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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.
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
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
weight loss from the obese state, providing a reasonable picture REFERENCES
of how the energy gap is sustained as weight regain occurs.
However, we acknowledge that it is not substantiated, nor is it 1. Adam TC, Jocken J, and Westerterp-Plantenga MS. Decreased glu-
cagon-like peptide 1 release after weight loss in overweight/obese sub-
likely to be substantiated, at every step with definitive proof. jects. Obes Res 13: 710 –716, 2005.
As highly integrated as body weight regulation is, biology’s 2. Adam TC, Lejeune MP, and Westerterp-Plantenga MS. Nutrient-
drive to regain lost weight will certainly not be this simple and stimulated glucagon-like peptide 1 release after body-weight loss and
62. Doucet E, Tremblay A, Simoneau JA, Joanisse DR. Skeletal muscle 84. Gilbert JA, Drapeau V, Astrup A, Tremblay A. Relationship between
enzymes as predictors of 24-h energy metabolism in reduced-obese diet-induced changes in body fat and appetite sensations in women.
persons. Am J Clin Nutr 78: 430 –435, 2003. Appetite 52: 809 –812, 2009.
63. Drapeau V, King N, Hetherington M, Doucet E, Blundell J, Trem- 85. Gloy VL, Lutz TA, Langhans W, Geary N, Hillebrand JJ. Basal
blay A. Appetite sensations and satiety quotient: predictors of energy plasma levels of insulin, leptin, ghrelin, and amylin do not signal
intake and weight loss. Appetite 48: 159 –166, 2007. adiposity in rats recovering from forced overweight. Endocrinology 151:
64. Ducluzeau PH, Perretti N, Laville M, Andreelli F, Vega N, Riou JP, 4280 –4288, 2010.
Vidal H. Regulation by insulin of gene expression in human skeletal 86. Golay A. Blunted glucose-induced thermogenesis: a factor contributing
muscle and adipose tissue. Evidence for specific defects in type 2 to relapse of obesity. Int J Obes Relat Metab Disord 17 Suppl 1:
diabetes. Diabetes 50: 1134 –1142, 2001. S23–S27, 1993.
65. Dulloo AG, Calokatisa R. Adaptation to low calorie intake in obese 87. Goldsmith R, Joanisse DR, Gallagher D, Pavlovich K, Shamoon E,
mice: contribution of a metabolic component to diminished energy Leibel RL, Rosenbaum M. Effects of experimental weight perturbation
expenditures during and after weight loss. Int J Obes 15: 7–16, 1991. on skeletal muscle work efficiency, fuel utilization, and biochemistry in
66. Dulloo AG, Girardier L. 24-hour energy expenditure several months human subjects. Am J Physiol Regul Integr Comp Physiol 298: R79 –
after weight loss in the underfed rat: evidence for a chronic increase in R88, 2010.
whole-body metabolic efficiency. Int J Obes Relat Metab Disord 17: 88. Gourcerol G, Wang L, Wang YH, Million M, Tache Y. Urocortins and
115–123, 1993. cholecystokinin-8 act synergistically to increase satiation in lean but not
67. Dulloo AG, Girardier L. Adaptive changes in energy expenditure obese mice: involvement of corticotropin-releasing factor receptor-2
to weight regain after weight loss in obesity-prone rats. Am J Physiol during energy restriction involves a melanocortin-independent, estrogen-
Regul Integr Comp Physiol 287: R1306 –R1315, 2004. sensitive mechanism. Peptides 25: 667–674, 2004.
150. MacLean PS, Higgins JA, Johnson GC, Fleming-Elder BK, Peters 169. Muccioli GG, Naslain D, Backhed F, Reigstad CS, Lambert DM,
JC, Hill JO. Metabolic adjustments with the development, treatment, Delzenne NM, Cani PD. The endocannabinoid system links gut micro-
and recurrence of obesity in obesity-prone rats. Am J Physiol Regul biota to adipogenesis [Online]. Mol Syst Biol 6: 392, 2010.
