweight or obese (35, 174). A number of effective with obesity (138, 251, 252), understanding the integrative nature
weight loss strategies are available, but most are only transiently of the response in the obese is pertinent to therapeutic develop-
effective over a period of 3 to 6 mo. Less than 20% of individuals ment. Although homeostatic systems are clearly operational in
that have attempted to lose weight are able to achieve and both lean and obese individuals and, in both, underlie the tendency
maintain a 10% reduction over a year (128). Over one-third of lost for lost weight to be regained, the central and peripheral adapta-
weight tends to return within the first year, and the majority is tions involved in weight recovery can differ with one’s starting
gained back within 3 to 5 years (3, 246). A number of reasons weight. These differences may provide insight as to what com-
have been proposed for the high incidence of weight regain (69, ponents of the homeostatic system would be most effectively
246), and several point to the biological response to weight loss. targeted in those who have the most difficulty controlling their
The objective of this review is to examine the role of this weight. To this end, we examined weight loss studies in clinically
biological response in the process of weight regain. Biological overweight and obese adults, in diet-induced, polygenic animal
regulation is first discussed in relation to other nonbiological models of obesity, and with dietary (nonsurgical) interventions
pressures that affect body weight as weight is gained, lost, and involving an energy-restricted, low-fat diet. We would assert that,
regained. The specific biological adaptations to the most common in contrast to its subtle, permissive role in the development of
form of dieting, an energy-restricted low-fat diet, are then dis- obesity, biology has a more prominent, causal role in weight
cussed in more detail. Previous reviews provide extensive descrip- regain after energy-restricted weight loss. Countering this meta-
tions of the normal adaptive response to energy restriction. We do bolic drive to regain lost weight may be the most significant
not attempt to recapitulate those efforts here. Rather, the unique challenge for obesity therapeutics in the coming decades.
perspective of this review summarizes those adaptations that have
been confirmed or specifically observed in the overweight or Our Biology in the Context of Other Pressures
Affecting Body Weight
Address for reprint requests and other correspondence: P. S. MacLean,
Univ. of Colorado Denver, Center for Human Nutrition, Mailstop F8305,
Body weight is affected by biological, environmental, and
Research Complex I North, Rm. 5108, 12800 East 19th Ave., Aurora, CO behavioral pressures, all of which are inherently influenced by
80045 (e-mail: paul.maclean@ucdenver.edu). genetics (Fig. 1). These pressures interact with one another,
http://www.ajpregu.org 0363-6119/11 Copyright © 2011 the American Physiological Society R581
Review
R582 BIOLOGICAL RESPONSE TO DIETING

Over the past 50 years, our environment has become more


obesogenic, favoring behavioral choices that increase the in-
take of energy in excess of energy requirements (99). When an
individual is subjected to these pressures, stored energy accu-
mulates, and metabolism gradually adapts to prevent perpetual
weight gain (Fig. 2B). At some point, for most people, these
biological adaptations reestablish a balance with the obeso-
Fig. 1. Pressures affecting the steady-state weight. The three pressures, all genic pressures, and a new, albeit higher, steady-state weight is
influenced by the underlying genetic disposition, interact with one another, achieved (Fig. 2C).
culminate in a steady state weight at which the body resides. Changing any one In rodents, the variability in this metabolic defense against
of these pressures can alter this steady state weight.
perpetual weight gain when challenged with similar obeso-
genic pressures (high-fat, high-carbohydrate feeding; limited
physical activity) is what separates the obesity-resistant (OR)
and their integrated effect establishes a “steady state” weight in
from the obesity-prone (OP) (140). Both initially experience a
adults. Humans exhibit a broad weight range, because of the
positive energy imbalance, but the OR sense the nutrient
variability in each of these pressures and the genetic diversity
overload, increase fat oxidation, elevate expended energy, and
that underlies them. Changing any one of these pressures can
alter the steady-state weight. To appreciate the biological reestablish energy balance (106, 107). OP rodents, on the other
influence, it is helpful to conceptualize how the homeostatic hand, continue to eat to excess until expenditure increases from
system changes with respect to these other pressures during the their accumulated mass to reestablish energy balance. This
development of obesity, during weight loss, and during weight polygenic predisposition for biology to respond (OR), or not
regain. For this purpose, we use a steady-state weight graph respond (OP), to obesogenic pressures leads to the diet-induced
linked to an energy balance (Fig. 2A). The three pressures that obese (DIO) and the diet resistance (DR) phenotypes. The
affect body weight are positioned atop the balance, and the DIO/DR model is reflective of the human condition from the
fulcrum of the balance represents the underlying genetic dis- perspective that some people become obese and others do not,
position. Moving the pressures to either side of the fulcrum tips when obesogenic pressures appear to be similar. In the graphic
the balance toward weight gain (to the left) or weight loss (to representation, a polygenic predisposition for obesity would be
the right). The biological component (homeostatic pressures) is akin to the fulcrum shifting right of center. If sufficiently extreme,
responsible for reestablishing a balance when the environmen- the genetic disposition could make it practically impossible for
tal or behavioral pressures change, preventing the organism homeostatic counter-regulatory measures to reestablish a new
from wasting away or from gaining weight indefinitely. steady state. Weight would continue to creep up.

Fig. 2. Biology’s influence during obesity development, treatment, and relapse. Homeostatic systems adapt to prevent perpetual weight loss or gain when
environmental and behavioral pressures change. The interplay of this balance between the changes in nonhomeostatic pressures and homeostatic adaptations is
shown for the initial development and progression of obesity (A–C), during energy-restricted weight loss (D), during weight maintenance after weight loss (E),
and during the relapse to obesity (F). Biology may play a more subtle, permissive role during the initial development of obesity, but it becomes a driving force
for weight regain after weight loss.

