Você está na página 1de 7

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Modulation of hunger and satiety: hormones
and diet
Christine Feinle-Bisset
Purpose of review
To highlight recent research developments relating to the effects of, and interactions between, hormones
and diet, as well as underlying mechanisms, on appetite, energy intake and body weight. For this purpose,
clinically relevant English language articles were reviewed from October 2012 to April 2014.
Recent findings
The mechanisms underlying nutrient-induced energy intake suppression differ between dietary protein and
lipid. High-fat, energy-dense diets compromise the satiating effects of gut hormones, and, therefore,
promote further overconsumption. These effects are mediated by changes in the signalling in both
peripheral and central pathways, and may only be partially reversible by dietary restriction. Additional
factors, including probiotics, meal-related factors (e.g., eating speed and frequency), circadian influences
and gene polymorphisms, also modify energy intake and eating behaviour.
Research continues to unravel the pathways and mechanisms underlying the nutrient-induced and diet-
induced regulation of energy intake, as well as the changes, both peripherally and in the central nervous
system, brought about by the consumption of high-fat, energy-dense diets. Much further work is required to
translate this knowledge into novel, and effective, approaches for the management and treatment of obesity
and associated metabolic disorders.
central mechanisms, cholecystokinin, dietary protein, energy intake, fat, gastrointestinal, genetic,
glucagon-like peptide-1, meal frequency, peptide YY
Meal-induced changes in gastrointestinal function,
particularly the release of gut hormones, mediate, at
least in part, the effects of ingested nutrients on
satiation and satiety. Although all macronutrients
reduce energy intake, there has been a focus on
protein, as protein is the most satiating nutrient,
and also has a range of metabolic benefits. The effect
of protein on energy intake may not predominantly
be mediated by gut hormones, and a research focus
on the role for specific amino acids is beginning to
emerge. In addition, the gut hormone-related mech-
anisms underlying the relative satiating effects of
dietary protein and fat in lean and obese individuals
have not been fully elucidated. The gastrointestinal
responses to nutrients can be modified by changes
in dietary intake, so that dietary excess reduces
gastrointestinal sensitivity to the satiating effects
of nutrients and peripheral and central hormones,
whereas subsequent restriction may only partially
reverse these effects. Furthermore, the peripheral
and central pathways involved in mediating the
effects of endogenous and exogenous gut hormones
continue to be unravelled. There is also an increas-
ing recognition for roles of probiotics, meal fre-
quency (in addition to meal size) and circadian
influences on energy intake, and associations
between gene variations, appetite and nutrient
intake continue to emerge. This review aims to
highlight some of the extensive recent research
on the effects, and interactions, of hormones and
diet, as well as underlying mechanisms, on appetite,
energy intake and body weight.
National Health and Medical Research Council of Australia (NHMRC)
Centre of Research Excellence in Translating Nutritional Science to
Good Health, Royal Adelaide Hospital, University of Adelaide Discipline
of Medicine, Adelaide, South Australia, Australia
Correspondence to Prof Christine Feinle-Bisset, PhD, NHMRC Senior
Research Fellow, University of Adelaide Discipline of Medicine, Royal
Adelaide Hospital, Adelaide, SA 5000, Australia. Tel: +61 8 8222 5247;
fax: +61 8 8223 3870; e-mail: christine.feinle@adelaide.edu.au
Curr Opin Clin Nutr Metab Care 2014, 17:458464
www.co-clinicalnutrition.com Volume 17 Number 5 September 2014
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The potent eating-inhibitory effects of dietary
protein are maintained in the longer term, whereas
the satiating effect of fat appears to be reduced in
obesity. Because gut hormones have potent energy
intake-suppressant effects, there has been substan-
tial interest in identifying the mechanisms under-
lying the effects of protein, particularly relative to
dietary fat.
Comparative effects of macronutrients on gut
hormones, appetite and energy intake
Two studies have recently evaluated the effects of
high-protein, high-fat and high-carbohydrate meals
on gut hormone profiles and subsequent energy
intake [1
,2]. Brennan et al. [1
] found that
although in lean individuals hunger was less, full-
ness greater, and subsequent energy intake reduced,
following both standardized high-protein and high-
fat meals, compared with a high-carbohydrate meal,
in the obese individuals only the high-protein, but
not the high-fat, meal reduced hunger, increased
fullness and reduced subsequent energy intake.