Integr Comp Physiol 287: R288 –R297, 2004. 170. Nadal I, Santacruz A, Marcos A, Warnberg J, Garagorri M, Moreno
151. MacLean PS, Higgins JA, Wyatt HR, Melanson EL, Johnson GC, LA, Martin-Matillas M, Campoy C, Marti A, Moleres A, Delgado M,
Jackman MR, Giles ED, Brown IE, Hill JO. Regular exercise atten- Veiga OL, Garcia-Fuentes M, Redondo CG, Sanz Y. Shifts in clos-
uates the metabolic drive to regain weight after long-term weight loss. tridia, bacteroides and immunoglobulin-coating fecal bacteria associated
Am J Physiol Regul Integr Comp Physiol 297: R793–R802, 2009. with weight loss in obese adolescents. Int J Obes (Lond) 33: 758 –767,
152. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei 2009.
H, Kim S, Lallone R, Ranganathan S, Kern, P.A., Friedman, J. M. 171. Nicklas BJ, Dennis KE, Berman DM, Sorkin J, Ryan AS, Goldberg
Leptin levels in human and rodent: measurement of plasma leptin and ob AP. Lifestyle intervention of hypocaloric dieting and walking reduces
RNA in obese and weight-reduced subjects. Nat Med 1: 1155–1161, abdominal obesity and improves coronary heart disease risk factors in
1995. obese, postmenopausal, African-American and Caucasian women. J
153. Maraki MI, Aggelopoulou N, Christodoulou N, Anastasiou CA, Gerontol 58: 181–189, 2003.
Toutouza M, Panagiotakos DB, Kavouras SA, Magkos F, Sidossis 172. Oberkofler H, Fukushima N, Esterbauer H, Krempler F, Patsch W.
LS. Lifestyle intervention leading to moderate weight loss normalizes Sterol regulatory element binding proteins: relationship of adipose tissue
solids in morbid obesity. Int J Obes Relat Metab Disord 20: 200 –205, 243. Weigle DS, Brunzell JD. Assessment of energy expenditure in ambu-
1996. latory reduced-obese subjects by the techniques of weight stabilization
230. Tremblay A, Boule N, Doucet E, Woods SC. Is the insulin resistance and exogenous weight replacement. Int J Obes 14 Suppl 1: 69 –77;
syndrome the price to be paid to achieve body weight stability? Int J discussion 77– 81, 1990.
Obes (Lond) 29: 1295–1298, 2005. 244. Weigle DS, Sande KJ, Iverius PH, Monsen ER, Brunzell JD. Weight
231. Turnbaugh PJ, Gordon JI. The core gut microbiome, energy balance loss leads to a marked decrease in nonresting energy expenditure in
and obesity. J Physiol 587: 4153–4158, 2009. ambulatory human subjects. Metabolism 37: 930 –936, 1988.
232. Urayama A, Banks WA. Starvation and triglycerides reverse the obe- 245. Weinsier RL, Nagy TR, Hunter GR, Darnell BE, Hensrud DD, Weiss
sity-induced impairment of insulin transport at the blood-brain barrier. HL. Do adaptive changes in metabolic rate favor weight regain in
Endocrinology 149: 3592–3597, 2008. weight-reduced individuals? An examination of the set-point theory. Am
233. Valderas JP, Irribarra V, Boza C, de la Cruz R, Liberona Y, Acosta J Clin Nutr 72: 1088 –1094, 2000.
AM, Yolito M, Maiz A. Medical and surgical treatments for obesity 246. Weiss EC, Galuska DA, Kettel Khan L, Gillespie C, Serdula MK.
have opposite effects on peptide YY and appetite: a prospective study Weight regain in U.S. adults who experienced substantial weight loss,
controlled for weight loss. J Clin Endocrinol Metab 95: 1069 –1075, 1999 –2002. Am J Prev Med 33: 34 –40, 2007.
2010. 247. Westerterp-Plantenga MS, Kempen KP, Saris WH. Determinants of
234. Valtuena S, Blanch S, Barenys M, Sola R, Salas-Salvado J. Changes weight maintenance in women after diet-induced weight reduction. Int J
in body composition and resting energy expenditure after rapid weight Obes Relat Metab Disord 22: 1–6, 1998.
loss: is there an energy-metabolism adaptation in obese patients? Int J 248. Williams G, Shellard L, Lewis DE, McKibbin PE, McCarthy HD,