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BIOLOGICAL RESPONSE TO DIETING R583
This upward drift in weight (Fig. 2C) is observed in some restricted, and the response, in general, promotes a positive
DIO models. The drift occurs with some permanence in the energy imbalance, the replenishment of energy stores, and an
homeostatic system, continually retuning it to target the newly increase in nutrient availability. Numerous components of the
achieved level of adiposity (138, 139, 148, 149). There is little homeostatic system contribute to this normal physiological
evidence to suggest that circumstances would be any different response. The various components are inherently linked, and
for humans, when immersed in an environment with readily the integrated adaptations work in concert. Obesity imposes
available foods high in fat and simple sugars and permissive to additional adjustments in energy homeostasis, which make
physically inactivity. Both OP-like and OR-like responses some aspects of this adaptive response distinctly different
would emerge. Adding highly palatable and rewarding com- (138, 251, 252). For this reason, we limit this summary of
ponents to the diet recruits hedonic systems in the brain to eat the homeostatic adaptations to those that have been ob-
even more, further challenging homeostatic systems to adapt served in the overweight or obese humans, as well as in DIO
and reestablish a steady state (136, 139). Although some models of the human condition, in response to an energy-
weight loss can occur by returning to a lower-energy diet that restricted, low-fat diet.
is less palatable, satisfactory amounts of weight loss usually do
not occur without intentionally restricting energy intake. Adipose Signals: Low Reserves and an Empty Fuel Tank
The most common diet is the restricted consumption of
low-fat foods, which is sometimes, but not always, accompa- Adiposity signals do not remain proportional to fat mass
nied by regular exercise. In our graphic model, these dramatic when it is changing. Two hallmarks of energy-restricted weight
changes in environmental and behavioral pressures initially loss in obese and overweight individuals are a decline in
work in concert with the biological adaptations to induce fasting leptin and insulin (Table 1). Leptin and insulin have
weight loss (Fig. 2D). However, the homeostatic system im- been termed “adiposity signals,” because their levels generally
mediately begins to adapt to prevent the individual from reflect fat mass, and they convey this signal of peripheral
wasting away. At some point, a balance is achieved at a lower, energy storage to the brain when energy balance is maintained
steady state weight, and the individual hits the well-known (16, 19). Reduced leptin levels are more intuitive, as leptin is
“wall” or plateau in their weight loss efforts. To lose more secreted from adipose tissue. Lower insulin levels can be
weight, the environmental and behavioral strategies must be explained by improved insulin sensitivity (109, 124, 142, 158)
stepped up a notch. To maintain the reduced weight, these and a reduced fasting and postprandial response in glucose-
weight loss strategies must be maintained indefinitely (Fig. dependent insulinotropic polypeptide (121, 238). The low
2E), as the homeostatic system does not appear to “reset” at levels of leptin and insulin levels have been traditionally
this lower weight, at least in DIO rodents, even with long-term thought to convey a message of “depleted energy” stores to key
weight reduction (149). Unfortunately, most people view their regulatory areas in the brain (Fig. 3A). As our understanding of
weight loss program as a transient change in their lifestyle and these hormones has increased, the role of these hormones in the
dietary habits or have difficulty in sustaining the changes that homeostatic response to weight reduction has become more
they have made to lose the weight (52, 69). If the strategies are complex.
not maintained, the biological adaptations become a driving Recent studies have revealed that leptin, and perhaps insulin,
force for weight regain (Fig. 2F). reflects both the amount of adipose tissue and the size of the
Two critical points emerge from this graphical description of constituent adipocytes (6). Smaller adipocytes secrete less
the interplay between these pressures affecting body weight. leptin and result in lower circulating levels for a given fat mass.
Initially, our biology, or this homeostatic system, is actually Smaller adipocytes are also more insulin sensitive (25, 146),
working for us in an attempt to minimize the impact of which presumably means they require lower circulating levels
obesogenic environmental and behavioral pressures, although of insulin to impart the same metabolic control. Energy-
with better results in OR than in OP individuals. Second, restricted weight loss in the obese reduces cell size, not number
because of the upward retuning of the homeostatic system, at (91, 148, 151, 160, 184). While total mass declines, the
least for those prone to obesity, metabolic conditions after maximal capacity to store energy (the projected mass if all
weight loss may not be the same as they were prior to gaining adipocytes were filled to capacity) remains the same. The
the weight in the first place. Instead of working in our favor to decline in total fat mass and the reduced percentage of total
prevent weight gain, biology becomes one of the driving capacity that is filled would compound the reduction in insulin
pressures that underlie weight regain. and leptin. Consistent with this assertion, a number of studies
have observed that leptin and insulin are reduced to a greater
Adaptations in Homeostatic Control extent than would be expected for the amount of fat mass that
is lost after weight is stabilized (110, 140, 145, 148, 196). The
A complex picture of the biological system controlling body integrated adipose signal conveyed to the brain and peripheral
weight regulation has emerged over the last several decades. In tissues is, therefore, that energy reserves are low and the fuel
its simplest version, it is dominated by a feedback loop be- tank is far from full (Fig. 3A).
tween the brain and periphery. The brain receives signals from To make the role of leptin and insulin more complex, they
the periphery regarding energy stores (long term) and nutrient reflect adipose stores only when subjects are in energy balance.
availability (short term), and on the basis of these integrated When an imbalance occurs, leptin and insulin reflect the
signals, adjusts energy balance to meet both the long-term metabolic state (anabolic or catabolic) of adipose tissue, as it
storage and short-term nutrient status objectives of energy deposits or mobilizes energy. When weight is forcefully per-
homeostasis. This feedback system adapts when energy intake turbed by overfeeding, leptin and insulin are predictably ele-
is cognitively (in humans) or forcefully (in animal models) vated as weight is gained (85). However, when again allowed

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R584 BIOLOGICAL RESPONSE TO DIETING

Listed studies reflect observations in overweight and obese humans during weight maintenance after energy restricted weight loss. *Visual Analog Scale, corresponding to hunger, desire to eat, or prospective
to eat ad libitum, both leptin and insulin resolve much faster

(40, 42, 59, 61, 63, 84, 95, 117,


than when the excess weight is lost. The same has been

(18, 50, 82, 133, 142, 153)


observed with energy-restricted weight loss. Leptin is lower
No effect observed

during weight loss than it is once weight is stabilized at the


reduced weight (196), and a single day of overfeeding leads to

(18, 53, 109, 193)

(2, 153, 166, 219)


187, 233, 238)
the complete resolution of insulin and ⬃80% of the reduction

(164, 175, 233)


(143, 155, 164)

(18, 51, 142)


in leptin in postobese rats (Fig. 4). Given that it takes several
(2, 94, 95)

(129, 175)
(42, 233) weeks of overfeeding for lost weight to return in this model,
leptin and insulin, by themselves, do not appear to sustain the
Table 1. Effects of weight loss on adipose signals, appetite sensations, and signals of nutrient availability in obese and overweight humans

signal of energy depletion as the weight is regained.


These observations, however, should not discount a role for
low leptin and insulin in weight regain. Overfeeding with diets
(42, 48, 171, 188, 193, 238)

(1, 42, 48, 109, 204, 238)


(1, 42, 48, 133, 153, 166,
higher in fat significantly blunts the resolution of insulin (Fig.

(48, 109, 153, 187, 213)


171, 188, 219, 238)
4A), even though these animals experience an energy imbal-
Meal/day Long/Glucose Load

ance 50 to 100% higher (Fig. 4B). Other factors may also be


potentiating the conveyance or reception of their energy de-
+

pletion signal as relapse progresses. Furthermore, postobese


(71, 233)

humans rarely gorge themselves continually back to obesity,


(1, 2)

like our animal models. Intermittent periods of weight stability,


(42)

in between bouts of overfeeding, may allow these signals to


normalize and reassert their influence as descriptors of energy
stores under energy balance conditions. Therefore, the decline
(61, 117)

(51, 164)

(95, 121)

of these adipose signals represent significant adaptations that


*

(238)

contribute to weight regain (Fig. 3A), but their impact during


sustained periods of overfeeding is somewhat in question (Fig.
3B). Later in this review, we present a novel alternative for
(18, 34, 50, 51, 53, 54, 95, 97, 100, 109, 117, 133,

(1, 48, 54, 117, 133, 171, 175, 201, 219, 221, 238)

food consumption. **Visual Analog Scale, corresponding to satiety, feeling of fullness, or satisfaction with appetite.

how this energy depletion signal is conveyed during the dy-


(18, 34, 50, 51, 94, 95, 97, 117, 142, 152, 153,

namic metabolic state of weight regain.


(34, 38, 48, 53, 95, 100, 171, 181, 219, 221)

Drive to Regain in the Brain


The two areas of the brain that are traditionally considered
142, 153, 175, 196, 201, 238)

the homeostatic regions controlling weight are the hypothala-


+

mus (22, 113) and the hindbrain (249). Here, we do not attempt
to review in detail every region of these and other areas of the
196, 201, 221, 228)

(34, 142, 221, 238)

brain that are involved in weight regulation nor describe every


(18, 71, 142, 180)

aspect of the normal response to calorie restriction. Rather, we


PreMeal/Fasting

summarize aspects of the adaptive response and their conse-


quences that have been confirmed or observed to be different in
(4, 53)

overweight and obese subjects in response to an energy-


(18)
(18)

restricted, low-fat diet.