Despite these differences, no major differences were
found in gut hormone responses between lean and
obese individuals; indeed, both the stimulation of
cholecystokinin(CCK) and suppressionof ghrelinin
response to the high-protein meal were sustained in
both groups. It is worth noting that, in the absence
of any substantial differences in habitual energy
intake, gut functions and energy intake may not
differ substantially between lean and obese indivi-
duals [3
], perhaps explaining, at least in part, dis-
crepancies between some published studies. In a
small study in eight healthy individuals [2], who
ingested pancake-based breakfasts containing 60%
energy from either protein, fat or carbohydrate, the
high-protein breakfast increased plasma glucagon-
like peptide-1 (GLP-1) and, particularly, peptide-YY
(PYY) concentrations much more than the high-fat
or high-carbohydrate meals. However, despite these
differential effects, there were no differences in
energy intake at lunch 4h later. Differences in the
palatability and composition (e.g., the high-fat
pancake was supplemented with bacon and grated
cheese) of the breakfast meals may have counter-
acted any effects of macronutrients on subsequent
intake suppression.
Intraduodenal nutrient administration is often
used to bypass any orosensory influences or inter-
individual variations in gastric emptying. Although
both intraduodenal protein and lipid (infused for
90min at 3kcal/min to mimic average gastric emp-
tying) significantly reduced subsequent energy
intake [4
], with no differences between them, infu-
sion of lipid was associated with much greater
stimulation of plasma CCK and GLP-1, whereas
protein more potently stimulated insulin and glu-
cagon. Thus, although the eating-inhibitory effect
of lipid is most likely mediated through gastrointes-
tinal mechanisms, other factors, not assessed in the
study, may mediate the effects of protein.
Mediation of effects of dietary protein by
amino acids
A recent study in rats has provided the most com-
prehensive evaluation of the potential eating-
inhibitory effects of amino acids [5
]. Intragastric
administration of high amounts (1g/kg body
weight and 27% of daily intake) of L-Arg, L-Lys
and L-Glu reduced food intake (in grams), when
compared with control (water), by up to 50%.
Surprisingly, L-Phe, L-Trp and L-Leu, which have
previously been reported to reduce energy intake
in humans and/or rodents, were ineffective. Further
studies, using much lower loads, are required to
establish physiological relevance, as well as applica-
bility of these findings, to humans. One recent study
in healthy, normal-weight males has demonstrated
that intraduodenal infusion of L-Trp, at the lowload
of 0.15kcal/min (providing 3.3g L-Trp, or 13.5kcal
over 90min) substantially suppressed subsequent
energy intake by 20668 kcal) [6
]. Inmice, dietary
L-Leu supplementation mimics, to an extent, the
The effect of dietary protein on energy intake appears
to not be predominantly mediated by gut hormones.
There is a growing research interest in characterizing
the effects of amino acids on energy intake regulation.
Excess energy intake, particularly from a high-fat diet,
impairs nutrient and transmitter (CCK, leptin, GLP-1,
oleoylethanolamine) signalling from the gastrointestinal
tract and gut brain communication.
Dietary restriction appears to reinstate, but possibly
only partially, gastrointestinal sensitivity to nutrients,
associated with reduced energy intake and
body weight.
Studies continue to unravel the peripheral and central
pathways, mediating the effects of gut hormones on
eating behaviour.
Gut hormone release and eating can also be modified
by a range of additional factors, including probiotics,
meal-related factors, circadian variation and
genetic polymorphisms.
Modulation of hunger and satiety: hormones and diet Feinle-Bisset
1363-1950 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-clinicalnutrition.com 459
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
effects of a high-proteindiet onfood intake, body fat
and insulin sensitivity, and a recent study [7] has
demonstrated that the effects of L-Leu (or a high-
protein content of the diet with the same L-Leu
content) on reductions in food intake and high-
fat diet-induced increase in fat mass are apparent
within 1 week. Fat accumulation was related directly
to energy intake, suggesting that the effects of L-Leu,
or high-protein, supplementation are related to
their effects on satiation. The effects of amino acids
on energy intake and metabolic control warrant
detailed investigation.
Factors contributing to fat-induced
suppression of eating
Fat-droplet size determines the speed of fat diges-
tion and subsequent liberation of fatty acids. Given
the potent effects of fatty acids on energy intake
suppression [8
], manipulation of fat-droplet size
may be a novel way of enhancing the appetite-
suppressant effect of dietary fat. A recent study [9]
in healthy humans who received either 5 or 9 g of
canola oil, with droplet sizes of either 0.1 or 3mm,
incorporated in a fat-free meal-replacement drink,
found that although plasma CCK concentrations
were greatest following the 9 g or 0.1mmcondition,
there were no differences in appetite or energy
intake at a meal 3h later between study conditions.
