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SYMPOSIUM / SYMPOSIUM
Appetite control after weight loss: what is the role
of bloodborne peptides?
E´ric Doucet and Jameason Cameron
Abstract: The literature presented in this paper argues that our limited ability to maintain energy balance in a weightreduced state is the product of our difficulty in compensating for the weight loss-induced reduction in total energy expenditure. The end result, translated into the overwhelming complexity of preserving long-term weight loss, is presented
as being a consequence of compromised appetite control. Given the present-day food landscape and the resultant susceptibility to passive overconsumption, the focus of this review will be on the peripheral (‘‘bottom-up’’) signals (leptin,
PYY, ghrelin, and GLP-1) and the evidence highlighting their influence on feeding behaviour. As we continue studying
paradigms of body mass reduction, specifically the data emerging from patients of bariatric surgery, it is becoming
clearer that counter-regulatory adaptations, possibly through down-(leptin, PYY, and GLP-1) or upregulation (ghrelin)
of peptides, have an impact on energy balance. In itself, food deprivation influences some of the peptides that ultimately provide the physiological input for the overt expression of feeding behaviour; these peripheral adaptations are
expected to serve as feeding cues — cues that, in the end, can serve to compromise the maintenance of energy balance. In a potentially novel intervention to increase compliance to long-term reductions in energy intake, it is proposed
that manipulating the pattern of food intake to favourably alter the profile of gastrointestinal peptides would lead to
better dietary control.
Key words: weight loss, appetite, gut hormones, energy balance.
Re´sume´ : D’apre`s la litte´rature recense´e dans cet article, l’incapacite´ ge´ne´ralement re´pandue de maintenir l’e´quilibre e´nerge´tique apre`s avoir perdu du poids est due a` la diminution de la de´pense e´nerge´tique totale cause´e par la perte de poids.
En fin de compte, la tre`s grande difficulte´ de garder a` long terme son nouveau poids rele`ve d’un proble`me concernant le
controˆle de l’appe´tit. Du fait de l’acce`s facile a` la nourriture et de la tendance a` la surconsommation passive, cet article se
concentre sur les signaux issus de la pe´riphe´rie (leptine, PYY, ghre´line et GLP-1) et sur les observations mettant en e´vidence leurs influences sur le comportement alimentaire. Compte tenu des diverses approches dans l’e´tude de la perte de
poids et des re´centes observations, notamment en chirurgie bariatrique, il semble de plus en plus clair que des adaptations
a` contresens produisent un effet sur l’e´quilibre e´nerge´tique, probablement par un processus de re´gulation a` la baisse (leptine, PYY et GLP-1) ou a` la hausse (ghre´line) des peptides. En soi, la privation de nourriture exerce un effet sur des peptides, ce qui constitue le signal physiologique de la manifestation du comportement alimentaire ; on attend de ces
adaptations en pe´riphe´rie qu’elles servent d’indices de comportement alimentaire, mais ces indices, en fin de processus,
peuvent compromettre l’e´quilibre e´nerge´tique. On propose un nouveau type d’intervention pour faciliter la diminution de
l’apport e´nerge´tique a` long terme: le controˆle des modalite´s de l’apport alimentaire a` des fins de modification favorable du
bilan des peptides gastrointestinaux afin de conduire a` un meilleur controˆle du re´gime alimentaire.
Mots-cle´s : perte de poids, appe´tit, hormones gastrointestinales, e´quilibre e´nerge´tique.
[Traduit par la Re´daction]
Introduction
The fact that rates of obesity are increasing all over the
globe is now well documented (WHO 2003). The countless
nonsurgical approaches that have been developed to combat
excess adiposity still only result in limited success, as evidenced by the fact that many individuals are still obese or
overweight after weight loss (Tremblay and Doucet 2000).
Furthermore, resistance to slimming is often observed
(Miller and Parsonage 1975), and the relapse to initial levels
of adiposity is, in more cases than not, the fate of most
weight losers (Anderson et al. 2001). These effects could be
facilitated by counter-regulatory adaptations that appear in
response to prolonged energy-restricted diets (Tremblay and
Received 4 July 2006. Accepted 26 January 2007. Published on the NRC Research Press Web site at http://apnm.nrc.ca on 1 May 2007.
E´. Doucet1 and J. Cameron. Behavioural and Metabolic Research Unit, School of Human Kinetics, University of Ottawa, ON
K1N 6N5, Canada.
1Corresponding
author (e-mail: [email protected]).
Appl. Physiol. Nutr. Metab. 32: 523–532 (2007)
doi:10.1139/H07-019
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Doucet 2000; MacLean et al. 2004, 2006). As such, it would
be relevant to consider these counter-regulatory adaptations
when designing weight-loss and weight-maintenance interventions aimed at increasing the compliance to long-term reductions in energy intake.
Obesity treatment: a partly successful endeavour
The fact that obesity has now reached the status of global
epidemic (WHO 2003) is no longer debated. Regardless of
the observation that energy-restricted diets can produce significant weight loss (Wadden 1993; Miller et al. 1997; Anderson et al. 2004) and substantial improvements of the
determinants of the metabolic risk profile (Wing and Jeffery
1995; Tremblay et al. 1999), the fact remains that most
weight losers will likely regain (Anderson et al. 2001) or
even overshoot their preintervention body mass when severely food deprived (Dulloo et al. 1997). The cyclical path
of weight loss to weight regain is in itself a troublesome situation, as the number of previous weight-loss attempts is a
risk factor for subsequent major weight gain (Korkeila et al.
1999). Some results have also shown that humans (Dulloo et
al. 1997) and animals (Ouellet et al. 1997) often overshoot
their initial levels of body fat after being food deprived. In
fact, there is evidence from a meta-analysis that reducedobese subjects only maintain 20% (3 kg) of their initial
weight loss after a 2 to 5 year follow-up (Anderson et al.
2001), in which case the term ‘‘reduced-obese’’ refers to an
individual who was successful at achieving weight loss but
could still be classified as an obese individual based on his/
her post weight-loss body mass index. The high incidence of
relapse supports the perception that energy balance may be
compromised in a reduced-obese state. In a study that surveyed the characteristics of a cohort of reduced-obese individuals who were successful at maintaining their weight
after weight loss, the reduced-obese subjects consumed lowcalorie – low-fat diets (~1400 kcal/day with less than 25%
dietary fat) and also engaged in purposeful physical activity
in excess of 2800 kcal/week from vigorous physical activity
or roughly the equivalent of 1 hour of exercise per day
(McGuire et al. 1999). It is becoming clearer that weight
maintenance after weight loss is illusive and that body mass
relapse is explained, at least in part, by counter-regulatory
adaptations that appear in response to energy deprivation. In
this paper, we will argue that feeding behaviour is compromised during and after body mass reduction.
Appetite in the regulation of body energy reserves
This review will focus on the homeostatic control
(‘‘bottom-up’’) of food-intake control. As such, it is not intended to diminish the complexity of feeding to a mere
‘‘bottom-up’’ regulation, or the idea that feeding is initiated
and terminated based solely on peripheral cues (humoral,
hormonal, mechanoreceptive, chemoreceptive, etc.). In fact,
this representation is incomplete and only characterizes one
limb of an integrated two-tier system guiding feeding behaviour (Berthoud 2000). The other limb of this model consists
of so-called indirect pathways, or a ‘‘top down’’ pattern of
organization involved in the interpretation of both external
and internal stimuli (Cameron and Doucet 2007). Although
both sides of the ‘‘two-tiered’’ model of feeding must be acknowledged, from this point onward, the impact of periph-
Appl. Physiol. Nutr. Metab. Vol. 32, 2007
eral signals, namely bloodborne peptides that have been
shown to contribute to the regulation of appetite and food
intake in humans and animals, will be discussed. These peripheral signals are integrated on a hierarchy of levels and
have the potential to influence feeding behavior; however, it
is understood that up- or down-regulation of these signals
does not necessarily translate into cause–effect changes in
feeding.