The hypothalamus: converging peripheral signals of energy
depletion. The arcuate nucleus (ARC) of the hypothalamus
(4, 40, 53, 59, 61, 63, 84, 95, 238)

undergoes wholesale changes in neuronal activity and neuro-


peptide expression in response to an energy deficit (202),
integrating numerous signals from the periphery as it develops
(94, 95, 163, 164, 254)

the overall picture of energy depletion. Key aspects of this


general response persist after long-term weight reduction from
*

an obese state, including increased expression of ARC neuro-


peptide Y (NPY) (24, 137, 168, 248, 251) and Agouti-related
peptide (AgRP) (168, 251), as well as decreased expression of
proopiomelanocortin (POMC) (137). Concomitant elevations
in the firing of NPY/AgRP neurons and reductions in the firing
rate of POMC neurons would be expected with this gene
expression profile. These changes are the hypothalamic hall-
Hunger/satiety signals

Circulating nutrients
Appetite sensations

mark of an “anabolic” state, which would lead to a positive


Adipose signals

energy imbalance and weight gain (Fig. 3A).


The ARC projects this signal of energy depletion to other areas
Satiety**
Hunger*

Glucose
Ghrelin
Insulin

GLP-1

of the hypothalamus. In DIO models, first-order projections to the


Leptin

CCK
PYY

FFA
TG

paraventricular nucleus (PVN) reduce the expression of cortico-


trophin-releasing hormone (137). Other projections impart modest

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BIOLOGICAL RESPONSE TO DIETING R585
changes in neural peptide profiles in the lateral hypothalamus the reduced-obese human exhibits neural imaging responses to
(168, 252), which interfaces with the cortico-limbic system. Still food-related stimuli that would favor increased motivation and
other projections extend into the ventromedial hypothalamus drive to eat (46, 197), and many of these responses resolve with
(VMH), known for its high density of nutrient (glucose, fatty leptin therapy (197). However, it is important to recognize that
acids) sensing neurons (218). DIO rodents exhibit fewer glu- communication between the hypothalamus and these nonho-
cose-sensing neurons in the VMH (218) and lower VMH meostatic areas occurs in both directions. These areas may
brain-derived neurotrophic factor expression (253). Neither receive peripheral signals of energy depletion or impose hedo-
VMH-associated abnormality resolves after weight loss in DIO nic control to affect how homeostatic centers receive and
models, and their influence on weight gain may reemerge after integrate peripheral signals of energy depletion and nutrient
weight loss, as other homeostatic circuits adapt to weight loss status. Given the importance of cognitive and reward-based
(135, 253). While the interaction between the ARC and the eating behaviors in humans (26, 47, 134), their role in the
dorsomedial nucleus (DMN) of the hypothalamus is not clearly adaptive response to weight loss will continue to be studied.
understood (24, 123), DMN NPY expression is higher (137) Neuroendocrine signals: enhancing efficiency of fuel utili-
and DMN cocaine- and amphetamine-regulated transcript ex- zation and storage. The energy depletion signal, via the PVN
pression is lower (252), after weight loss from obesity. Other in some cases, results in a number of neuroendocrine adapta-
components of homeostatic body weight regulation in the tions that ultimately target peripheral tissues (Fig. 3A). Energy-
hypothalamus may indeed be changed after energy-restricted restricted weight loss from obesity is accompanied by a re-
weight loss, but they have yet to be reported in DIO models of duced sympathetic (SNS) tone (7, 110, 138, 191, 193, 221),
obesity. reduced thyroid hormone levels (127, 193, 205, 228), and
While confirmation of these hypothalamic adaptive re- increased activity of the hypothalamic-pituitary-adrenal (HPA)
sponses in obese humans is difficult to come by, a plethora of axis (59, 157, 227, 228). In contrast to the effects on SNS, the
indirect and genetic evidence would suggest that the hypothal- effects on thyroid hormones and the HPA axis are observed
amus is inherently involved in the human response to energy
less consistently and/or are more transiently tied to the early
deficit (202). In addition, functional magnetic resonance imag-
stages of weight loss (103, 228, 245). Collectively, the neu-
ing (fMRI) studies have reported altered neural activity in the
roendocrine changes that occur with weight loss target periph-
hypothalamus in postobese humans, which is normalized after
eral tissues that use and store energy, increasing efficiency to
3 wk of leptin replacement therapy (194). For these reasons,
conserve energy and readying them for energy repletion (Fig.
the hypothalamus remains a critical node for integrating and
processing the homeostatic signal of peripheral energy deple- 3A). In postobese humans, leptin therapy normalizes some of
tion (Fig. 3A). However, we have yet to understand whether these neuroendocrine responses to weight loss (191). However,
these same adaptive responses are sustained during the dy- more studies are needed to understand the impact of these
namic state of weight regain (Fig. 3B). signals on energy deposition and storage during weight regain
The hindbrain: reduced sensitivity to satiety signals. The (Fig. 3B).
energy depletion signal from the hypothalamus likely translates
into a reduced sensitivity to satiety signals, increased meal size, The Energy Gap: Promoting a Positive Energy Imbalance
and higher food intake (Fig. 3A). The nucleus of the solitary
An elevated appetite. One of the primary outcomes from the
tract and area postrema are among the areas in the hindbrain
neural adaptations to energy-restricted weight loss in obese
that receive input via gut-derived CCK and vagal afferent
individuals is an elevated appetite (Fig. 3, A and B). This is
signals. Monogenic obese rats that lack the leptin receptor are
less responsive to CCK-induced meal size reduction, and the more often detected in premeal or postabsorptive appetite
effects of CCK are partially restored when hypothalamic leptin sensations related to hunger, desire to eat, and prospective food
receptors are generated via adenoviral gene delivery (167). consumption, but it has also been observed in postprandial and
Prior to the development of obesity, the hindbrain of OP rats day-long assessments of these measures (Table 1). Measures of
may be less sensitive to peripheral satiety signals (39, 223). hunger predict future weight regain in weight-reduced individ-
Whether this characteristic reemerges after weight loss to uals (177). Surprisingly, an effect of energy-restricted weight
facilitate weight regain needs to be studied. Evidence from loss on measures of satiety and satiation has rarely been
human fMRI studies does show weight-reduced subjects have observed (Table 1). This presents, to some extent, a disconnect
altered neural activity in the brain stem (197), but, unlike other between basic and clinical scientific communities. Studies in
neural responses to weight reduction, this does not normalize genetically manipulated animals have emphasized the impor-
with leptin therapy. Taken together, the sensitivity of the brain tance of satiety and satiation in energy homeostasis, but hunger
to gut-derived signals appears to be depressed in the obese and meal initiation appear to be more important in humans and
(31), but the improved sensitivity after weight loss and during often involve nonhomeostatic cues or motivations. Some of
weight regain needs to be confirmed in DIO models of obesity this discrepancy may be due to the difficulty in making a clear
(Fig. 3, A and B). distinction between hunger and satiety in laboratory animals.
Integration of homeostatic and nonhomeostatic adaptations. In contrast to the food questionnaires used to gauge hunger in
A host of neural projections, both to and from the hypothala- humans prior to a meal, animal studies often simply measure
mus, establishes a complex network of cross talk that integrates how much food is eaten when food is made available. The
the homeostatic system with other regions of the brain that are overeating that occurs may result from increased hunger and/or
more traditionally considered “nonhomeostatic” (22). The ef- a delay of (or a modification of) satiation. However, the more
fect of weight loss on these neural networks is beginning to substantial difference between human and animal studies are
emerge in DIO models (253). In these hedonic-cognitive areas, the nonbiological pressures affecting body weight (Fig. 1),

