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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
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.
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
(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
(51, 164)
(95, 121)
(238)
(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.
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)
Circulating nutrients
Appetite sensations
Glucose
Ghrelin
Insulin
GLP-1
CCK
PYY
FFA
TG
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-
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.
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
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-
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-
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.
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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