Furthermore, in addressing the ‘‘bottom-up’’ regulation of
feeding, both acute and long-term controls must also be
briefly discussed. Since the issue has been extensively reviewed elsewhere (Druce and Bloom 2003, 2006a; Korner
and Leibel 2003; Woods 2005), only a short description
will be given here. Gastrointestinal factors (peptides, nutrients, mechanoreceptors, chemoreceptors, etc.) act mainly
in the satiety cascade to limit meal size (Havel 2001). This
pathway has been coined the short-term signaling of feeding
regulation. In contrast, the long-term modulators of feeding
and energy intake are up- or down-regulated according to
fluctuations in body energy reserves, mainly adipose tissue,
in line with Kennedy’s adipostat theory (Kennedy 1953).
Leptin (Considine et al. 1996), ghrelin (Cummings et al.
2002), and insulin (Woods et al. 1974) are amongst these
long-term modulators and consequently fluctuate with
changes in energy reserves. Current obesity trends and the
apparent lack of success in treating excess adiposity may
also indicate that these peptides are more potent in their protection against energy deprivation (Bowles and Kopelman
2001) than against chronic overfeeding.
Considering that energy expenditure is continuous and
that food intake is episodic, it is remarkable that, over an individual’s lifetime, there is a rather precise regulation between energy intake and expenditure (Je´quier and Tappy
1999), as body mass gain for most individuals is the result
of slight energy imbalances that are sustained over prolonged periods of time. Nevertheless, there is evidence to
support that the control of food intake is compromised
when body energy reserves are being depleted. A welldocumented observation is that the reduction in body mass
leads to a decrease in energy expenditure (Bray 1969;
Doucet et al. 2000c) — a decrease that has been shown to
be even greater than that predicted from changes in body
mass and composition (Leibel et al. 1995; Dulloo and
Jacquet 1998; Doucet et al. 2001, 2003). Data from animal
models have shown that these changes actually contribute to
weight relapse (MacLean et al. 2004, 2006). Oddly, despite
a decrease in total energy expenditure, there seems to be a
concomitant increase in the drive to eat under such circumstances (Doucet et al. 2000a), an effect that is also observed
early into energy deprivation (Doucet et al. 2004a) and that
has been shown to predict weight relapse (Pasman et al.
1999). In practical terms, a reduction in energy expenditure
as observed after weight loss is not necessarily accompanied
by a proportionate decrease in the drive to eat. Further evidence as to the effect of a reduction in body energy reserves
on appetite are presented in the reanalysis (Dulloo et al.
1997) of the Minnesota semi-starvation study by Ancel
Keys and colleagues (Keys et al. 1950). Briefly, this experiment involved a 24 week food deprivation period (50% of
caloric needs), followed by a 12 week restricted refeeding
and, finally, by an additional 8 week free-feeding period.
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Doucet and Cameron
Fig. 1. Percentage of baseline values for resting energy expenditure (REE) (*), body mass (^), fat mass (^), hunger (&), and
energy intake (~) at different time points. Values presented at day
5 represent baseline values and no data were available at week 2.
Data are adapted from Doucet et al. (2001, 2003, 2004a).
Both fat-free mass and, to a much greater extent, fat mass
were reduced. Of interest to this review is the fact that, during the free-feeding phase of the experiment, subjects had
sustained hyperphagia (up to 160% of baseline energy intake) beyond the point where they had reached their baseline fat mass and body mass. It is agreed that the
conditions of this study are not typical of usual weight-loss
strategies. Presented in Fig. 1 is a compilation of results
from our own work that employed a ~25% reduction in energy needs (more typical of widespread weight-loss programs) to induce weight loss (Doucet et al. 2000a, 2001),
or to measure the acute effects of an energy-restricted diet
(Doucet et al. 2004a). As could be expected, body mass,
fat mass, and resting energy expenditure all progressively
decreased as the energy-restricted diet progressed. What is
also apparent in Fig. 1 is that there was an increase in hunger ratings that appeared very early during the energyrestricted diet and continued to progress throughout the
food deprivation period.
As mentioned earlier in the text, weight loss is accompanied by a decrease in energy expenditure (Bray 1969; Doucet et al. 2000c). In addition, there is evidence to support
that, matched on body mass, the reduced-obese tend to display lower energy expenditure than never-obese subjects
(Astrup et al. 1999). The problem of maintaining energy balance after weight loss is then likely to be one of reducing
the energy intake to compensate for a chronic decrease in
energy expenditure, considering that large amounts of energy from purposeful engagement in exercise programs are
needed to maintain weight stability after weight loss
(McGuire et al. 1999).
525
Feeding-related peptides and their changes during food
deprivation
In recent years, many peptides originating from the gut or
adipose tissue have been linked with feeding in both humans
and animals (Korner and Leibel 2003; Druce et al. 2004;
Broberger 2005; Cummings et al. 2005; Druce and Bloom
2006a). Of interest to this review are those peptides that
have also been shown to fluctuate with acute and chronic
food deprivations. These peptides include leptin, ghrelin,
peptide tyrosine-tyrosine (PYY), and glucagon-like peptide
(GLP) 1. Although other peptides, such as insulin, fall into
this category, they will not be discussed in this paper. The
following sections illustrate how changes in the circulating
levels of these peptides contribute to the fragility of appetite
control upon food deprivation.
Leptin
The fact that leptin is primarily produced and secreted by
white adipose tissue (Zhang et al. 1994; Masuzaki et al.
1995) is commonly recognized, even if other sites, such as
the gastric mucosa, secrete this hormone (Mix et al. 1999,
2000). Whether acute food intake impacts leptin concentrations is still a matter of controversy, as some investigators
reported a postprandial increase in leptin concentration in
response to a single meal test (Pratley et al. 1997; Dallongeville et al. 1998; Joannic et al. 1998; Romon et al. 1999;
Imbeault et al. 2001), whereas others did not (Considine et
al. 1996; Dagogo-Jack et al. 1996; Sinha et al. 1996; Clapham et al. 1997; Weigle et al. 1997). There is, however,
greater agreement regarding the notion that fat loss triggers
a decrease in plasma leptin (Considine et al. 1996; Doucet
et al. 2000b); furthermore, the decrease in leptin is greater
than that predicted by the reduction in body fat (Considine
et al. 1996; Wadden et al. 1998; Doucet et al. 2004a). Several studies have shown that the decrease in leptin observed
after acute energy deprivation (Doucet et al. 2004a) and
after weight loss (Heini et al. 1998a, 1998b; Doucet et al.
2000a) is associated with increased appetite ratings. Given
the effects of leptin on energy balance, it is not surprising
that recombinant leptin therapy in human subjects with congenital leptin deficiency has proven to be an effective
weight-loss intervention (Farooqi et al. 1999). However,
this therapy has limited potential when applied to overweight subjects, as exemplified by their very modest weight
loss (Heymsfield et al. 1999). That peripheral leptin does
not produce significant weight loss under such circumstances is likely explained by the fact that obese individuals
not only show grossly elevated plasma leptin concentrations
(Considine et al. 1996; Wadden et al. 1998; Doucet et al.
2004a), but also demonstrate resistance to signaling at the
level of the blood brain barrier (Banks 2001). It should
nonetheless be pointed out that when leptin therapy is used
in conjunction with dietary energy restrictions, it seemingly
attenuates both the weight-loss-induced reduction of energy
expenditure (Rosenbaum et al. 2002) and the increase in appetite (Westerterp-Plantenga et al. 2001). In brief, leptin is
decreased upon food deprivation, leading to weight loss,
and this decrease has also been shown to be associated
with the increase in appetite observed under such circumstances.