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R586 BIOLOGICAL RESPONSE TO DIETING

which can work with or against the biologically driven appetite satiety (89). Those who actively seek out weight loss, and thus
(Fig. 2). more likely to enter a weight loss study, exhibit more re-
Humans are motivated by psychosocial pressures, with vary- strained eating behavior (27). Moreover, individuals who do
ing degrees of success, to keep weight off. The characteristics lose weight exhibit increased cognitive restraint, lower disin-
of cognitive restraint, disinhibition, and susceptibility to hun- hibition, and lower susceptibility to hunger (2, 40, 42, 76, 114,
ger, can affect energy intake (186) and measures of hunger and 179, 247). These cognition-driven eating behaviors undoubt-

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BIOLOGICAL RESPONSE TO DIETING R587
edly lead to variability in the assessment of biology’s overall What is often overlooked because of the aforementioned
impact and may explain why humans often exhibit different confusion is the most fundamental adaptation and its implica-
patterns of hyperphagia during postobese weight regain (240). tions: total energy expenditure declines (Fig. 3, A and B). This
It would be a mistake, however, to discount biology’s influence adaptation to weight loss has been shown in numerous studies
because the presence of these psychosocial pressures makes it of overweight and obese humans (8, 60, 62, 131, 132, 159, 189,
difficult to measure. 192, 196, 242–244) and in polygenic models of obesity (45,
The picture of biology is much clearer in postobese DIO 65– 67, 148 –151, 199), and every component of energy expen-
rodents, which are not subject to the same complex psychosocial diture is affected to some extent (Fig. 5). The mechanisms are
influences and environmental variability. Driven mostly by their linked to both the loss of body mass and enhanced metabolic
biological urges, these models consistently show that appetite efficiency.
increases such that they want to eat well in excess of what The lower body mass contributes to the decline in expended
they were eating before they lost weight (17, 65, 104, energy in three ways. First, there is often less lean mass
137–139, 148, 151), an effect on appetite that persists until contributing to the basal tissue maintenance costs of the or-
the lost weight is regained. An increase in meal size, rather ganism. This manifests in a reduced basal metabolic rate
than number, is involved in the development of the DIO (resting energy expenditure, REE), reported for both obese
phenotype (73) and in the hyperphagia following energy humans (8, 60, 70, 77, 78, 80, 102, 132, 159, 189, 192, 196,
restriction in normal weight animals (55). We suspect the 234, 245) and obese animals (45, 66, 149 –151) after energy-
same will be reported in the DIO during weight regain. restricted weight loss. Second, less total mass must be moved
Suppressed energy expenditure. The significance of the during physical activity, so the same activity will be less
adaptive response in energy expenditure has been less appre- energetically expensive. If activity levels are the same, this is
ciated and somewhat confounded by the lack of consensus on observed as a decline in the nonresting component of energy
how to normalize and interpret data. The confounding issues expenditure (NREE), which has also been consistently reported
include: 1) the methods used to adjust for the loss of tissue that after weight loss (66, 132, 191, 192, 196, 242–244). Finally,
contributes to basal energy requirements; and 2) what body the loss in fat mass reduces energy expenditure, primarily by
compartments (fat mass, lean mass, both) should be used as the altering metabolic efficiency via its role in homeostatic regu-
estimated amount of tissue that contributes to basal energy lation (i.e., reduced leptin, insulin) (112).
requirements. The recent emergence in preclinical research This regulatory effect on efficiency affects both basal me-
communities of regression analysis for normalization (5, 33, tabolism and the energy expended during physical activity. The
112, 149) may help to resolve the first issue. Although this majority of studies show that a portion of the decline in REE
approach has been the general standard in clinical research for remains significant after adjusting for the loss in lean mass (8,
some time, its application in animal research has been rela- 45, 60, 65, 66, 70, 102, 132, 149, 150, 234). The enhanced
tively rare. On the other hand, clinical researchers continue to work efficiency during physical activity impacts both nonex-
include fat mass in their regression models to correct for the ercise and exercise activity thermogenesis (66, 198), at least
decline in basal tissue energy requirements when studying with activity at lower levels of intensity. These effects ulti-
metabolic efficiency. The recent work of Kaiyala et al. (112) mately reduce NREE, when activity levels are the same. Leptin
provides strong evidence that the primary impact of fat mass on therapy reverses these adaptive responses in postobese humans
energy expenditure is not in its contribution to the basal energy (191, 195).
requirements for tissue maintenance, but instead regulatory in A more fundamental biological adaptation may occur to
nature, as a node in the homeostatic feedback loop controlling reduce NREE by simply reducing the amount of activity. In
body weight. These recent developments should bring both stark contrast to most rodents (202), DIO rats that have lost
research communities together and move this field toward a weight lower their volitional wheel running (137) and exhibit
unified gold standard for the presentation and interpretation of reduced compliance to daily treadmill exercise during weight
metabolic data (147). regain (151). These observations suggest a reduced biological

Fig. 3. Homeostatic adaptations to an energy-restricted, low-fat diet. A: adaptations in the homeostatic system that are observed during weight maintenance, while
in energy balance, are summarized. Neuroendocrine signals from the periphery (green arrows) convey a message of energy depletion (low leptin and insulin)
and low nutrient availability (favoring signals of hunger over satiety/satiation) to the brain. Trafficking of absorbed nutrients (glucose, Glu; free fatty acids, FFA;
triglycerides, TGs) to and from circulation is shown for both postprandial and postabsorptive metabolic states (blue arrows). Enhanced nutrient clearance reduces
postprandial excursions in Glu and TGs and potentiates the postprandial suppression of FFAs, which may also convey a signal of nutrient deprivation to the brain.
The signals of energy depletion and nutrient deprivation create an “anabolic” neural profile in the hypothalamus and hindbrain, increasing appetite (solid black
arrows) and sending efferent signals to enhance metabolic efficiency in peripheral tissues (purple arrows). Both the reduced metabolic mass and enhanced
metabolic efficiency reduce expended energy (dotted black lines). A large energy gap is created between appetite and expenditure, and food intake must be
cognitively (in humans) or forcefully (in animals) restricted to maintain the reduced weight. B: when overfeeding occurs, a persistent postprandial state is created
and the traditional signals of energy depletion resolve. Glu becomes the primary fuel for energy production, and the rate of clearance of all nutrients is maximized.
This enhanced rate of nutrient clearance may be potentiated in some cases by the formation of very small adipocytes. Glu and TG levels in circulation become
a function of the high rate of absorption from the gut and the high rate of clearance in peripheral tissues, while FFAs levels in circulation become persistently
suppressed. Little is known about how the neuroendocrine signals of nutrient status, the neural profile of the hypothalamus and hindbrain, and the efferent signals
sent to the periphery change during this dynamic state of weight gain. With more food absorbed and metabolized, the suppressed energy expenditure resolves
to some extent because of an increase in thermic effect of food (TEF). However, the energy gap between appetite and expended energy continues until adipose
depots achieve a cell size frequency distribution profile that was present prior to weight loss. At present, circulating FFAs represent the only known signal that
changes during this dynamic state of weight regain in a manner that would be permissive to continued overfeeding, while having an inverse relationship with
the size of adipocytes in peripheral depots.