Providing the drink in closer temporal proximity to
the main meal may be more likely to reduce sub-
sequent energy intake. There has also been increas-
ing interest in the use of bile acids to modulate gut
hormone release, as a strategy to reduce energy
intake (and improve glycaemic control). For
example, rectal administration of taurocholic acid
caused dose-related increases in plasma GLP-1 and
PYY, as well as fullness, and a reduction in prospec-
tive consumption [10]. The doses of taurocholic
acid were high (1.5 and 3.5g); thus, the physiologi-
cal relevance of the findings needs to be confirmed
using lower doses.
Increasing evidence suggests that overeating is
associated with inadequate energy compensation,
and compromised gut function that may reinforce
overeating and, thus, weight gain. Following 2-day
overeating, compensation for excess energy intake
in humans was only 30%, and particularly the high-
fat, high-energy-density diet was associated with
greater food cravings and hunger, and reduced satis-
faction [11
]. Moreover, obese individuals ingested a
larger amount of calories, despite slower gastric
emptying, which in turn led to a compromised
release of gut hormones, including GLP-1 and PYY
], suggesting reduced gastric and small intestinal
sensitivity to nutrients, compared with lean con-
trols. Indeed, excess high-fat intake leads to com-
promised lipid-induced CCK satiation signalling
], so that only higher doses of intraperitoneal
CCK-8 reduced food intake in obesity-prone rats,
which showed reduced CCK-secretory responses to
lipid-gavage, and down-regulation of CCK-1 recep-
tors in nodose ganglia following high-fat feeding,
when compared with obesity-resistant rats. Leptin
resistance invagal afferent neurons is responsible for
reducing CCKsignalling and satiationinresponse to
high-fat feeding in diet-induced obese mice [14
In mice, a high-fat diet also reduces mechanosensi-
tivity in gastric tension receptors, which is further
inhibited by leptin, when compared with the stand-
ard laboratory diet [15
]. Furthermore, eating inhi-
bition by the GLP-1 agonists, exendin-4 and
liraglutide, was delayed in rats on a high-fat diet,
compared with low-fat diet-fed rats [16
]. Interest-
ingly, once eating inhibition occurred, the effect
persisted for longer in the high-fat, compared with
the low-fat, fed rats.
A landmark study has examined the gut-brain
connections involved in the compensatory over-
feeding in response to high-fat diet [17
]. When
administered into the gastrointestinal lumen in
mice, the gastrointestinal lipid messenger, oleoyl-
ethanolamine, whose synthesis is reducedby chronic
high-fat intake, reinstated dopamine release in
high-fat-fed mice (in whom dopamine deficiency
exacerbates overeating), leading to a reduced intake
of high-fat food. Moreover, restoring lipid signalling
by administering oleoylethanolamine enhanced the
reward value of low-fat foods in high-fat-fed mice.
It appears [15
] that following a high-fat diet, a
return to the standard laboratory diet, mimicking
dietary restriction, only partially reverses the high-
fat diet-induced disruption in gastric vagal afferent
function, and leptin receptor expression in mucosal
afferents also remained lower, and comparable to
levels on the high-fat diet, possibly promoting
resistance to weight loss. In contrast, in obese
humans, 12-week 30% dietary restriction signifi-
cantly increased the plasma PYY responses to intra-
duodenal lipid towards levels observed in lean
controls [18
], suggesting an increase in gastroin-
testinal sensitivity to the actions of intraluminal
lipid, associated with a trend for reduced energy
intake and significant weight loss.
CCK-58 is now emerging as the major form of CCK
that is released from I cells in rats, dogs and humans
Nutrition and the gastrointestinal tract
460 www.co-clinicalnutrition.com Volume 17 Number 5 September 2014
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
]. Although inthis study inrats both CCK-8 and
CCK-58 reduced intake, CCK-8 was associated witha
shortening of the subsequent intermeal interval; in
contrast, CCK-58 increased the satiety ratio, calcu-
lated as intermeal interval or size of preceding meal.
In the light of these results, studies in humans are
required to re-examine previous findings.
A study in patients that had undergone truncal
vagotomy provides evidence that an intact vagus is
required for the effects of exogenous GLP-1 on food
intake [20
]. However, the dose of GLP-1 (1.2pmol/
kg/min) was very high, and the relevance for
endogenous GLP-1, as well as the relative roles of
the gastric vs. hepatic branches, remains to be estab-
lished. Within the central nervous system, GLP-1
receptor activation in the ventral tegmental area
(VTA) is important for the control of palatable food
intake [21
]; intra-VTA injections of the GLP-1
antagonist, exendin-4, reduced palatable high-fat
food intake, an effect mediated in part by glutama-
tergic a-amino-3-hydroxy-5-methyl-4-isoxazolepro-
pionic acid or kainite, but not N-methyl-D-
aspartate, signalling. Furthermore, exendin-4-
stimulated tyrosine hydroxylase levels suggest
GLP-1 receptor involvement in VTA dopaminergic
signalling. Cytokines also mediate the CNS effects of
GLP-1 [22
]. Administration of antibodies for inter-
leukin-1b and interleukin-6 reversed the effect of
exendin-4 in the lateral ventricle on food intake
suppression in rats, and combined blockade of the
cytokines resulted in more pronounced effects on
both intake and body weight. Thus, studies are now
increasingly unravelling the central mechanisms
mediating the effects of GLP-1.