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Ghrelin
Ghrelin, a ligand for the GH secretagogue receptor, and
the only known orexigenic hormone, was isolated from gastric extracts (Kojima et al. 1999). Unlike leptin, ghrelin is
acutely reduced in response to nutrient intake (Ariyasu et
al. 2001). As reviewed elsewhere, carbohydrates seem to
have the greatest effect on ghrelin suppression, with proteins
and fats exerting a lower suppressing effect on this peptide
(Cummings et al. 2005; Overduin et al. 2005; Gil-Campos
et al. 2006; Prodam et al. 2006). It has also been suggested
that the preprandial rise in ghrelin could serve as a meal initiation signal (Cummings et al. 2001), and that intravenous
administration (Wren et al. 2001) and subcutaneous injection
(Druce et al. 2006b) of this peptide can increase appetite
and food intake in both lean and obese humans (Druce et
al. 2005). These observations led to the assumption that this
orexigenic hormone plays an important role in the acute regulation of energy and nutrient intake. The fact that ghrelin is
reduced in obesity (Tschop et al. 2001; Lindeman et al.
2002), increased in aneroxia nervosa (Otto et al. 2001), and
in response to sustained energy restriction leading to weight
loss (Cummings et al. 2002; Hansen et al. 2002) implies that
ghrelin is, as is leptin, influenced by energy imbalances.
Given the role of ghrelin in the short-term regulation of
feeding, its post weight-loss increase could complicate the
control of meal size and frequency.
Peptide tyrosine-tyrosine
Other peptides secreted by endocrine L-cells in the distal
part of the small intestine and proximal colon have been
shown to exert a potent effect on the short-term downregulation of appetite and energy intake (Batterham et al. 2003b;
Cohen et al. 2003). One of these, peptide tyrosine-tyrosine
(PYY)3–36, a truncated version of PYY1–36, exhibits anorectic effects in humans (Batterham and Bloom 2003a; Batterham et al. 2003b). PYY3–36 was first isolated from
colonic extracts (Tatemoto and Mutt 1980) and is part of
the same pancreatic peptide family as are polypancreatic
peptide and neuropeptide Y (NPY) (Onaga et al. 2002).
The postprandial increase of PYY3–36 has been extensively
documented in numerous species (Onaga et al. 2002) and
has been shown to be proportional to calories ingested
(Adrian et al. 1985a). Furthermore, PYY levels rise within
30 min of nutrients reaching the gut (Anini et al. 1999),
reaching maximal levels within 1 to 2 h (Adrian et al.
1985b; Laviolette et al. 2005). Recent results support the
idea that, when equicaloric meal challenges are given, the
greatest postprandial PYY levels are observed under the
high-protein condition in both lean and human subjects
(Batterham et al. 2006), although earlier results had shown
that fat elicited greater secretion of PYY (Onaga et al.
2002). Of note is the fact that PYY levels were comparable
between the high-fat and high-protein conditions in lean
subjects during the first 2 h of the measurement (Batterham
et al. 2006), which may help reconcile this apparent difference between the two studies. Contrary to ghrelin, when administered intravenously, PYY3–36 reduces appetite and
energy intake (Batterham and Bloom 2003a; Batterham et
al. 2003b), but recent results have shown that pharmacological levels need to be achieved for these effects to occur
(Degen et al. 2005). PYY3–36 infusion also attenuates the
Appl. Physiol. Nutr. Metab. Vol. 32, 2007
Fig. 2. Fasting and postprandial (60 min after the meal) plasma
total PYY (pg/mL) before (&) and after (&) a 4 day energy restriction. Effect of the meal (p < 0.01) and effect of the energy restriction (p < 0.05). No meal by energy restriction interaction
(Doucet et al. 2004b). Values are mean ± SEM.
pre-meal rise in ghrelin (Batterham et al. 2003b). It could
be postulated from these observations that part of the anorectic effects of PYY3–36 may be, in part, mediated by the
reduced levels of ghrelin (Batterham et al. 2003b). To date,
a single study has reported the effects of dietary-induced
weight loss on PYY. In this study, fasting total PYY was
shown to increase after successful weight loss in children
(Roth et al. 2005). In contrast, there is also limited evidence
to indicate that acute food deprivation leads to a decrease of
PYY levels in adults (Doucet et al. 2004b; Chan et al.
2006b). In fact, Chan et al. (2006b) have recently reported
that, after a 2–3 day fast, fasting circulating total PYY was
reduced by as much as 50%. In agreement with this previous study, we also reported a decrease (–11%) of both
fasting and postprandial total PYY after 4 days of a 25%
reduction in energy intake (Doucet et al. 2004b) (Fig. 2). In
summary, PYY has been shown to be a potent downregulator of appetite and energy intake in both humans and animals. Some evidence supports the idea that PYY may also
be downregulated in response to food deprivation, an effect
that could likely impact appetite control upon food deprivation.
GLP-1
Like PYY, GLP-1 (Lund et al. 1982; Bell et al. 1983) is
secreted by endocrine L-cells and is increased after the ingestion of a mixed meal (Holst 1994; Naslund and Hellstrom 1998), whereas carbohydrates elicit a greater
secretion of this peptide (Elliott et al. 1993). There is evidence to show that GLP-1 reduces energy intake (12%) and
appetite, when administered intravenously to human subjects
(Flint et al. 1998). A contributing factor to the GLP-1-induced decrease in energy intake may be its effects on gastric
emptying and the ileal brake (Nauck et al. 1997). Moreover,
there seems to be an additive effect when both PYY3–36
and GLP-1 are administered simultaneously (Neary et al.
2005). Whereas some investigators have reported hyperse#
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Doucet and Cameron
cretion of GLP-1 in the obese (Fukase et al. 1993), others
have reported lower secretion of this peptide, particularly
in the severely obese (Verdich et al. 2001). Similarly, there
are also discrepant results for post-weight loss GLP-1 levels. Indeed, one study has shown GLP-1 response to a
standard meal to be increased in reduced-obese subjects
(Verdich et al. 2001). In contrast, two more recent studies
have shown GLP-1 to be reduced after weight loss. In the
first of these studies, it was reported that fasting and nutrient-stimulated GLP-1 were reduced after a 6 kg weight
loss (Adam et al. 2005). Despite the fact that no differences
in fasting GLP-1 levels were seen in this second study, a
significantly blunted postprandial response was also observed after weight loss (Adam et al. 2006). Evidence reviewed in this section suggests that post-weight-loss
secretion of GLP-1 in response to a meal test may be
blunted. If GLP-1 does indeed play an important role in
the short-term regulation of feeding, its reduction following
weight loss could contribute to looser controls of meal and
frequency.
As we continue studying paradigms of body mass reduction, it is becoming clearer that food deprivation triggers
counter-regulation adaptations, possibly through down(leptin, PYY, and GLP-1) or up- (ghrelin) regulation of peptides known to affect energy balance. The literature reviewed in this section supports a role for peptides secreted
by the gut and by adipose tissue in the expression of appetite control. This idea is congruent with the notion that the
main role of some of these peptides, namely leptin, might
be to safeguard energy reserves in response to food deprivation (Bowles and Kopelman 2001), and that there may well
be other hormonal players in the series of adaptations that
operate to re-establish energy balance during periods of
food deprivation. From a thermodynamic perspective, successful long-term treatment of obesity is dependent on the
ability to compensate for the weight-loss-induced decrease
in total energy expenditure, either through increased physical activity or via a sustained decrease in food intake. However, as emphasized throughout this review, peripheral
adaptations that serve as feeding cues would, in the end,
compromise the maintenance of energy balance and contribute to relapse obesity upon cessation of weight-loss interventions. Evidence in support of this position comes from
the observation that reduced-obese individuals with the
greatest levels of hunger are likely to regain more body
mass over a 14 month follow-up (Pasman et al. 1999).
