Biochimie: Amy T. Hutchison, Leonie K. Heilbronn

Biochimie xxx (2015) 1e11
Contents lists available at ScienceDirect
Biochimie
journal homepage: www.elsevier.com/locate/biochi
Review
Metabolic impacts of altering meal frequency and timing e Does when

we eat matter?
Amy T. Hutchison a, b, Leonie K. Heilbronn a, b, c, *
a
Discipline of Medicine, The University of Adelaide, Australia

South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, SA, 5005, Australia
c
Robinson Research Institute, The University of Adelaide, Australia
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 April 2015
Accepted 25 July 2015
Available online xxx
Obesity prevalence continues to rise throughout the developed world, as a result of positive energy
balance and reduced physical activity. At present, there is still a perception within the general community, and amongst some nutritionists, that eating multiple small meals spaced throughout the day is
benecial for weight control and metabolic health. However, intervention trials do not generally support
the epidemiological evidence, and data is emerging to suggest that increasing the fasting period between
meals may benecially impact body weight and metabolic health. To date, this evidence is of short term
duration, and it is becoming increasingly apparent that meal timing must also be considered if we are to
ensure optimal health benets in response to this dietary pattern. The purpose of this review is to
summate the existing human literature on modifying meal frequency and timing on body weight control,
appetite regulation, energy expenditure, and metabolic health under conditions of energy balance, restriction and surplus.
Crown Copyright 2015 Published by Elsevier B.V. All rights reserved.
Keywords:
Meal frequency
Time-restricted feeding
Alternate-day fasting
Metabolic health
1. Introduction
Obesity and overweight is a serious medical condition, and the
prevalence of this continues to rise in developed nations, now
affecting up to 60% of individuals. Worldwide in 2014, 39% of adults
were overweight, and 13% were obese [1]. If the current rates of
obesity continue, projections predict that by 2030, around 1.9
billion adults will be overweight or obese [2]. Obesity is associated
with multiple metabolic abnormalities including low grade
inammation, hepatic steatosis, and insulin resistance that markedly increase the risk of developing type 2 diabetes, cardiovascular
disease, infertility, and some types of cancers.
Identifying nutritional strategies that help regulate appetite and
limit energy intake is a key goal of many researchers, and the
consumption of small, regular meals has frequently been touted as
Abbreviations: ADF, alternate day fasting; AUC, area under the curve; DIT, diet
induced thermogenesis; EE, energy expenditure; HDL-C, high-density lipoprotein;
LDL-C, low-density lipoprotein; OGTT, oral glucose tolerance test; RMR, resting
metabolic rate; RQ, respiratory quotient; TRF, time restricted feeding; VAS, visual
analogue scale.
* Corresponding author. South Australian Health and Medical Research Institute
(SAHMRI), North Terrace, Adelaide, SA, 5005, Australia.
E-mail address: leonie.heilbronn@adelaide.edu.au (L.K. Heilbronn).
a dietary approach that may limit weight gain [3e5]. The original
concept for this approach was based on epidemiological evidence
that shows an inverse relationship between adiposity, metabolic
health and meal frequency [6e8]. Increased meal frequency has
also been advocated as a dietary strategy to promote weight loss by
enhancing satiety and reducing hunger [9], increasing energy
expenditure [10], and improving metabolic health [11,12]. However,
the evidence arising from intervention studies that have examined
nibbling vs. gorging eating patterns in energy balance or under
hypocaloric conditions shows limited benet [13e21]. Furthermore, prescribing for increased eating opportunities must be
carefully considered in today's obesogenic environment, since this
may inadvertently result in over-consumption and weight gain
[22e25]. This is especially important in light of recent evidence that
shows that overconsumption of energy-dense foods with increased
frequency results in poorer metabolic health [26].
Attention has turned to reduced meal frequency regimens,
which prolong the fasting period between meals, and improve a
number of health parameters including glycaemic control [27],
lipid proles [28,29], oxidative stress, inammation [29,30], and
body composition. Two modied meal patterns are of particular
interest: 1) intermittent or alternate day fasting (ADF), or 2) timerestricted feeding (TRF). ADF is a dietary approach where food is
http://dx.doi.org/10.1016/j.biochi.2015.07.025
0300-9084/Crown Copyright 2015 Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: A.T. Hutchison, L.K. Heilbronn, Metabolic impacts of altering meal frequency and timing e Does when we eat
matter?, Biochimie (2015), http://dx.doi.org/10.1016/j.biochi.2015.07.025
A.T. Hutchison, L.K. Heilbronn / Biochimie xxx (2015) 1e11
either withheld, or minimal calories are consumed typically at 1

