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C
URRENT
O
PINION
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.
Summary
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.
Keywords
central mechanisms, cholecystokinin, dietary protein, energy intake, fat, gastrointestinal, genetic,
glucagon-like peptide-1, meal frequency, peptide YY
INTRODUCTION
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
DOI:10.1097/MCO.0000000000000078
www.co-clinicalnutrition.com Volume 17 Number 5 September 2014
REVI EW
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
RELATIONSHIPS BETWEEN
MACRONUTRIENTS, GUT HORMONES AND
APPETITE PERCEPTIONS
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
KEY POINTS
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
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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.
EFFECTS OF DIETARY MODIFICATIONS
ON GUT HORMONES AND EATING
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
[12
&
], 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
[13
&&
], 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.
GUT HORMONES AND EATING
BEHAVIOUR, AND PATHWAYS
MEDIATING THEIR EFFECTS
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
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[19
&&
]. 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
[24
&&
,25
&&
]. 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.
ADDITIONAL FACTORS INFLUENCING
APPETITE AND EATING
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.
Probiotics
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
&
,31
&
], 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
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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.
CONCLUSION
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
disorders.
Nutrition and the gastrointestinal tract
462 www.co-clinicalnutrition.com Volume 17 Number 5 September 2014
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Acknowledgements
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.
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Nutrition and the gastrointestinal tract
464 www.co-clinicalnutrition.com Volume 17 Number 5 September 2014