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R588 BIOLOGICAL RESPONSE TO DIETING

motivation to be physically active, in postobese individuals is


indeed part of the biological response to weight loss.
Finally, NREE also declines because less food is consumed.
Less food requires less energy for ingestion, absorption, me-
tabolism, and storage, and the consequence is a lower thermic
effect of food after energy-restricted weight loss (159, 243).
Beyond this predictable change related to the amount of food,
however, ingested food can also induce thermogenesis by
increasing sympathetic tone (224). Some studies have reported
that this facultative thermogenesis, particularly with respect to
glucose-induced thermogenesis, declines after energy-re-
stricted weight loss (86, 235), but other studies show the effect
is not sustained with long-term weight reduction (132, 235).
Regardless, the adaptations, if any, that do persist may be
inherently linked to the same mechanisms that underlie en-
hanced metabolic efficiency at rest and during exercise.
In summary, the reduction in mass and ingested energy, the
enhanced metabolic efficiency, and any decline in activity
levels, all contribute to lower expended energy (Fig. 3A).
Studies in rodents have shown that this hypometabolic state
persists during weight regain (Fig. 3B), normalizing only after
the lost weight returns or, in some cases, the original weight is
surpassed (67, 137, 148). Because much of this effect can be
explained by reduced mass, the relevance of this biological
response in energy expenditure is often discounted. However,
the brain does not reset the appetite to match the lower-energy
requirements of the remaining tissue. The lower-energy re-
quirements, whether from the loss of lean tissue or from
increased efficiency, become a quantifiable burden that must be
overcome in the pursuit to maintain the reduced weight. This
may be why the decline in energy expenditure, similar to the
elevated hunger, is predictive of weight regain (156).
Fig. 4. Effect of dietary fat on the resolution of insulin and leptin and the
The energy gap: biology’s drive to go off a diet. Because
energy gap at the maintenance-relapse transition. A: insulin and leptin, ex- both sides of the energy balance equation are affected after
pressed as a percentage of obese controls, are shown for energy-restricted, weight loss, the biological pressure to gain weight is a conse-
weight-maintained rats before (weight reduced and in energy balance) and quence of both increased appetite and suppressed energy ex-
after the first day of relapse. Data were drawn from three similar DIO rat penditure. We have termed this difference between appetite
weight loss studies of relapse on diets containing 12%, 25%, and 40% kcal fat.
B: energy gap at this transition from weight maintenance to relapse is estimated and expenditure requirements the “energy gap” (108, 148,
from the positive energy balance on the first day of relapse. [Data were adapted
from Am J Physiol Regul Integr Comp Physiol 294: R1117–R1129, 2008 and
two similar ongoing studies with higher levels of dietary fat (n ⫽ 6 –10/
group)]. *Significantly different from 12% kcal fat diet, P ⬍ 0.001.

drive to be physically active, which may be rooted in homeo-


static neural pathways that involve the orexin system (126).
These neuronal pathways are altered in OP rats, and the lower
intrinsic activity levels are thought to contribute to their DIO
phenotype when fed a high-fat diet. It is unclear how the orexin
neurons and their targets are altered in DIO models after
weight loss, but we suspect that at least the preexisting defects
are likely to reemerge. Some clinical studies have shown a
decline in activity during weight loss (241, 242). However,
physical activity and the desire to be physically active, like Fig. 5. Impact of weight loss on the components of total energy expenditure
(TEE). Energy-restricted weight loss impacts every component of energy
appetite sensations, are difficult to directly measure in humans. expenditure. The absolute levels of resting energy expenditure (REE) decline
Similar to nonhomeostatic influences of food intake, humans from a loss of metabolic mass and enhanced metabolic efficiency. Nonresting
are motivated to increase physical activity in their cognitive energy expenditure (NREE) declines, unless the level of physical activity and
pursuit of a lower weight and better health. Success is variable, its associated exercise activity thermogenesis (EAT) are substantially in-
creased. This increase must overcome the decline in the TEF that results from
however, as compliance to exercise prescriptions in combina- lower energy consumption and a decline in nonexercise activity thermogenesis
tion with dieting is notoriously poor (36). Additional studies (NEAT) related to loss in overall mass. Increased energetic efficiency of EAT,
are needed to clarify whether reduced activity, or reduced NEAT, and potentially TEF contribute to the overall decline in NREE.

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BIOLOGICAL RESPONSE TO DIETING R589
149). In humans, it is difficult to quantitatively measure appe- the type of macronutrient restricted in the diet (71, 95). Even
tite in terms of energy equivalents, so accurately estimating the under the same conditions of weight loss and maintenance,
energy gap becomes challenging. In lieu of this difficulty, the there is a wide variability in individual responses with respect
energy gap has also been discussed as the difference between to these adaptations in hunger and satiety signals (18). As such,
pre-weight loss energy requirements and post-weight loss en- these adaptations may be more or less influential, depending
ergy requirements (101). We would suggest this is a conser- upon the genetic disposition and diet composition.
vative estimate of biology’s impact, as animal studies clearly When they do persist into weight maintenance, these altered
show that the energetic equivalent of “appetite” more than signals could potentiate the effects of a brain that may already
surpasses the energy requirements of the obese state. In animal be more sensitive to hunger signals and less sensitive to satiety
models, both components of this energy gap can be directly signals (Fig. 3A). They may also act in the periphery to
measured by assessing energy balance in the weight-reduced indirectly alter food intake, insulin secretion, gastric emptying,
state and during a subsequent day of ad libitum feeding (108, fuel utilization, and energy expenditure (14, 203, 249, 255).
151). Less is known about vagal afferent signals and a large number
During weight maintenance after weight loss, this energy of other humoral factors known to regulate appetite and energy
gap reflects the magnitude of the daily burden that thwarts balance (88, 178), as they have yet to be studied in the obese
cognitive efforts to maintain the reduced weight. Our studies after weight loss or during weight regain (Fig. 3, A and B).
indicate that this energy gap at the maintenance-relapse tran- Changing gut microbiota-emerging implications for nutrient
sition is influenced by diet composition (Fig. 4B), by the length absorption. The effect of obesity on gastric emptying is equiv-
of time in weight maintenance after weight loss (149), and by ocal (98), but some studies show that emptying of solids may
physical activity levels (151). The relative contribution of the be slowed after weight loss (155, 229, 237). Other studies show
adaptations in appetite and expenditure can vary between and little effect of weight loss (105). Regardless, the effect in
even within animal models (92, 93). Regardless of which side humans appears to be transient, such that it does not persist
of the energy balance equation is most affected, the energy gap with long-term weight reduction.
imparts a substantial pressure to eat in excess of the energy More attention in recent years has been directed to gut
requirements. Obese humans may exhibit this same variability microbiota (231). Energy-restricted weight loss results in an
(240), which could explain the common observation of “re- increase in the proportion of Bacteroidetes/Firmicutes bacteria
sponders” and “nonresponders” in clinical studies focused only
in some studies (141, 170) and a diet-dependent reduction of
on one side of the energy balance equation.
butyrate, producing Firmicutes bacteria in others (68). The
Finally, studies in obese humans and rodents suggest that
implications and relevance of these adaptive responses in gut
weight regain reflects a first-order growth curve (3, 148, 151).
microbiota are as yet unclear, but there is evidence that micro-
The rate of gain, and, therefore, the energy gap and the energy
biome alterations like these can affect energy extraction, me-
imbalance it promotes, diminishes during the relapse to obesity
tabolism, and adiposity (10, 11, 169). It remains to be seen
as a function of this first-order relationship. In addition to diet
and physical activity, both the amount of weight lost and the whether the altered gut microflora after energy-restricted
time in weight maintenance may influence this relationship. weight loss contributes weight regain in obese humans, or is
The magnitude of the energy gap is greatest at the nadir weight simply coincidental to changes in diet.
after weight loss (108, 148, 151). Likewise, this energy gap
does not dissipate with time in weight maintenance. Rather, Enhanced Metabolic Flexibility: Improved
studies in DIO models indicate that the magnitude of the Nutrient Clearance
energy gap gradually increases the longer they maintain their
Improved metabolic regulation. Metabolic inflexibility re-
reduced weight with an energy-restricted diet (149). The im-
fers to an organismal impairment in regulation, which mani-
plications from these observations are that the biological pres-
fests as the inability to appropriately shift fuel preference in the
sures may strengthen with time and the amount of lost weight,
face of metabolic challenges, like fasting, exercise, a meal, or
gradually increasing their perceived influence.
overfeeding (119, 120, 220). The inflexible state of metabolism
results from a discordant attempt of numerous peripheral tis-
The Gut: Sensing the Prandial State sues to respond to changing fuel needs and nutrient availabil-
The gut plays a critical role in the homeostatic body weight ity, yielding little or no discernable response. Metabolic inflex-
regulation, as it is the origin of a number of neural, nutrient, ibility is a common characteristic of obesity (119, 220), and
and hormonal responses to ingested energy. These gut-derived energy-restricted weight loss reverses many of its associated
signals of the nutrient status are reviewed in more detail impairments in metabolic regulation (48, 81, 158, 188, 219).
elsewhere (74, 115, 249). In general, if these signals change in Because enhanced metabolic flexibility improves the metabolic
the obese humans in response to energy-restricted weight loss, response to ingested energy, it alters the peripheral signals of
a collective signal favoring hunger over satiety/satiation is nutrient status that are sent to the brain during weight mainte-
observed (Table 1). However, detection of this adaptive re- nance and during weight regain (Fig. 3, A and B). Because lean
sponse is much less consistent than that of circulating adipose subjects do not generally exhibit this global impairment in
signals and nutrients, as they may be dependent on the pres- metabolic regulation, the extent to which an improvement in
ence of a negative energy balance (2, 30, 42, 71, 133), the whole body responses to metabolic challenges, like overfeed-
amount of weight loss (71), the amount of physical activity ing, contributes to the general response to calorie restriction is
(121), the specific derivative of the hormone measured [peptide unclear. For the obese, enhanced metabolic flexibility, like
YY(PYY) vs. PYY3–36; total vs. acetylated ghrelin] (18) or other nodes in homeostatic regulation, may sustain the energy