Taken together, these observations emphasize the need for
interventions that minimize the impact of weight loss on appetite.
Manipulating peripheral feeding signals
As emphasized in the previous section, food deprivation
impacts some of the peptides that ultimately provide the
physiological input for the overt expression of feeding behaviour. However, long-term treatment with agonists/antagonists of these peptides largely remains to be investigated, or
has yielded disappointing outcomes, such as with leptin
(Heymsfield et al. 1999). Another avenue that has yet to be
explored is whether dietary manipulations that could in
theory favourably impact gut hormone profiles, would in
turn lead to an increased compliance to long-term reductions
527
in energy intake. Evidence from studies that investigated
bariatric surgery patients lends support to the possibility
that increased endogenous levels of some of these peptides
could actually contribute to successful obesity treatment.
Amongst other possibilities, the success of this approach is
at least partly related to the low levels of hunger reported
by these individuals. Korner et al. (2005) reported an early
and pronounced postprandial increase in PYY in obese subjects after Roux-en-Y surgery, a finding that has been since
reproduced on several occasions (Chan et al. 2006a; Korner
et al. 2006; le Roux et al. 2006; Morinigo et al. 2006). It is
generally concluded that this favourable PYY profile contributes to successful weight maintenance by possibly attenuating the effects of weight loss on appetite. In addition,
two other studies have also reported that GLP-1 secretion in
response to a standard nutrient intake is also significantly
more elevated in gastric bypass subjects that in obese or
lean controls (le Roux et al. 2006; Morinigo et al. 2006). Finally, data from animals also support these findings, as it
has been shown that ileal transposition (moving a 10 cm
segment of the distal small intestine proximal to the ileocecal valve and transposing it to a location within the jejunum)
produced marked increases in postprandial PYY and GLP-1
in these animals compared with the sham-operated controls
(Strader et al. 2005). In addition, these animals gained significantly less weight over a 45 day period (Strader et al.
2005). Taken together, these findings support the important
role of PYY and GLP-1 in energy balance. A question that
can be derived from the integration of this literature is
whether it would be possible to structure food intake and
meal patterning in a way to favourably alter daily gut peptides profiles in the absence of surgery. This issue will be addressed in the next section.
Meal frequency, energy intake, and gut peptide profiles
In addressing the question as to whether structuring food
intake is possible to take advantage of repeated nutrient intake on gut peptide secretion and, ultimately, on energy intake, it is relevant to summarize some of the literature on
increased meal frequency and energy intake. It has even
been hypothesized that an increased periodicity of eating
could favour the release of gastrointestinal hormones associated with improved appetite control (Speechly et al. 1999),
but studies have yet to be conducted to confirm this postulation. Nonetheless, there is evidence, albeit controversial, to
the effect that increased meal frequency is associated with a
lower energy intake. Several epidemiological studies have
observed a lower body mass in individuals eating smaller
quantities more frequently, suggesting that increased meal
frequency could lead to a decrease in food intake (Bellisle
et al. 1997). There is also evidence that high-frequency eating is associated with leanness in men, but not in women
(Drummond et al. 1998). Generally, energy intake in obese
and lean individuals seems to be lower when following a
regular meal pattern with higher frequency than during an
irregular meal pattern with lower frequency (Drummond et
al. 1998; Speechly et al. 1999; Westerterp-Plantenga et al.
2002; Farshchi et al. 2005). Some reports have also observed an inverse relationship between the number of meals
consumed in a day and the degree of adiposity (Bellisle et
al. 1997; Speechly et al. 1999). It should nonetheless be
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528
pointed out that the finding of reduced appetite (Farshchi et
al. 2005) and reduced energy intake (Taylor and Garrow
2001) after frequent meal consumption is not always consistent among studies (Farshchi et al. 2005). In summary, there
is evidence to suggest that increased meal frequency can
lead to beneficial effects on energy balance; whether this effect is indeed partly explained by the regular release of gastrointestinal peptides implicated in the satiety cascade
remains to be determined.
Overall, the integration of the literature presented in this
review suggests that it is relevant to consider postprandial
secretion of gastrointestinal peptides to maximize dietary
control, particularly after weight loss, and that increasing
meal frequency may be a way to test this hypothesis. It is
within this paradigm that the following is proposed.
Although the idea of designing low-calorie snacks to improve dietary control is not new, the wealth of knowledge
emerging from research aimed at better understanding how
humans regulate feeding, particularly in the context of food
deprivation, warrants further studies in this area. In fact, it
would be interesting to propose that offering snacks, specifically designed to elicit secretion of PYY and GLP-1 for example, so that their maximal (or minimal for ghrelin) postsnack levels would coincide with main courses, could lead
to better dietary control. Considering the literature on the
nutrient-specific effects of the peptides reviewed in previous
sections, it is proposed that a relatively high-protein and
high-carbohydrate content should be included into this mixture. Accordingly, if such a nutrient challenge leads to increases in pre-meal PYY and GLP-1, then it is reasonable
to assume that it could also attenuate the pre-meal rise in
ghrelin (Batterham et al. 2003b) and, possibly, energy intake.
Conclusion
Weight relapse after prolonged food deprivation is an outcome of obesity interventions. The literature presented in
this paper argues that the limited ability to maintain energy
balance in a weight-reduced state is a consequence of the incapacity to adequately compensate for the weight-lossinduced reduction in energy expenditure through sustained
changes in food intake. With the understanding that peripheral output (i.e., peptides that fluctuate with acute and
chronic nutrient balance) merely acts as cues that inform
feeding centers on the direction of feeding behaviour, it becomes nonetheless relevant to investigate strategies, be they
nutritional or pharmacological, to try to alleviate their influence on appetite upon food deprivation.
Acknowledgements
Eric Doucet is a recipient of a CIH/Merck-Frosst New Investigator Award, CFI/OIT New Opportunities Award, and
of an Early Research Award.
References
Adam, T.C., Jocken, J., and Westerterp-Plantenga, M.S. 2005. Decreased glucagon-like peptide 1 release after weight loss in overweight/obese subjects. Obes. Res. 13: 710–716. PMID:15897480.
Adam, T.C., Lejeune, M.P., and Westerterp-Plantenga, M.S. 2006.
Nutrient-stimulated glucagon-like peptide 1 release after body-
Appl. Physiol. Nutr. Metab. Vol. 32, 2007
weight loss and weight maintenance in human subjects. Br. J.
Nutr. 95: 160–167. doi:10.1079/BJN20051614. PMID:16441929.
Adrian, T.E., Ferri, G.L., Bacarese-Hamilton, A.J., Fuessl, H.S.,
Polak, J.M., and Bloom, S.R. 1985a. Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology, 89: 1070–1077. PMID:3840109.
Adrian, T.E., Savage, A.P., Sagor, G.R., Allen, J.M., BacareseHamilton, A.J., Tatemoto, K., et al. 1985b. Effect of peptide
YY on gastric, pancreatic, and biliary function in humans. Gastroenterology, 89: 494–499. PMID:3839479.
Anderson, J.W., Konz, E.C., Frederich, R.C., and Wood, C.L.
2001. Long-term weight-loss maintenance: a meta-analysis of
US studies. Am. J. Clin. Nutr. 74: 579–584. PMID:11684524.