The role of peripheral Y2 receptors in mediating
macronutrient-induced inhibition of food intake
was evaluated in rats [23
]. A peripheral Y2, but
not Y1 or Y5, antagonists, reversed the anorexic
effects of intravenous PYY(3-36), and attenuated
the eating-inhibitory effects of lower, but not
higher, loads of long-chain triglyceride and casein
hydrolysate, but not maltodextrin. The relative
importance of peripheral vs. central Y2 receptors,
also for the mediation of effects of higher nutrient
loads, remains to be determined. Recent landmark
studies evaluated the role of lingual Y2 receptors
and oral PYY exposure for ingestive behaviour
]. Thus, in mice, salivary PYY(3-36) binds
to lingual Y2 receptors to reduce food intake, in
the absence of conditioned taste aversions [24
from the tongue, PYY(3-36)-induced signals travel
through the brainstem into hypothalamic satiety
centres. Disruption of PYY signalling, using PYY
knock-out mice, resulted in a significantly reduced
taste response to both bitter substances and lipid,
but not salty, sweet or sour tastants [25
], and lipid,
but not bitter, taste responsiveness was reinstated by
treatment of salivary glands of knock-out mice with
a vector encoding a PYY transgene. These data pro-
vide critical evidence for a role of oral PYY receptors
for fat detection and food intake regulation.
Evidence for the interference of hyperglycaemia
with eating-regulatory mechanisms stems from a
recent study, in which experimental elevation of
blood glucose by 5.4mM above fasting levels in
overweight or obese individuals impaired postpran-
dial PYY(3-36) release, ghrelin suppression and sati-
ety, whereas increasing insulin, associated with an
absence of meal-induced fullness, when compared
with the control condition [26
]. Further studies are
warranted to elucidate underlying mechanisms.
It is increasingly apparent that eating is also influ-
enced by additional biological, environmental and
other factors that have previously been overlooked,
but are now receiving more recognition.
There is increasing evidence for a key role of micro-
biota for human health and disease, with important
implications for the pathogenesis of obesity and type
2 diabetes [27
]. A recent study in mice provided
evidence that probiotics stimulate a probiotic-gut
flora-butyrate-GLP-1 axis, which modulates micro-
biota, increases butyrate production, associated with
marked stimulation of GLP-1, reduces high-fat diet-
induced food intake, weight gain and insulin resist-
ance, and, thus, has the ability to reduce obesity and
diabetes [28
]. These findings, and their therapeutic
potential, warrant detailed evaluation in humans.
Meal-related factors
Research on intake regulation has, to date, pre-
dominantly focused on the evaluation of meal, or
portion, size, at the expense of examining the effects
of, and on, eating frequency. A recent review [29
presents detailed evidence that although both por-
tion sizes and eating frequency have increased inthe
population, the latter may, contrary to widely held
views, be more problematic for weight gain.
Although more frequent eating is thought to reduce
spikes in hunger throughout the day, the relation-
ship between eating frequency and hunger is weak;
indeed, eating frequency is related directly to energy
intake. Experimental support comes from two
studies [30
], which evaluated the effect of
ingesting a standardized breakfast either in one
Modulation of hunger and satiety: hormones and diet Feinle-Bisset
1363-1950 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-clinicalnutrition.com 461
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
eating episode or spread out over 3h. Although
increased eating frequency reduced appetite and
induced an anorexigenic gut hormone profile, sub-
sequent energy intake did not differ between con-
ditions. The finding of reduced lipolysis and diet-
induced thermogenesis in the increased-frequency-
condition may have additional detrimental effects
by adversely affecting energy balance.
Energy density also promotes overconsumption,
and increasing energy density of a meal by 33%
increased energy intake from that meal much more
than increasing portion size by 33% [32
], con-
versely, reducing energy density of foods by either
reducing fat intake, increasing fruit and vegetable
consumption or incorporating water into foods can
reduce daily energy intake [33
Slowing the speed of eating, either by reducing
the rate of ingestion [34] or by increasing the num-
ber of masticatory cycles [35], may reduce appetite
and subsequent energy intake moderately in nor-
mal-weight individuals, although the data in over-
weight or obese individuals are conflicting [34]. The
eating rate can further potentiate the effect of the
energy density of a meal on energy intake [36
], so
that energy intake innonobese menand womenwas
highest during a high-energy-dense meal eaten at a
fast rate. Thus, whether simple behavioural changes
may effectively reduce energy intake and body
weight warrants further study.