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R590 BIOLOGICAL RESPONSE TO DIETING

gap by minimizing the negative feedback that these nutrients and during weight regain (108). With every meal, every bout of
and their surrogate signals have. overfeeding, and sustained periods of a positive energy bal-
The normal response to a meal or overfeeding, which in- ance, the suppressive effects of FFAs on the energy gap would
cludes suppressing fat oxidation and increasing carbohydrate be minimized. As such, FFAs represent one signal of nutrient
oxidation when carbohydrates are sufficiently high in the diet, status after energy-restricted weight loss that could sustain a
reemerges after weight loss (12, 23, 108, 149, 150, 187, 211). message of nutrient deprivation during the dynamic metabolic
Dietary fat is preferentially trafficked to adipose and hepatic state of weight regain (Fig. 3B). Later in this review, we
triglyceride stores rather than being used for energy needs. connect this aspect of FFA metabolism to peripheral energy
This enhanced metabolic response to ingested nutrients occurs, repletion and the energy gap.
in part, from an increase in whole body insulin sensitivity (109,
124, 142, 148, 158). While beneficial for metabolic health, the Liver: Restored Function of a Transient Energy Depot
enhanced insulin sensitivity primes the body for rapid, ener-
getically efficient weight gain during chronic overfeeding (148, The nutrients and hormones discussed earlier in this review
230). As long as the weight-reduced subject restricts intake and are known to act directly on the liver (43), and their changes
stays in energy balance, there is little impact of enhanced after weight loss have dramatic effects on hepatic metabolism.
metabolic flexibility on 24-h substrate oxidation (32, 150, 151). Relief from the persistent nutrient overload that accompanies
However, the rapidity and efficiency of nutrient clearance the development and progression of obesity could alone im-
could reasonably hasten the transition to a postabsorptive state, prove metabolic regulation in the liver. However, the decline in
the reemergence of hunger pains, and the persistence of the leptin and insulin is also likely involved, as they support the
energy gap. expression of catabolic and anabolic genes, respectively, in this
When overfeeding occurs, the improved response to in- tissue (29). In addition, an emerging body of evidence suggests
gested energy transitions into a sustained suppression of fat that hepatic metabolism is also subject to hypothalamic regu-
oxidation and the trafficking of dietary fat to adipose tissue lation (20, 83, 165, 182, 183), which needs to be studied in
(108), ensuring the most efficient repletion of adipose stores obesity models after energy-restricted weight loss. While our
(75, 210). The energetic cost of depositing excess dietary fat focus is on the overweight and obese, the majority of the
into triglyceride depots is much less than an equivalent carbo- adaptations in the liver can be extended to energy restriction in
hydrate or protein (⬍2% vs. ⬃25% of the energy excess) general. As obese individuals are less glucose tolerant with a
(209). For protein and carbohydrate, additional energy is re- higher incidence of steatosis than the lean, these adaptive
quired to pay for converting these nutrients into fat via de novo responses may appear to be more dramatic in the overweight
lipogenesis. In DIO models, the preferential deposition of and obese.
dietary fat is observed even in minor bouts of overfeeding, The nutrient, hormonal, and potentially neural changes that
ensuring weight gain occurs at the highest rate and with the occur with weight loss from an obese state result in a global
greatest energetic efficiency (108). This increased rate and reduction in hepatic gene expression (100), and this is accom-
efficiency of weight gain may explain, in part, why weight panied by reduced markers of protein synthesis (214). These
regain is predicted by improved insulin sensitivity (250), an adaptations are indicative of a gross reduction of this tissue’s
enhanced response to a glucose load (28), and the preferential energy requirements, undoubtedly contributing to the reduced
use of carbohydrate for energy production (80). basal energy requirements measured over the whole body (Fig.
Nutrient availability declines. Improved insulin sensitivity is 3A). The liver’s regulation of both carbohydrate and lipid
often accompanied by lower fasting levels of glucose, free fatty metabolism improves within as little as 48 h of an energy
acids (FFAs), and triglycerides (TGs) in circulation (Table 1), deficit (124), and this improvement persists into weight main-
but more consistently yields reduced postprandial excursions tenance (109, 124). Hepatic lipid declines (38, 124, 219),
of glucose and TGs with potentiated postprandial reductions in splanchnic glucose uptake increases (206), and glucose pro-
FFAs (Table 1). These effects are often reflected in lower duction is reduced (124). Secretion of very low density lipo-
fasting levels of these nutrients as well (Table 1). This whole- proteins, ApoB-100 particles in circulation, and hepatic-trig-
sale, consistent change in circulating nutrients undoubtedly lyceride lipase, declines (38, 116). In postobese rodents, the
imparts some homeostatic influence on the signals of nutrient suppression of dietary fat oxidation during the dark cycle
status (Fig. 3A). Levels of glucose are detected by nutrient- (when they feed) is reversed later in the light cycle when their
sensing systems in both the periphery (15, 41, 56, 130, 212) energy balance provision of food is gone (108). The return of
and brain (111, 130), with consequences to energy balance and this diurnal cycle of anabolic and catabolic states reflects the
fuel utilization in the periphery. TGs may even be sensed via restored function of a transient depot for ingested energy,
their putative effects on leptin and insulin transport across the which can facilitate the rapid clearance of nutrients during
blood-brain barrier (13, 108, 232). However, FFAs present the bouts of overfeeding (Fig. 3B).
most intriguing of these nutrients, as their impact on energy Sustained periods of overfeeding lead to the induction of
balance regulation may be most relevant during the dynamic genes associated with de novo lipogenesis, similar to what is
metabolic state of overfeeding. observed in the “catch-up” fat phenomenon in younger animals
FFAs are sensed, just like glucose, in central and peripheral (49). In our postobese rats, de novo lipogenesis is readily
nutrient sensing systems. Dietary fat can impact hypothalamic apparent within 12 h of overfeeding, and a substantial retention
FFA levels (185), and FFAs reduce subsequent food intake of this newly formed fat is observed in the liver after 24 h
when infused into the gut (79, 144), into the circulation (236), (108). Studies in humans suggest that when hepatic regulation
or directly into the brain (44, 173). Unlike glucose and TGs, is intact, as it is after weight loss, chronic overfeeding of a
FFAs in postobese subjects decline postprandially (Table 1) low-fat, high-carbohydrate diet leads to the trafficking of