Anderson, J.W., Luan, J., and Hoie, L.H. 2004. Structured weightloss programs: meta-analysis of weight loss at 24 weeks and assessment of effects of intervention intensity. Adv. Ther. 21: 61–
75. PMID:15310080.
Anini, Y., Fu-Cheng, X., Cuber, J.C., Kervran, A., Chariot, J., and
Roz, C. 1999. Comparison of the postprandial release of peptide
YY and proglucagon-derived peptides in the rat. Pflugers Arch.
438: 299–306. doi:10.1007/s004240050913. PMID:10398859.
Ariyasu, H., Takaya, K., Tagami, T., Ogawa, Y., Hosoda, K., Akamizu, T., et al. 2001. Stomach is a major source of circulating
ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J. Clin. Endocrinol. Metab. 86:
4753–4758. doi:10.1210/jc.86.10.4753. PMID:11600536.
Astrup, A., Gotzsche, P.C., van de Werken, K., Ranneries, C., Toubro, S., Raben, A., et al. 1999. Meta-analysis of resting metabolic rate in formerly obese subjects. Am. J. Clin. Nutr. 69:
1117–1122. PMID:10357728.
Banks, W.A. 2001. Leptin transport across the blood-brain barrier:
implications for the cause and treatment of obesity. Curr. Pharm.
Des. 7: 125–133. doi:10.2174/1381612013398310. PMID:
11172704.
Batterham, R.L., and Bloom, S.R. 2003a. The gut hormone peptide
YY regulates appetite. Ann. N. Y. Acad. Sci. 994: 162–168.
PMID:12851312.
Batterham, R.L., Cohen, M.A., Ellis, S.M., Le Roux, C.W., Withers, D.J., Frost, G.S., et al. 2003b. Inhibition of food intake in
obese subjects by peptide YY3–36. N. Engl. J. Med. 349: 941–
948. doi:10.1056/NEJMoa030204. PMID:12954742.
Batterham, R.L., Heffron, H., Kapoor, S., Chivers, J.E., Chandarana, K., Herzog, H., et al. 2006. Critical role for peptide YY in
protein-mediated satiation and body-weight regulation. Cell Metab. 4: 223–233. PMID:16950139.
Bell, G.I., Santerre, R.F., and Mullenbach, G.T. 1983. Hamster preproglucagon contains the sequence of glucagon and two related
peptides. Nature (London), 302: 716–718. doi:10.1038/
302716a0. PMID:6835407.
Bellisle, F., McDevitt, R., and Prentice, A.M. 1997. Meal frequency and energy balance. Br. J. Nutr. 77(Suppl 1): S57–S70.
doi:10.1079/BJN19970104. PMID:9155494.
Berthoud, H.R. 2000. An overview of neural pathways and networks involved in the control of food intake and selection. In
Neural and Metabolic Control of Macronutrient Intake. Edited
by H.R. Berthoud and R.J. Seeley. CRC Press LLC, Florida.
Bowles, L., and Kopelman, P. 2001. Leptin: of mice and men? J.
Clin. Pathol. 54: 1–3. doi:10.1136/jcp.54.1.1. PMID:11271782.
Bray, G.A. 1969. Effect of caloric restriction on energy expenditure
in obese patients. Lancet, 2: 397–398. PMID:4184486.
Broberger, C. 2005. Brain regulation of food intake and appetite:
molecules and networks. J. Intern. Med. 258: 301–327. doi:10.
1111/j.1365-2796.2005.01553.x. PMID:16164570.
Cameron, J., and Doucet, E. 2007. Getting to the bottom of feeding
#
2007 NRC Canada
Doucet and Cameron
behaviour. Who’s on top? Appl. Physiol. Nutr. Metab. 32: 177–
189.
Chan, J.L., Mun, E.C., Stoyneva, V., Mantzoros, C.S., and Goldfine, A.B. 2006a. Peptide YY levels are elevated after gastric
bypass surgery. Obesity (Silver Spring), 14: 194–198.
PMID:16571843.
Chan, J.L., Stoyneva, V., Kelesidis, T., Raciti, P., and Mantzoros,
C.S. 2006b. Peptide YY levels are decreased by fasting and elevated following caloric intake but are not regulated by leptin.
Diabetologia, 49: 169–173. doi:10.1007/s00125-005-0041-2.
PMID:16362815.
Clapham, J.C., Smith, S.A., Moore, G.B., Hughes, M.G., Azam, H.,
Scott, A., et al. 1997. Plasma leptin concentrations and OB gene
expression in subcutaneous adipose tissue are not regulated
acutely by physiological hyperinsulinaemia in lean and obese
humans. Int. J. Obes. Relat. Metab. Disord. 21: 179–183.
doi:10.1038/sj.ijo.0800384. PMID:9080255.
Cohen, M.A., Ellis, S.M., Le Roux, C.W., Batterham, R.L., Park,
A., Patterson, M., et al. 2003. Oxyntomodulin suppresses appetite
and reduces food intake in humans. J. Clin. Endocrinol. Metab.
88: 4696–4701. doi:10.1210/jc.2003-030421. PMID:14557443.
Considine, R.V., Shina, M.K., Heiman, M.L., Kriauciunas, A., Stephens, T.W., Nyce, M.R., et al. 1996. Serum immunoreactiveleptin concentrations in normal-weight and obese subjects. N.
Engl.
J.
Med.
334:
292–295.
doi:10.1056/
NEJM199602013340503. PMID:8532024.
Cummings, D.E., Purnell, J.Q., Frayo, R.S., Schmidova, K., Wisse,
B.E., and Weigle, D.S. 2001. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes,
50: 1714–1719. PMID:11473029.
Cummings, D.E., Weigle, D.S., Frayo, R.S., Breen, P.A., Ma,
M.K., Dellinger, E.P., et al. 2002. Plasma ghrelin levels after
diet-induced weight loss or gastric bypass surgery. N. Engl. J.
Med. 346: 1623–1630. doi:10.1056/NEJMoa012908. PMID:
12023994.
Cummings, D.E., Foster-Schubert, K.E., and Overduin, J. 2005.
Ghrelin and energy balance: focus on current controversies.
Curr. Drug Targets, 6: 153–169. PMID:15777186.
Dagogo-Jack, S., Fanelli, C., Paramore, D., Brothers, J., and Landt,
M. 1996. Plasma leptin and insulin relationships in obese and
nonobese humans. Diabetes, 45: 695–698. PMID:8621026.
Dallongeville, J., Hecquet, B., Lebel, P., Edme, J.L., Le Fur, C.,
Fruchart, J.C., et al. 1998. Short term response of circulating
leptin to feeding and fasting in man: influence of circadian cycle. Int. J. Obes. Relat. Metab. Disord. 22: 728–733. doi:10.
1038/sj.ijo.0800648. PMID:9725631.
Degen, L., Oesch, S., Casanova, M., Graf, S., Ketterer, S., Drewe,
J., et al. 2005. Effect of peptide YY3–36 on food intake in humans. Gastroenterology, 129: 1430–1436. doi:10.1053/j.gastro.
2005.09.001. PMID:16285944.
Doucet, E., Imbeault, P., St-Pierre, S., Alme´ras, N., Maurie`ge, P.,
Richard, D., et al. 2000a. Appetite after weight loss by energy
restriction and a low-fat diet-exercise follow-up. Int. J. Obes.
Relat. Metab. Disord. 24: 906–914. doi:10.1038/sj.ijo.0801251.
PMID:10918539.
Doucet, E., St-Pierre, S., Alme´ras, N., Maurie`ge, P., Despre´s, J.-P.,
Richard, D., et al. 2000b. Fasting insulin levels influence plasma
leptin levels independently from the contribution of adiposity:
evidence from both a cross-sectional and an intervention study.