Circadian variation
There is increasing interest in the metabolic con-
sequences of disruption of the circadian rhythm.
Circadian variations in rat gastric vagal mechano-
receptors [37
], and the existence of circadian
patterning for hunger in humans [38
], have been
demonstrated recently, underlining the role of cir-
cadian influences on energy intake and metabolism.
Peak levels (acrophase) for hunger were apparent,
between main meals, between 10 amand 7 pm[38
This study also evaluated the relationship between
energy expenditure and hunger, and the effect of
exercise on hunger, and found that suppression of
hunger during exercise was confined to the acro-
phase, that is, when hunger levels were above a
certain threshold, an effect that did not occur out-
side this time frame. Shift work has been associated
with a shift in gut hormone profiles towards a
positive energy balance. A recent study [39
] dem-
onstrated that female, overweight night-shift
workers exhibited blunted postmeal ghrelin sup-
pression and no stimulation of xenin, lower insulin
sensitivity, greater habitual energy intakes and a
trend for greater waist circumferences, in the
absence of differences in BMI, and increased trigly-
cerides, compared with their day-shift controls,
suggesting that shift work disrupts at least some
aspects of normal metabolic control.
Genetic influences
A number of gene variations have been identified
with associations to changes in appetite, and poten-
tial relevance for obesity. Individuals with the A
allele of the rs9939609 variant of the fat mass-associ-
ated and obesity-associated (FTO) gene respond to a
high-protein, but not a low-protein, reduced-calorie
diet with greater reductions in food cravings and
appetite scores [40
]. This effect diminished during
weight regain, possibly due to a reduction in protein
intake and essential amino acids, reducing FTO
messenger RNA expression [41]. Polymorphisms of
the rs17782313 variant of the melanocortin-4 recep-
tor have been associated strongly with obesity [42].
Given the relationship between gastrointestinal
function and eating, a recent study evaluated links
between rs17782313 polymorphisms with gastric
motor function, satiation and satiety in obesity
[43] and found that the rs17782313C allele was
associated with a lower nausea response, but not
any changes in appetite, to a caloric meal and slower
gastric emptying. How the findings may relate to an
increased BMI remains unclear. Although it is
tempting to envisage a rationale for genotyping in
the future to provide personalized nutrition inter-
ventions [40
], much more research is required in
this field to establish causal links between gene
polymorphisms and disturbed eating behaviour.
Recent research has continued to unravel the path-
ways and mechanisms underlying the nutrient-
induced and diet-induced regulation of energy
intake, as well as the changes, both peripherally
and in the central nervous system, brought about
by the consumption of high-fat, energy-dense diets,
as well as interactions with other influences, includ-
ing meal-related factors (e.g., meal frequency, eating
speed, energy density), circadian variation and
genetic factors. Much further work is required in
these areas, including the peripheral and central
mediation of gastrointestinal nutrient sensitivity
by gut hormones, the factors that determine the
reinstatement of nutrient sensitivity in response
to dietary restriction to maintain weight loss, the
determination of peripheral and central targets and
pathways for gut hormone analogues, to ultimately
translate this knowledge into novel, effective and
side-effect-free approaches for the management and
treatment of obesity and associated metabolic
Nutrition and the gastrointestinal tract
462 www.co-clinicalnutrition.com Volume 17 Number 5 September 2014
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
C.F.-B. is supported by a National Health and Medical
Research Council of Australia (NHMRC) Senior Research
Fellowship (grant no. 627002, 2010-14).
Conflicts of interest
There are no conflicts of interest.
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
Brennan IM, Luscombe-Marsh ND, Seimon RV, et al. Effects of fat, protein,
and carbohydrate and protein load on appetite, plasma cholecystokinin,
peptide YY, and ghrelin, and energy intake in lean and obese men. Am J
Physiol Gastrointest Liver Physiol 2012; 303:G129G140.
This study comparing the relative effects of equally palatable high-protein, high-fat
and high-carbohydrate meals on appetite perceptions, gut hormones and sub-
sequent energy intake in lean and obese individuals found that high-protein meals
suppress energy intake in both lean and obese individuals, an effect potentially
mediated by CCK and ghrelin, whereas obese individuals appear to be less
sensitive to the satiating effects of fat, in the absence of major differences in
gut hormone responses.
2. van der Klaauw AA, Keogh JM, Henning E, et al. High protein intake stimulates
postprandial GLP1 and PYY release. Obesity (Silver Spring) 2013; 21:1602
Seimon RV, Brennan IM, Russo A, et al. Gastric emptying, mouth-to-cecum
transit, glycemic, insulin, incretin and energy intake responses to a mixed-
nutrient liquid in lean, overweight and obese males. Am J Physiol Endocrinol
Metab 2013; 304:E294E300.