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BIOLOGICAL RESPONSE TO DIETING R591
glucose to fat depots rather than glycogen pools (161, 162). energy requirements, the increased metabolic efficiency, and
This is consistent with what is observed in postobese rats the enhanced muscle work efficiency observed with energy-
during the early stages of weight regain (108). Once converted restricted weight loss in postobese subjects (192, 198) (Fig.
to fat, this energy cannot be remobilized to support gluco- 3A). These adaptations also limit the body’s capacity to dissi-
homeostatic objectives. The implications are that the transition pate excess fat when overfeeding occurs (Fig. 3B).
to the postabsorptive state would be hastened and the periph-
eral signal of low nutrient availability promoting further over- Adipose Tissue: an Expanding, Empty Fuel Tank, Primed
feeding would be sent sooner. for Filling

Skeletal Muscle: Reduced Energy Requirements and A Like the liver, adipose tissue experiences a global down-
Preference for Carbohydrate regulation of metabolic gene expression in obese subjects in
response to energy-restricted weight loss (34). Unlike the liver,
The same neural, endocrine, and nutrient signals affecting much of this adaptation is reversed at the transition to weight
the liver also reduce the energy requirements of skeletal mus- maintenance, favoring a gene expression profile that would
cle, which has a more substantial impact on daily expended enhance energy conservation during weight maintenance and
energy because of its overall mass. This increased metabolic the repletion of energy stores during meals or periods of
efficiency is a general characteristic of the adaptive response to chronic overfeeding (21, 34, 90, 122, 125, 222, 239). Markers
energy restriction and occurs to some extent in all animals, of oxidative stress and inflammatory cytokines, which are also
regardless of their adiposity level. What may be different for known to suppress appetite and increase expenditure, decline
the obese is the impact on fuel utilization. Like hepatic de novo (104, 122, 176). The impaired induction of lipogenesis by insulin,
lipogenesis, adaptations in skeletal muscle facilitate the clear- glucose, and feeding associated with obesity (57, 58, 64, 162)
ance and dissipation of excess carbohydrate, as glucose be- resolves after energy-restricted weight loss (72, 108, 122, 172,
comes the preferred fuel under postprandial conditions (Fig. 204). The enhanced metabolic response to ingested energy en-
3A). Metabolic regulation improves in skeletal muscle, as hances nutrient clearance during weight maintenance (Fig. 3A)
insulin’s stimulation of glucose uptake and its suppression of and during sustained periods of overfeeding (Fig. 3B).
fat oxidation are enhanced (48, 118, 207, 226). As lean subjects The reduction in average adipocyte size rather than a decline
generally have muscles that are more insulin sensitive and in cell number (91, 148, 151, 160, 184) likely contributes to the
already exhibit this preferential use of fuels in response to improved metabolic regulation in this tissue. Total capacity of
overfeeding, the shift in fuel utilization and its impact on the tissue to store fat remains the same, but stored energy falls
nutrient clearance may be less apparent. For the obese, the well below capacity (Fig. 6A). Regardless of overall adiposity,
improvement in metabolic regulation could have consequences smaller adipocytes, compared with larger adipocytes, are more
during maintenance and regain. When energy balance is main- sensitive to the antilipolytic effects of insulin, exhibit a lower
tained by cognitive (humans) or forced (animals) restriction, basal and catecholamine-induced lipolysis, have a lower rate of
enhanced insulin sensitivity has little effect on 24-h substrate turnover of the stored lipid, and express genes favoring energy
balance or weight gain (32), but the increased clearance rate of storage (25, 146, 222). Reducing the size of adipocytes with
circulating nutrients and lower nutrient availability could help energy-restricted weight loss primes them to take up and store
create the large energy gap between appetite and expenditure excess energy when overfeeding occurs. This would presum-
requirements during weight maintenance (Fig. 3A). When ably contribute to the metabolic drive to regain weight for both
overfeeding occurs, more discernable effects on energy bal- lean and obese subjects.
ance have been observed (108, 151), as the fuel preference of The impact on nutrient clearance may be further exacerbated by
this tissue ensures that carbohydrate loads are rapidly dissi- the formation of new adipocytes (Fig. 6B). Our studies of weight
pated through oxidation, and excess nutrients are stored in an regain in DIO rats that are prone to obesity revealed the emer-
energetically efficient manner (Fig. 3B). gence of a population of very small (⬍20 ␮m) adipocytes during
While the improvement in insulin sensitivity in muscle is the early stages of weight regain. Their appearance was accom-
responsible for this postprandial fuel preference, the critical panied by an increase in total number of adipocytes in the depot
energy sensor in muscle, AMPK (200), also becomes more (108). As weight gain proceeded, preferential hypertrophy of
responsive. Its regulation by leptin, insulin, and sympathetic these small cells was observed, while the higher cell number
neural efferents is impaired in DIO models of obesity (154), persisted (Fig. 6C). By 10 –14 days of relapse, the small cells
and some aspects of AMPK regulation appear to resolve after become indistinguishable from the preexisting adipocytes in the
energy-restricted weight loss (81, 108). This fuel preference fat pad. As the relapse to obesity continues, hypertrophy occurs
may be exacerbated by an inherent impairment in the capacity more broadly across the entire depot (Fig. 6D), and the increase in
to oxidize fat, which underlies the genetic predisposition for cell number continues to persist. Most animals in this DIO model
obesity (106, 107). Unlike lean subjects, energy-restricted gain more weight than they originally lose before the rate of gain
weight loss in obese subjects fails to increase skeletal muscle normalizes (148, 151). Yet, after surpassing their previous weight,
oxidative capacity (215, 225, 226) unless the energy-restricted these relapsed animals still have smaller adipocytes on average
diet is accompanied by regular exercise (96, 207, 208). Mito- and more adipocytes per fat pad than an obese rat that had never
chondrial respiratory capacity declines (188), glycolytic capac- lost or regained the weight (Fig. 6E). While substantiating the
ity declines (87, 215), and the expression of enzymes associ- temporal changes in cell size frequency distribution and total cell
ated with ␤-oxidation and mitochondrial enzyme activities number in humans presents a substantial challenge, a hypercellu-
remain low and, if anything, decline (62, 188, 215, 225). larity phenomenon with similar characteristics has been reported
Collectively, these adaptations in muscle underlie the reduced in postobese humans (145). Even so, this relapse-induced hyper-