J. Clin. Endocrinol. Metab. 85: 4231–4237. doi:10.1210/jc.85.
11.4231. PMID:11095459.
Doucet, E., St Pierre, S., Alme´ras, N., Maurie`ge, P., Richard, D.,
and Tremblay, A. 2000c. Changes in energy expenditure and
substrate oxidation resulting from weight loss in obese men and
529
women: is there an important contribution of leptin? J. Clin. Endocrinol. Metab. 85: 1550–1556. doi:10.1210/jc.85.4.1550.
PMID:10770196.
Doucet, E., St-Pierre, S., Alme´ras, N., Despre´s, J.-P., Bouchard, C.,
and Tremblay, A. 2001. Evidence for the existence of adaptive
thermogenesis during weight loss. Br. J. Nutr. 85: 715–723.
PMID:11430776.
Doucet, E., Imbeault, P., St-Pierre, S., Almeras, N., Mauriege, P.,
Despres, J.P., et al. 2003. Greater than predicted decrease in energy expenditure during exercise after body weight loss in obese
men. Clin. Sci. (London), 105: 89–95. PMID:12617720.
Doucet, E., Pomerleau, M., and Harper, M.-E. 2004a. Fasting and
postprandial total ghrelin remain unchanged after a short-term
energy restriction. J. Clin. Endocrinol. Metab. 89: 1727–1732.
doi:10.1210/jc.2003-031459. PMID:15070937.
Doucet, E., Pomerleau, M., and Harper, M.-E. 2004b. Pre- and
postprandial levels of total PYY are decreased in response to a
short-term energy restriction. Obes. Res. 12: A114.
Druce, M., and Bloom, S.R. 2003. Central regulators of food intake. Curr. Opin. Clin. Nutr. Metab. Care, 6: 361–367. doi:10.
1097/00075197-200307000-00002. PMID:12806207.
Druce, M., and Bloom, S.R. 2006a. The regulation of appetite.
Arch. Dis. Child. 91: 183–187. PMID:16428368.
Druce, M.R., Small, C.J., and Bloom, S.R. 2004. Minireview: Gut
peptides regulating satiety. Endocrinology, 145: 2660–2665.
doi:10.1210/en.2004-0089. PMID:15044353.
Druce, M.R., Wren, A.M., Park, A.J., Milton, J.E., Patterson, M.,
Frost, G., et al. 2005. Ghrelin increases food intake in obese as
well as lean subjects. Int. J. Obes. (London), 29: 1130–1136.
doi:10.1038/sj.ijo.0803001. PMID:15197842.
Druce, M.R., Neary, N.M., Small, C.J., Milton, J., Monteiro, M.,
Patterson, M., et al. 2006b. Subcutaneous administration of
ghrelin stimulates energy intake in healthy lean human volunteers. Int. J. Obes. (London), 30: 293–296. doi:10.1038/sj.ijo.
0803158. PMID:16247504.
Drummond, S.E., Crombie, N.E., Cursiter, M.C., and Kirk, T.R.
1998. Evidence that eating frequency is inversely related to
body weight status in male, but not female, non-obese adults reporting valid dietary intakes. Int. J. Obes. Relat. Metab. Disord.
22: 105–112. doi:10.1038/sj.ijo.0800552. PMID:9504318.
Dulloo, A.G., and Jacquet, J. 1998. Adaptive reduction in basal metabolic rate in response to food deprivation in humans: a role for
feedback signals from fat stores. Am. J. Clin. Nutr. 68: 599–606.
PMID:9734736.
Dulloo, A.G., Jacquet, J., and Girardier, L. 1997. Poststarvation hyperphagia and body fat overshooting in humans: a role for feedback signals from lean and fat tissues. Am. J. Clin. Nutr. 65:
717–723. PMID:9062520.
Elliott, R.M., Morgan, L.M., Tredger, J.A., Deacon, S., Wright, J.,
and Marks, V. 1993. Glucagon-like peptide-1 (7–36)amide and
glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h
secretion patterns. J. Endocrinol. 138: 159–166. PMID:
7852887.
Farooqi, I.S., Jebb, S.A., Langmack, G., Lawrence, E., Cheetham,
C.H., Prentice, A.M., et al. 1999. Effects of recombinant leptin
therapy in a child with congenital leptin deficiency. N. Engl. J.
Med. 341: 879–884. doi:10.1056/NEJM199909163411204.
PMID:10486419.
Farshchi, H.R., Taylor, M.A., and Macdonald, I.A. 2005. Beneficial
metabolic effects of regular meal frequency on dietary thermogenesis, insulin sensitivity, and fasting lipid profiles in healthy
obese women. Am. J. Clin. Nutr. 81: 16–24. PMID:15640455.
Flint, A., Raben, A., Astrup, A., and Holst, J.J. 1998. Glucagon#
2007 NRC Canada
530
like peptide 1 promotes satiety and suppresses energy intake in
humans. J. Clin. Invest. 101: 515–520. PMID:9449682.
Fukase, N., Igarashi, M., Takahashi, H., Manaka, H., Yamatani, K.,
Daimon, M., et al. 1993. Hypersecretion of truncated glucagonlike peptide-1 and gastric inhibitory polypeptide in obese patients. Diabet. Med. 10: 44–49. PMID:8435987.
Gil-Campos, M., Aguilera, C.M., Canete, R., and Gil, A. 2006.
Ghrelin: a hormone regulating food intake and energy homeostasis. Br. J. Nutr. 96: 201–226. doi:10.1079/BJN20061787.
PMID:16923214.
Hansen, T.K., Dall, R., Hosoda, H., Kojima, M., Kangawa, K., Christiansen, J.S., et al. 2002. Weight loss increases circulating levels
of ghrelin in human obesity. Clin. Endocrinol. (Oxford), 56: 203–
206. doi:10.1046/j.0300-0664.2001.01456.x. PMID:11874411.
Havel, P.J. 2001. Peripheral signals conveying metabolic information to the brain: short-term and long-term regulation of food intake and energy homeostasis. Exp. Biol. Med. (Maywood), 226:
963–977. PMID:11743131.
Heini, A.F., Kirk, K.A., Lara-Castro, C., and Weinsier, R.L. 1998a.
Relationship between hunger-satiety feelings and various metabolic parameters in women with obesity during controlled
weight loss. Obes. Res. 6: 225–230. PMID:9618127.
Heini, A.F., Lara-Castro, C., Kirk, K.A., Considine, R.V., Caro,
J.F., and Weinsier, R.L. 1998b. Association of leptin and hunger-satiety ratings in obese women. Int. J. Obes. Relat. Metab.
Disord. 22: 1084–1087. doi:10.1038/sj.ijo.0800731. PMID:
9822946.
Heymsfield, S.B., Greenberg, A.S., Fujioka, K., Dixon, R.M.,
Kushner, R., Hunt, T., et al. 1999. Recombinant leptin for
weight loss in obese and lean adults: a randomized, controlled,
dose-escalation trial. JAMA, 282: 1568–1575. doi:10.1001/jama.
282.16.1568. PMID:10546697.
Holst, J.J. 1994. Glucagonlike peptide 1: a newly discovered gastrointestinal hormone. Gastroenterology, 107: 1848–1855.
PMID:7958701.
Imbeault, P., Doucet, E., Mauriege, P., St-Pierre, S., Couillard, C.,
Almeras, N., et al. 2001. Difference in leptin response to a highfat meal between lean and obese men. Clin. Sci. (London), 101:
359–365. PMID:11566073.
Je´quier, E., and Tappy, L. 1999. Regulation of body weight in humans. Physiol. Rev. 79: 451–480. PMID:10221987.
Joannic, J.L., Oppert, J.M., Lahlou, N., Basdevant, A., Auboiron,
S., Raison, J., et al. 1998. Plasma leptin and hunger ratings in
healthy humans. Appetite, 30: 129–138. doi:10.1006/appe.1997.