Thisstudyinlean, overweight andobeseindividualsdemonstratesthat, intheabsence
of any substantial differences in habitual energy intake, gastric emptying and energy
intake do not differ amongst individuals, despite substantial differences in BMI.
Ryan AT, Luscombe-Marsh ND, Saies AA, et al. Effects of intraduodenal lipid
and protein on gut motility and hormone release, glycemia, appetite, and
energy intake in lean men. Am J Clin Nutr 2013; 98:300311.
This study demonstrates that the eating-inhibitory effects of intraduodenal protein
are not predominantly mediated by changes in upper gastrointestinal motility and
gut hormones.
Jordi J, Herzog B, Camargo SM, et al. Specic amino acids inhibit food intake
via the area postrema or vagal afferents. J Physiol 2013; 591:56115621.
First comprehensive assessment of the comparative effects of the 20 proteogenic
amino acids on food intake in rats.
Steinert RE, Luscombe-Marsh ND, Little TJ, et al. Effects of intraduodenal
infusion of L-tryptophan on ad libitum eating, antropyloroduodenal motility,
glycemia, insulinemia and gut peptide secretion in healthy men. J Clin
Endocrinol Metab 2014. [Epub ahead of print]
Key study demonstrating that the amino acid, L-Trp, when administered intraduo-
denally in healhty, lean males, has major energy intake-suppressant effects, in clear
excess of its own energy content.
7. Freudenberg A, Petzke KJ, Klaus S. Dietary L-leucine and L-alanine supple-
mentation have similar acute effects in the prevention of high-fat diet-induced
obesity. Amino Acids 2013; 44:519528.
Feltrin KL, Brennan IM, Rades T, et al. Acute oral administration of lauric acid
reduces energy intake in healthy males. e-SPEN 2014; 9:e69e75.
Study demonstrating the potent effect of the fatty acid, lauric acid, when ingested
orally in encapsulated form, on subsequent energy intake, in the absence of any
adverse effects, including nausea.
9. Peters HP, Bouwens EC, Schuring EA, et al. The effect of submicron fat
droplets in a drink on satiety, food intake, and cholecystokinin in healthy
volunteers. Eur J Nutr 2014; 53:723729.
10. Wu T, Bound MJ, Standeld SD, et al. Effects of rectal administration of
taurocholic acid on glucagon-like peptide-1 and peptide YY secretion in
healthy humans. Diabetes Obes Metab 2013; 15:474477.
Apolzan JW, Bray GA, Hamilton MT, et al. Short-term overeating results in
incomplete energy intake compensation regardless of energy density or
macronutrient composition. Obesity 2014; 22:119130.
Following a short-term (2 days) of overeating, compensation for excess energy
intake is incomplete, and particularly a high-fat, energy-dense diet has detrimental
effects on hunger, cravings and satisfaction.
Meyer-Gerspach AC, Wo lnerhanssen B, Beglinger B, et al. Gastric and
intestinal satiation in obese and normal weight healthy people. Physiol Behav
2014; 129:265271.
Study demonstrating that in obese individuals with delayed gastric emptying,
nutrient exposure to the small intestine is delayed, leading to reduced gut hormone
release and greater energy intake.
Duca FA, Zhong L, Covasa M. Reduced CCK signaling in obese-prone rats
fed a high fat diet. Horm Behav 2013; 64:812817.
High-fat diet leads to compromised lipid-induced CCK satiation signalling in
obesity-prone, but not obesity-resistant, rats.
de Lartigue G, Barbier de la Serre C, Espero E, et al. Leptin resistance in vagal
afferent neurons inhibits cholecystokinin signalling and satiation in diet
induced obese rats. PLoS One 2012; 7:e32967.
Leptin enhances the sensitivity of vagal afferent neurons to CCK, and leptin
resistance in these neurons underlies reduced CCK signalling in diet-induced
Kentish SJ, ODonnell TA, Frisby CL, et al. Altered gastric vagal mechan-
osensitivity in diet-induced obesity persists on return to normal chow and is
accompanied by increased food intake. Int J Obes 2014; 38:636642.
High-fat diet compromises gastric vagal afferent mechanosensitivity in mice, an
effect only partially reversed by a change to a low-fat, standard laboratory diet.
Mul JD, Begg DP, Barrera JG, et al. High-fat diet changes the temporal prole
of GLP-1 receptor-mediated hypophagia in rats. Am J Physiol Regul Integr
Comp Physiol 2013; 305:R68R77.