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R592 BIOLOGICAL RESPONSE TO DIETING

Fig. 6. The change in adipocyte cell size frequency distribution with weight loss and weight regain. Data from our published weight regain studies in DIO rats
(108, 148, 151), as well as ongoing studies, were examined in a combined analysis of retroperitoneal adipocyte cellularity characteristics. In all, the analysis
included 21,710 adipocytes from 115 animals at the specified stages of the weight regain process. Cell size frequency distributions, with the effect on average
cell size and total number of cells in the depot, are shown for the sequential steps of loss and regain: weight loss and long term (⬎8 wk) maintenance (A), after
the first few days of weight regain (B), after relapse continues into the second week of weight regain (C), and after surpassing their preweight loss weight (D).
E: when relapse animals are compared again to obese rats that never lost weight, they have more cells and still have a smaller average size. The profile shift
at each stage of weight loss and regain, indicated with dotted arrows, is statistically significant (␹2 analysis, P ⬍ 0.05).

plasia of adipose tissue, if it does occur, is likely limited to An Integrated Picture of the Biological Drive
individuals who have a genetic predisposition for obesity. We to Regain Weight
have yet to observe an increase in cell number in DR rats or in
DIO mice, which tend to relapse to their previous weight. If this No single adaptation that we have discussed provides a
does occur in some humans, particularly those who are obese or stand-alone explanation for biological drive to regain weight
are prone to obesity, the consequences lie not only in facilitating after weight loss. These adaptations are interdependent and
rapid, energetically efficient regain early in relapse (Fig. 3B), but integrated, establishing a system filled with redundancy. Com-
also in permanently expanding the total storage capacity of the paring Fig. 3, A and B, it is clear that we have a better
depot. understanding of the homeostatic adaptations that are observ-

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BIOLOGICAL RESPONSE TO DIETING R593
able during weight maintenance after weight loss. Consider- blunted glucose excursions and suppressed FFAs levels during
ably less is known about the signals that sustain the energy gap this sustained, anabolic state may then be sensed by the brain
during dynamic metabolic states when the well-known adipose directly, via hypothalamic nutrient sensing neurons, or indi-
signals, leptin and insulin, do not reflect levels of stored energy rectly, via neuroendocrine signals reflecting nutrient status.
in the periphery. From the information presented in this review, With this model, the adipose tissue’s capacity to clear excess
we have developed one model of how this message is sustained energy is pitted against the rate at which nutrients are ingested
during the relapse process. and absorbed. Excessively large bouts of overfeeding may
The nutrient clearance model for the dynamic metabolic temporarily overwhelm the clearance rate, elevating glucose to
state of weight regain. The model we propose suggests that the the extent it negatively affects appetite despite FFAs levels
energy-depletion signal from adipose tissue is inherently linked remaining suppressed. When adipose tissues eventually catch
to the cellularity characteristics of adipocytes in the body and up, circulating glucose and its associated neuroendocrine
is conveyed to the brain by the levels of circulating nutrients markers would decline, appetite would increase, and additional
(or their neuroendocrine surrogate signals) during postprandial, bouts of overfeeding would ensue. At some point, a regular,
anabolic conditions (Fig. 7). Energy-depleted adipose tissues sustained supply of energy would be achieved to match the
have smaller adipocytes with an exceptionally high capacity to high clearance rate of adipose tissues. As the adipocytes
clear ingested energy from circulation (Fig. 7, A and B). This expand, their capacity to clear excess energy diminishes and
capacity would be further enhanced if very small, new fat cells the suppressive effects on circulating nutrients under dynamic
appear at the maintenance/relapse transition (Fig. 7C). The (postprandial) states of metabolism would decline. If adipocyte
enhanced clearance rate of adipose tissues would attenuate hyperplasia occurs early in relapse, as it does in our DIO rats,
postprandial glucose excursions and potentiate the postprandial relapsing to the previous weight would return the animal to the
suppression of circulating FFAs. During sustained periods of same fat mass, but the adipocytes on average would be smaller
overfeeding, the link between adipose-specific nutrient clear- (Fig. 7D). Rates of nutrient clearance would remain somewhat
ance and circulating levels would become stronger, as storage elevated and the impact on postprandial nutrients would per-
depots in other tissues (liver, muscle, etc.) fill to capacity. The sist, gradually declining as the adipocytes become larger, more

Fig. 7. Model linking adipocyte cellularity and peripheral nutrient clearance to the energy gap during dynamic weight regain. For reference, weight and cellularity
characteristics from the studies presented in Fig. 6 are shown for each stage of weight loss and regain (A–C, E), while hypothetical data for the relapse to the
preweight loss weight is extrapolated (D). The metabolic state during weight regain reflects sustained postprandial conditions. The proposed model links relative
whole body insulin sensitivity, adipocyte cellularity characteristics, the capacity of adipose tissue to clear excess nutrients, and postprandial nutrient levels in
circulation. Circulating levels of these nutrients are sensed by the brain directly or indirectly (via neuroendocrine signals reflecting nutrient status), thereby
affecting energy balance. A and B: weight loss from the obese state reduces the size of adipocytes, improving insulin sensitivity, enhancing the clearance of
absorbed nutrients, reducing postprandial levels of glucose (Glu) and free fatty acids (FFAs), and minimizing their inhibition of the energy gap. B and C: during
the early stages of relapse, the formation of very small, new adipocytes, further enhances insulin sensitivity and the capacity of adipose tissue to clear nutrients
from circulation. The rate at which nutrients are ingested and cleared is pitted against the rate at which these nutrients are cleared from circulation by adipose
tissue. Circulating glucose levels become a function of this competition between absorption and clearance, while FFA levels are persistently suppressed. FFAs
represent the only known signal that would attenuate the energy gap but is persistently suppressed during this dynamic state of weight gain. C and D: after
relapsing to the previous weight, the same fat mass is now composed of smaller adipocytes (on average), and insulin sensitivity and nutrient clearance rates are
still higher than prior to weight loss. The impact on postprandial nutrients sustains the energy gap as weight gain continues. D and E: clearance rates, the
suppressive effects on postprandial nutrients in circulation, and their minimized feedback energy balance regulation gradually resolve as adipocytes expand to
the size they were prior to weight loss. With more cells at the same average size, total fat mass is higher than what it was prior to weight loss.

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R594 BIOLOGICAL RESPONSE TO DIETING

insulin resistant, and less capable of clearing excess energy. As persistent, and redundant, as the biological adaptations they are
adipocytes become filled to capacity, postprandial glucose attempting to counter.
excursions would reflect those prior to weight loss and post-
prandial suppression of FFAs would be abolished. The high GRANTS
levels of these nutrients, or their neuroendocrine mediators, This work was supported by grants from the National Institutes of Health
would feed back to the brain, minimize the energy gap, and (DK038088 to P. S. MacLean) and P30DK45820.
normalize the rate of weight gain (Fig. 7E). DISCLOSURES
This “nutrient clearance” model is generally consistent with
No conflicts of interest, financial or otherwise, are declared by the authors.
preclinical and clinical observations of energy-restricted
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