0112. PMID:9573448.
Kennedy, G.C. 1953. The role of fat depot in the hypothalamic
control of food intake in the rat. Proc. R. Soc. London B. Biol.
Sci. 140B: 578–592.
Keys, A., Brozek, J., Henschel, A., Mickelsen, O., and Taylor, H.L.
1950. The biology of human starvation. University of Minnesota
Press, Minneapolis, Minnesota.
Kojima, M., Hosoda, H., Date, Y., Nakazato, M., Matsuo, H., and
Kangawa, K. 1999. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature (London), 402: 656–660.
doi:10.1038/45230. PMID:10604470.
Korkeila, M., Rissanen, A., Kaprio, J., Sorensen, T.I., and Koskenvuo, M. 1999. Weight-loss attempts and risk of major weight
gain: a prospective study in Finnish adults. Am. J. Clin. Nutr.
70: 965–975. PMID:10584040.
Korner, J., and Leibel, R.L. 2003. To eat or not to eat – how the
gut talks to the brain. N. Engl. J. Med. 349: 926–928. doi:10.
1056/NEJMp038114. PMID:12954739.
Korner, J., Bessler, M., Cirilo, L.J., Conwell, I.M., Daud, A., Restuccia, N.L., et al. 2005. Effects of Roux-en-Y gastric bypass
Appl. Physiol. Nutr. Metab. Vol. 32, 2007
surgery on fasting and postprandial concentrations of plasma
ghrelin, peptide YY, and insulin. J. Clin. Endocrinol. Metab.
90: 359–365. PMID:15483088.
Korner, J., Inabnet, W., Conwell, I.M., Taveras, C., Daud, A.,
Olivero-Rivera, L., et al. 2006. Differential effects of gastric bypass and banding on circulating gut hormone and leptin levels.
Obesity (Silver Spring), 14: 1553–1561. PMID:17030966.
Laviolette, M.A., Imbeault, P., Prud’homme, D., Rabassa-Lhoret,
R., and Doucet, E. 2005. Ghrelin, but not PYY, is correlated to
spontaneous food intake in healthy premenopausal women. A
MONET Study. Obes. Res. 13: A47.
le Roux, C.W., Aylwin, S.J., Batterham, R.L., Borg, C.M., Coyle,
F., Prasad, V., et al. 2006. Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and
improve metabolic parameters. Ann. Surg. 243: 108–114.
doi:10.1097/01.sla.0000183349.16877.84. PMID:16371744.
Leibel, R.L., Rosenbaum, M., and Hirsch, J. 1995. Changes in energy expenditure resulting from altered body weight. N. Engl. J.
Med. 332: 621–628. doi:10.1056/NEJM199503093321001.
PMID:7632212.
Lindeman, J.H., Pijl, H., Van Dielen, F.M., Lentjes, E.G., Van Leuven, C., and Kooistra, T. 2002. Ghrelin and the hyposomatotropism of obesity. Obes. Res. 10: 1161–1166. PMID:12429880.
Lund, P.K., Goodman, R.H., Dee, P.C., and Habener, J.F. 1982.
Pancreatic preproglucagon cDNA contains two glucagon-related
coding sequences arranged in tandem. Proc. Natl. Acad. Sci.
U.S.A. 79: 345–349. doi:10.1073/pnas.79.2.345. PMID:7043459.
MacLean, P.S., Higgins, J.A., Johnson, G.C., Fleming-Elder, B.K.,
Donahoo, W.T., Melanson, E.L., et al. 2004. Enhanced metabolic efficiency contributes to weight regain after weight loss in
obesity-prone rats. Am. J. Physiol. Regul. Integr. Comp. Physiol.
287: R1306–R1315. PMID:15331386.
MacLean, P.S., Higgins, J.A., Jackman, M.R., Johnson, G.C.,
Fleming-Elder, B.K., Wyatt, H.R., et al. 2006. Peripheral metabolic responses to prolonged weight reduction that promote rapid, efficient regain in obesity-prone rats. Am. J. Physiol.
Regul. Integr. Comp. Physiol. 290: R1577–R1588. PMID:
16455763.
Masuzaki, H., Ogawa, Y., Isse, N., Satoh, N., Okazaki, T., Shigemoto, M., et al. 1995. Human obese gene expression. Adipocyte-specific expression and regional differences in the adipose
tissue. Diabetes, 44: 855–858. PMID:7789654.
McGuire, M.T., Wing, R.R., Klem, M.L., Lang, W., and Hill, J.O.
1999. What predicts weight regain in a group of successful
weight losers? J. Consult. Clin. Psychol. 67: 177–185. PMID:
10224727.
Miller, D.S., and Parsonage, S. 1975. Resistance to slimming:
adaptation or illusion? Lancet, 1: 773–775. PMID:48002.
Miller, W.C., Koceja, D.M., and Hamilton, E.J. 1997. A metaanalysis of the past 25 years of weight loss research using diet,
exercise or diet plus exercise intervention. Int. J. Obes. Relat.
Metab. Disord. 21: 941–947. doi:10.1038/sj.ijo.0800499.
PMID:9347414.
Mix, H., Manns, M.P., Wagner, S., Widjaja, A., and Brabant, G.
1999. Expression of leptin and its receptor in the human stomach. Gastroenterology, 117: 509. doi:10.1053/gast.1999.
0029900509b. PMID:10465633.
Mix, H., Widjaja, A., Jandl, O., Cornberg, M., Kaul, A., Goke, M.,
et al. 2000. Expression of leptin and leptin receptor isoforms in
the human stomach. Gut, 47: 481–486. doi:10.1136/gut.47.4.481.
PMID:10986207.
Morinigo, R., Moize, V., Musri, M., Lacy, A.M., Navarro, S.,
Marin, J.L., et al. 2006. Glucagon-like peptide-1, peptide YY,
hunger, and satiety after gastric bypass surgery in morbidly ob#
2007 NRC Canada
Doucet and Cameron
ese subjects. J. Clin. Endocrinol. Metab. 91: 1735–1740. doi:10.
1210/jc.2005-0904. PMID:16478824.
Naslund, E., and Hellstrom, P.M. 1998. Glucagon-like peptide-1 in
the pathogenesis of obesity. Drug News Perspect. 11: 92–97.
doi:10.1358/dnp.1998.11.2.659947. PMID:15616656.
Nauck, M.A., Niedereichholz, U., Ettler, R., Holst, J.J., Orskov,
C., Ritzel, R., et al. 1997. Glucagon-like peptide 1 inhibition
of gastric emptying outweighs its insulinotropic effects in
healthy humans. Am. J. Physiol. 273: E981–E988. PMID:
9374685.
Neary, N.M., Small, C.J., Druce, M.R., Park, A.J., Ellis, S.M.,
Semjonous, N.M., et al. 2005. Peptide YY3–36 and glucagonlike peptide-17–36 inhibit food intake additively. Endocrinology,
146: 5120–5127. doi:10.1210/en.2005-0237. PMID:16150917.
Onaga, T., Zabielski, R., and Kato, S. 2002. Multiple regulation of
peptide YY secretion in the digestive tract. Peptides, 23: 279–
290. doi:10.1016/S0196-9781(01)00609-X. PMID:11825643.
Otto, B., Cuntz, U., Fruehauf, E., Wawarta, R., Folwaczny, C.,
Riepl, R.L., et al. 2001. Weight gain decreases elevated plasma
ghrelin concentrations of patients with anorexia nervosa. Eur. J.
Endocrinol. 145: 669–673. PMID:11720888.
Ouellet, J.-P., Heard, C.D., Boutin, S., and Mulders, R. 1997. A
comparison of body condition and reproduction of caribou on
two predator-free arctic islands. Can. J. Zool. 75: 11–17.