In rats fed a high-fat diet, the feeding-inhibitory effects of the GLP-1 receptor
agonists, exendin-4 and liraglutide, occurred later, than in rats fed a low-fat diet.
However, once eating inhibition set in, the effect persisted for a longer period of time.
Tellez LA, Medina S, Han W, et al. A gut lipid messenger links excess dietary
fat to dopamine deciency. Science 2013; 341:800802.
A landmark study characterizing the important role of the lipid messenger,
oleoylethanolamine, in the mediation of gastrointestinal lipid-induced central
dopamine release, and its relevance for lipid-related control of meal intake and
reward-related eating.
Seimon RV, Taylor P, Little TJ, et al. Effects of acute and longer-term dietary
restriction on upper gut motility, hormone, appetite, and energy-intake re-
sponses to duodenal lipid in lean and obese men. Am J Clin Nutr 2014;
Dietary restriction in obese humans improves gastrointestinal sensitivity to intra-
duodenal lipid, associated with increased suppression of energy intake and weight
Overduin J, Gibbs J, Cummings DE, Reeve JR Jr. CCK-58 elicits both satiety
and satiation in rats while CCK-8 elicits only satiation. Peptides 2014; 54:71
A key study characterizing the relative effects of CCK-8 and CCK-58 in rats.
Although both isoforms reduced food intake, infusion of CCK-8 was associated
with a shortening of the subsequent inter-meal interval, whereas CCK-58 had the
opposite effect and, in fact, increased the satiety ratio.
Plamboeck A, Veedfald S, Deacon CF, et al. The effect of exogenous GLP-1
on food intake is lost in male truncally vagotomized subjects with pyloroplasty.
Am J Physiol Gastrointest Liver Physiol 2013; 304:G1117G1127.
In humans, an intact vagus is required for the effects of exogenous GLP-1 on food
Mietlicki-Baase EG, Ortinski PI, Rupprecht LE, et al. The food intake-sup-
pressive effects of glucagon-like peptide-1 receptor signaling in the ventral
tegmental area are mediated by AMPA/kainate receptors. Am J Physiol
Endocrinol Metab 2013; 305:E1367E1374.
A key study providing novel insights into the mechanisms, by which GLP-1
receptor agonists in the mesolimbic system control palatable food intake.
Shirazi R, Palsdottir V, Collander J, et al. Glucagon-like peptide 1 receptor
induced suppression of food intake, and body weight is mediated by central
IL-1 and IL-6. Proc Natl Acad Sci USA 2013; 110:1619916204.
First characterization of a role of the cytokines, interleukin-1b and interleukin-6, in
mediating the effects of GLP-1 receptor activation on the suppression of food
intake and body weight loss.
Reidelberger R, Haver A, Chelikani PK. Role of peptide YY(3-36) in the satiety
produced by gastric delivery of macronutrients in rats. AmJ Physiol Endocrinol
Metab 2013; 304:E944E950.
Demonstration of the importance of peripheral Y2 receptors in the mediation of
food intake-inhibitory effects of intragastric long-chain triglycerides and casein
hydrolysate, but not maltodextrin.
Hurtado MD, Sergeyev VG, Acosta A, et al. Salivary peptide tyrosine-tyrosine
3-36 modulates ingestive behavior without inducing taste aversion. J Neurosci
2013; 33:1836818380.
Landmark study on the role of oral PYY signaling for oral fat tasting.
La Sala MS, Hurtado MD, Brown AR, et al. Modulation of taste responsive-
ness by the satiation hormone peptide YY. FASEB J 2013; 27:50225033.
Another landmark study evaluating the role of oral PYY signalling for oral fat tasting.
Knudsen SH, Karstoft K, Solomon TP. Hyperglycemia abolishes meal-induced
satiety by a dysregulation of ghrelin and peptide YY3-36 in healthy over-
weight/obese humans. Am J Physiol Endocrinol Metab 2014; 306:E225
Experimentally induced hyperglycaemia compromises meal-related gut hormone
and insulin release, as well as the perception of fullness.
Nieuwdorp M, Gilijamse PW, Pai N, Kaplan LM. Role of the microbiome in
energy regulation and metabolism. Gastroenterology 2014; 146:1525
Excellent review of the relationships between the intestinal microbiota and host
metabolism, including energy intake, use and expenditure, in relation to glucose
and lipid metabolism, to reveal potential mechanisms by which the microbiota
affect metabolism.
Modulation of hunger and satiety: hormones and diet Feinle-Bisset
1363-1950 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-clinicalnutrition.com 463
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Yadav H, Lee JH, Lloyd J, et al. Benecial metabolic effects of a probiotic via
butyrate-induced GLP-1 hormone secretion. J Biol Chem2013; 288:25088
Demonstration of a key role for a probiotic in preventing and reversing high-fat diet-
induced obesity and associated metabolic complications by stimulating butyrate
production and butyrate-stimulated GLP-1 secretion.