meal, for 2e3 non-consecutive days per week followed by ad-libitum consumption for 4e5 days per week. TRF is a dietary pattern
whereby food intake is restricted to short windows of time, ranging
from 4 to 13 h. In this review, the evidence for modied meal frequency and timing on appetite regulation, body weight, energy
metabolism, and metabolic health parameters, including glycaemic
control and lipid proles will be compared. We will also examine
the role that circadian rhythms may play in mediating the physiological responses to a meal.
2. The effects of increased meal frequency on the energy
balance equation
Over 50 years ago, it was reported that lower meal frequency
was associated with increased body weight [6]. Since then, a
number of observational studies have supported this notion
[7,8,31]. However, as recently reviewed [32], these data should be
interpreted with caution. Most of these studies have relied solely on
self-reported diet records or 24-h recollections. Self-report is prone
to under-reporting of both caloric intake and meal frequency,
especially in overweight, obese and diet-restrained individuals
[33e35]. When under-reporting was accounted for, McCrory et al.
observed that greater eating frequency was associated with positive energy balance [32]. This highlights the need for controlled
intervention studies to delineate these effects. However, a paucity
of high quality studies exist. Most of these are acute studies of small
sample sizes [9,10,14,27,36e47], a handful are of short term duration [19,28,47e50], and few have examined effects over a longer
term [51e54].
2.1. Does increased meal frequency alter appetite regulation or
energy expenditure acutely?
The division of a meal into 4e5 smaller portions signicantly
reduced subsequent energy intake in lean men [9], although
perceived hunger and satiety were not different between meal
conditions. This response was not observed consistently [36] or in
obese men [37,44], and still yet other studies have reported reduced
feelings of fullness [40] and increased feelings of hunger in
response to increased meal frequency [27,41]. Of note, studies are of
small sample size (Table 1) and have not examined energy intake at
dinner, or subsequent meals. A study that was conducted for 6-days
inside a metabolic chamber showed that altering meal frequency
by delivering meals two or six times per day did not inuence
additional snacking on foods that were provided ad libitum [14].
Mechanistically, increased meal frequency may modulate the
pattern of release of the orexigenic hormone ghrelin [36,37,43].
However, total area under the curve (AUC) for ghrelin release was
not different between meal frequencies in lean [36,43] or overweight or obese [37,40] individuals acutely, or following an 8 week
hypocaloric intervention [19]. Thus, based on the available data,
following a nibbling meal pattern does not have superior effects
on appetite control, subsequent energy intake, or the modulation of
ghrelin release, at least acutely.
It was originally postulated that increasing meal frequency
would enhance energy expenditure through an increase in dietinduced thermogenesis (DIT) [55]. DIT was doubled in dogs that
were fed 4 small meals as compared with the same number of
calories consumed as a single meal [55]. However, studies in
humans have generally failed to detect differences in DIT in
response to increased meal frequency [39,45] (Table 1). Similarly,
studies that have examined energy expenditure over 24-h in
metabolic chambers, have not detected any effect of consuming 6
vs. 3 meals/d [41] or 3e5 meals/d vs. 1e2 meals/d [14,42,47]. It
should be noted that whilst these studies were well controlled, they
have been performed in small cohorts.
2.2. Does increasing meal frequency impact body weight
management or preserve lean mass?