Overduin, J., Frayo, R.S., Grill, H.J., Kaplan, J.M., and Cummings,
D.E. 2005. Role of the duodenum and macronutrient type in ghrelin regulation. Endocrinology, 146: 845–850. PMID:15528308.
Pasman, W.J., Saris, W.H., and Westerterp-Plantenga, M.S. 1999.
Predictors of weight maintenance. Obes. Res. 7: 43–50.
PMID:10023729.
Pratley, R.E., Nicolson, M., Bogardus, C., and Ravussin, E. 1997.
Plasma leptin responses to fasting in Pima Indians. Am. J. Physiol. 273: E644–E649. PMID:9316457.
Prodam, F., Me, E., Riganti, F., Gramaglia, E., Bellone, S., Baldelli, R., et al. 2006. The nutritional control of ghrelin secretion
in humans: the effects of enteral vs. parenteral nutrition. Eur. J.
Nutr. 45: 399–405. doi:10.1007/s00394-006-0613-z. PMID:
17061019.
Romon, M., Lebel, P., Velly, C., Marecaux, N., Fruchart, J.C., and
Dallongeville, J. 1999. Leptin response to carbohydrate or fat
meal and association with subsequent satiety and energy intake.
Am. J. Physiol. 277: E855–E861. PMID:10567012.
Rosenbaum, M., Murphy, E.M., Heymsfield, S.B., Matthews, D.E.,
and Leibel, R.L. 2002. Low dose leptin administration reverses
effects of sustained weight-reduction on energy expenditure and
circulating concentrations of thyroid hormones. J. Clin. Endocrinol. Metab. 87: 2391–2394. doi:10.1210/jc.87.5.2391. PMID:
11994393.
Roth, C.L., Enriori, P.J., Harz, K., Woelfle, J., Cowley, M.A., and
Reinehr, T. 2005. Peptide YY is a regulator of energy homeostasis in obese children before and after weight loss. J. Clin. Endocrinol. Metab. 90: 6386–6391. doi:10.1210/jc.2005-1357.
PMID:16204364.
Sinha, M.K., Ohannesian, J.P., Heiman, M.L., Kriauciunas, A., Stephens, T.W., Magosin, S., et al. 1996. Nocturnal rise of leptin in
lean, obese, and non-insulin-dependent diabetes mellitus subjects. J. Clin. Invest. 97: 1344–1347. PMID:8636448.
Speechly, D.P., Rogers, G.G., and Buffenstein, R. 1999. Acute appetite reduction associated with an increased frequency of eating
in obese males. Int. J. Obes. Relat. Metab. Disord. 23: 1151–
1159. doi:10.1038/sj.ijo.0801046. PMID:10578205.
Strader, A.D., Vahl, T.P., Jandacek, R.J., Woods, S.C., D’Alessio,
D.A., and Seeley, R.J. 2005. Weight loss through ileal transposition is accompanied by increased ileal hormone secretion and
531
synthesis in rats. Am. J. Physiol. Endocrinol. Metab. 288:
E447–E453. doi:10.1152/ajpendo.00153.2004. PMID:15454396.
Tatemoto, K., and Mutt, V. 1980. Isolation of two novel candidate
hormones using a chemical method for finding naturally occurring polypeptides. Nature (London), 285: 417–418. doi:10.1038/
285417a0. PMID:6892950.
Taylor, M.A., and Garrow, J.S. 2001. Compared with nibbling,
neither gorging nor a morning fast affect short-term energy balance in obese patients in a chamber calorimeter. Int. J. Obes.
Relat. Metab. Disord. 25: 519–528. doi:10.1038/sj.ijo.0801572.
PMID:11319656.
Tremblay, A., and Doucet, E. 2000. Obesity: a disease or a biological adaptation? Obes. Rev. 1: 27–35. doi:10.1046/j.1467-789x.
2000.00006.x. PMID:12119642.
Tremblay, A., Doucet, E., Imbeault, P., Maurie`ge, P., Despre´s, J.P., and Richard, D. 1999. Metabolic fitness in active reducedobese individuals. Obes. Res. 7: 556–563. PMID:10574514.
Tschop, M., Weyer, C., Tataranni, P.A., Devanarayan, V., Ravussin, E., and Heiman, M.L. 2001. Circulating ghrelin levels are
decreased in human obesity. Diabetes, 50: 707–709.
PMID:11289032.
Verdich, C., Toubro, S., Buemann, B., Lysgard Madsen, J., Juul
Holst, J., and Astrup, A. 2001. The role of postprandial releases
of insulin and incretin hormones in meal-induced satiety – effect
of obesity and weight reduction. Int. J. Obes. Relat. Metab. Disord. 25: 1206–1214. doi:10.1038/sj.ijo.0801655. PMID:
11477506.
Wadden, T.A. 1993. Treatment of obesity by moderate and severe
caloric restriction. Results of clinical research trials. Ann. Intern.
Med. 119: 688–693. PMID:8363198.
Wadden, T.A., Considine, R.V., Foster, G.D., Anderson, D.A.,
Sarwer, D.B., and Caro, J.S. 1998. Short- and long-term changes
in serum leptin dieting obese women: effects of caloric restriction and weight loss. J. Clin. Endocrinol. Metab. 83: 214–218.
doi:10.1210/jc.83.1.214. PMID:9435444.
Weigle, D.S., Duell, P.B., Connor, W.E., Steiner, R.A., Soules,
M.R., and Kuijper, J.L. 1997. Effect of fasting, refeeding, and
dietary fat restriction on plasma leptin levels. J. Clin. Endocrinol. Metab. 82: 561–565. doi:10.1210/jc.82.2.561. PMID:
9024254.
Westerterp-Plantenga, M.S., Saris, W.H., Hukshorn, C.J., and
Campfield, L.A. 2001. Effects of weekly administration of pegylated recombinant human OB protein on appetite profile and energy metabolism in obese men. Am. J. Clin. Nutr. 74: 426–434.
PMID:11566639.
Westerterp-Plantenga, M.S., Kovacs, E.M., and Melanson, K.J.
2002. Habitual meal frequency and energy intake regulation in
partially temporally isolated men. Int. J. Obes. Relat. Metab.
Disord. 26: 102–110. doi:10.1038/sj.ijo.0801855. PMID:
11791154.
WHO. 2003. Diet, nutrition and the prevention of chronic diseases.
Geneva.
Wing, R.R., and Jeffery, R.W. 1995. Effect of modest weight loss
on changes in cardiovascular risk factors: are there differences
between men and women or between weight loss and maintenance? Int. J. Obes. Relat. Metab. Disord. 19: 67–73.
PMID:7719395.
Woods, S.C. 2005. Signals that influence food intake and body
weight. Physiol. Behav. 86: 709–716. doi:10.1016/j.physbeh.
2005.08.060. PMID:16260007.
Woods, S.C., Decke, E., and Vasselli, J.R. 1974. Metabolic hormones and regulation of body weight. Psychol. Rev. 81: 26–43.
PMID:4812879.
Wren, A.M., Seal, L.J., Cohen, M.A., Brynes, A.E., Frost, G.S.,
#
2007 NRC Canada
532
Murphy, K.G., et al. 2001. Ghrelin enhances appetite and increases food intake in humans. J. Clin. Endocrinol. Metab. 86:
5992. doi:10.1210/jc.86.12.5992. PMID:11739476.
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., and
Appl. Physiol. Nutr. Metab. Vol. 32, 2007
Friedman, J.M. 1994. Positional cloning of the mouse obese
gene and its human homologue. Nature (London), 372: 425–
432. doi:10.1038/372425a0. PMID:7984236.
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2007 NRC Canada