Mattes R. Energy intake and obesity: Ingestive frequency outweighs portion
size. Physiol Behav 2013; Nov 28. doi: 10.1016/j.physbeh.2013.11.012.
Most comprehensive review summarizing the evidence for roles of both portion
size and eating frequency as contributors to overeating and obesity.
Allirot X, Saulais L, Seyssel K, et al. An isocaloric increase of eating episodes
in the morning contributes to decrease energy intake at lunch in lean men.
Physiol Behav 2013; 110-111:169178.
Allirot X, Seyssel K, Saulais L, et al. Effects of a breakfast spread out over time
on the food intake at lunch and the hormonal responses in obese men. Physiol
Behav 2014; 127:3744.
Two studies demonstrating in lean [11
] and obese [12
] men that although
spreading out breakfast over time, rather than eating in one episode, may
favourably reduce appetite and modulate gut hormones, but it does not affect
subsequent energy intake and, in fact, reduces diet-induced thermogenesis and
lipolysis, with potential detrimental effects on energy balance in the longer-term.
Williams RA, Roe LS, Rolls BJ. Assessment of satiety depends on the energy
density and portion size of the test meal. Obesity 2014; 22:318324.
This study showed that although a low-calorie salad ingested before a main meal
can reduce energy intake at the main meal, but it does not affect total energy intake.
Moreover, both an increase in the energy density, and the portion size, of the main
meal, both increased energy intake from that meal, with energy density having a
substantially greater effect.
Williams RA, Roe LS, Rolls BJ. Comparison of three methods to reduce
energy density. Effects on daily energy intake. Appetite 2013; 66:7583.
Reduction of energy density of foods using different strategies, including reduction
in fat content, increasing water content or increasing consumption of fruit and
vegetables, leads to a reduction in daily energy intake.
34. Shah M, Copeland J, Dart L, et al. Slower eating speed lowers energy intake in
normal-weight but not overweight/obese subjects. J Acad Nutr Diet 2014;
35. Zhu Y, Hsu WH, Hollis JH. Increasing the number of masticatory cycles is
associated with reduced appetite and altered postprandial plasma concen-
trations of gut hormones, insulin and glucose. Br J Nutr 2013; 110:384
Karl JP, Young AJ, Rood JC, Montain SJ. Independent and combined effects
of eating rate and energy density on energy intake, appetite, and gut
hormones. Obesity 2013; 21:E244E252.
Study demonstrating that a fast eating rate potentiates the effect of the energy
density of a meal on subsequent intake.
Kentish SJ, Frisby CL, Kennaway DJ, et al. Circadian variation in gastric vagal
afferent mechanosensitivity. J Neurosci 2013; 33:1923819242.
Elegant demonstration that the responses of gastric vagal afferent bres to
mechanical stimuli vary markedly throughout the light or dark cycle.
Wuorinen EC, Borer KT. Circadian and ultradian components of hunger in
human nonhomeostatic meal-to-meal eating. Physiol Behav 2013; 122:816.
Demonstration of a circadian patterning for hunger, with an acrophase apparent
between 10 am and 7 pm. Suppression of hunger during exercise was conned to
this phase, and absent outside of this time frame.
Schiavo-Cardozo D, Lima MM, Pareja JC, Geloneze B. Appetite-regulating
hormones from the upper gut: disrupted control of xenin and ghrelin in night
workers. Clin Endocrinol 2013; 79:807811.
Shift-work disrupts aspects of normal metabolic control, including postmeal
suppression of ghrelin and stimulation of xenin.
Huang T, Qi Q, Li Y, et al. FTO genotype, dietary protein, and change in
appetite: the Preventing Overweight Using Novel Dietary Strategies trial. AmJ
Clin Nutr 2014; 99:11261130.
Individuals with the FTOrs9939609 A allele respond to a high-protein, weight loss
diet with a reduction in food cravings and appetite.
41. Cheung MK, Gulati P, ORahilly S, Yeo GS. FTO expression is regulated by
availability of essential amino acids. Int J Obes 2013; 37:744747.
42. Xi B, Chandak GR, Shen Y, et al. Association between common polymor-
phism near the MC4R gene and obesity risk: a systematic review and meta-
analysis. PLoS One 2012; 7:e45731.
43. Acosta A, Camilleri M, Shin A, et al. Association of melanocortin 4 receptor
gene variation with satiation and gastric emptying in overweight and obese
adults. Genes Nutr 2014; 9:384.
Nutrition and the gastrointestinal tract
464 www.co-clinicalnutrition.com Volume 17 Number 5 September 2014