In humans, body weight was not altered in lean individuals who
were instructed to alter meal frequency by consuming 3 or 6
[56,57], 2, 3 or 9 [58], or 1, 3 or 6 meals/d over 5e8 weeks [59]
(Table 2). Similarly, body weight was not altered in men who
reduced habitual meal frequency from 4 to 3 meals/d or increased
habitual meal frequency from 3 to 4 meals/d for 4 weeks, although
fat mass was increased by 360 g when meal frequency was reduced
[50]. This study is in contrast to rats that gained more weight when
allowed to nibble continuously, or fed 12 meals/d, as compared to
rats that were fed 2 meals/d either ad libitum or at 1.25 energy
requirements [60]. Of note, increased meal frequency did not
differentially affect weight, body composition or energy expenditure after 131 days of consuming a 20% energy restricted diet in rats
[61]. Similarly, Bortz et al. reported no effects of increased meal
frequency on weight loss following a 600 kcal/d diet in obese
women [62]. The rate of weight loss, fat loss and fat free mass loss
was also not different in overweight women who were prescribed a
1000 kcal/d energy restricted diet as either 2 or 3e5 meals daily for
4 weeks [47]. There was also no difference in weight loss in obese
men and women who were randomised to consume 3 meals, or
3 meals 3 snacks for 12 months [52]. Similar ndings have been
reported in other studies that have been conducted for between 4
and 26 weeks in obese individuals [19,53,63], supporting the
conclusion that there is little benet to increasing meal frequency
of hypocaloric diets, at least in terms of total weight loss.
Increased meal frequency may also promote fat mass loss and
preserve lean mass under hypocaloric conditions [64]. Lean mass
was preserved in obese women who consumed a hypocaloric diet
as 6 vs. 3 meals/d over 14 days, although differences in the
macronutrient composition may have impacted this outcome [48].
Three groups of obese patients were fed very low calorie diets on a
metabolic ward to alter the protein content of the diet (n 10),
meal frequency (n 14) or both (n 14) in a crossover design for
1 week each. Nitrogen loss was greater when obese individuals
were fed 1 vs. 5 meals/d and when fed 10% vs. 15% protein. Of note,
these effects were additive [65]. Similar trends were observed in a
subsequent study by Arciero et al. [66]. These studies suggest that
manipulating both protein and meal frequency are important to
minimise lean mass loss under hypocaloric conditions. Further, a
meta-analysis examining the effects of increased meal frequency
on body composition in 15 studies [64] reported that increased
meal frequency was linked with greater fat loss, and preservation of
lean mass. However, the authors conceded that a single study may
have inuenced this result. When this study, which was conducted
in amateur but well-trained boxers [67], was removed from the
analysis these relationships were lost. Collectively, the available
data suggests that increasing meal frequency does not confer
additional benets for appetite regulation, energy expenditure, or
body weight, and limited data supports the hypothesis that this
may spare lean mass under hypocaloric conditions.
2.3. Does increased meal frequency improve glycaemic control and
cardiovascular risk?
Epidemiological research shows more frequent meal intakes are
associated with lower fasting blood glucose and insulin, cholesterol
and triglycerides, and a reduced risk of developing type 2 diabetes
and coronary heart disease [12,68]. Acute intervention studies have
partially supported these ndings (Table 1), showing that division
Table 1
Randomised crossover trials examining the acute effects of increasing meal frequency on appetite, glycaemic response, energy intake and energy metabolism.
Subjects (n)
Duration
h: hours,
d: days
Test meal
frequency
Meal energy and composition (P: %

protein, F: % fat, C: % carbohydrate)
Appetite (VAS)
Glycaemic
response
Energy intake at
subsequent meal
Energy
metabolism
Reference
Lean men (8)

Lean men and
women (6)
Lean men (12)
6.75 h
4h
1 vs. 5
1 vs. 4
33% TDE (15P, 15F, 70C)

710 kcal (12P, 46F, 42C)
4 satiety
e
3 vs. 14
2866 kcal (15P, 30F, 55C)
Lean men (20)

Obese men (20)
Obese women (8)
4h
4h
12 h
1 vs. 4
1 vs. 4
3 vs. 6
675 kcal (6P, 37F,57C)

675 kcal (6P, 37F,57C)
1500 kcal (14P, 21F, 65C)
[ hunger, Y
satiety
Y hunger
Y hunger
e
4
e
e
[ DIT and fat
oxidation
Y protein oxidation
and RMR
Y DIT
Y DIT
e
[9]
[10]
36 h
4 insulin AUC
Y insulin and
glucose AUC
[ glucose AUC
[36]
[37]
[38]
Lean women (18)
6h
1 vs. 2
4 DIT
[39]
Overweight and
obese men (13)
Lean men and
women (15)
Lean men (5)
Obese men (7)
Lean men and
women (13)
11 h
3 vs. 6
1200 kcal (HCLF: 11P, 19F, 70C)

(LCHF: 11P, 65F, 24C)
2100e2180 kcal (14P, 26F, 60C)
[40]
4d
3
6
2
1
2
7
4 24 h EE, RQ or
fat oxidation
e
e
4 24 h EE
[41]
8h
6.75 h
2d
vs.
meals/d
vs. 12
vs. 5
vs.
meals/d
RMR 1.5 (15P, 30F, 55C)

66% TDE (13P, 23F, 64C)
33% TDE (15P, 15F, 70C)
1.4 sleeping metabolic rate
Y insulin AUC
Y insulin AUC
Y insulin AUC
and TAG
e
Y fullness, 4
hunger
[ hunger and
desire to eat
e
4
e
Y insulin and
glucose AUC
Y insulin AUC
4 glucose AUC
4
4 insulin AUC
e
e
Y
e
[27]
[43]
[44]
[46]
All effects are compared with reduced meal frequency. AUC: area under the curve; C: carbohydrate; DIT: diet-induced thermogenesis; EE: energy expenditure; F: fat; HCLF:
high carbohydrate, low fat; LCHF: low carbohydrate, high fat; MF: meal frequency; P: protein; RQ: respiratory quotient; TDE: total daily energy requirements; TAG:
triacylglycerol; VAS: visual analogue scale.
of a meal into smaller portions reduces the insulin excursion in

response to each meal and overall [38,43,69], although one study
did not detect a difference in the overall insulin AUC [43]. However,
increased meal frequency did not alter glucose response acutely
[27,38] or after 2-weeks [13,69]. Fasting glucose was not different in
obese men and women who consumed hypocaloric diets as either 3
or 6 meals per day for 12 months [52] or in individuals with type 2
diabetes after 4 weeks [70] (Table 2). One study reported that a
hypocaloric diet consumed as 2 meals/d (breakfast and lunch) v.
6 meals/d produced greater weight loss, reduced hepatic lipid
content, and improved insulin sensitivity in response to a GTT after
12 weeks in individuals with type 2 diabetes [54]. However, those
on the 2 meal/day condition fasted for a longer period prior to
testing, which may have contributed to some of these outcomes.
Further research, over a medium to long term is required to
examine the time course effects of increased meal frequency on
glycaemic control, particularly in at-risk individuals.
Eating three meals per day reduced blood triacylglycerols and
increased HDL-cholesterol (Table 2) [38,69], but total and LDLcholesterol levels were lowest after consuming meals with a
higher frequency (9e17 meals/day) [20,69]. Other studies show
that increasing meal frequency does not alter blood lipids after
2e4 weeks [71] or 12 months [52]. To demonstrate the importance
of considering meal frequency in the current obesogenic environment, Koopman et al. prescribed a 40% hypercaloric diet, as
either high-fat and high-sugar (HFHS), or high-sugar (HS), with
the excess calories consumed either at meals (increased meal size)
or between meals (increased meal frequency). Although, no differences in weight gain were observed, this study elegantly
showed that increased meal frequency, in the presence of caloric
excess, increased abdominal adipose tissue deposition, increased
hepatic triglyceride content, reduced insulin-induced suppression
of free fatty acids and reduced hepatic insulin sensitivity [26].
Hence, in the presence of potential caloric excess, increased meal
frequency may actually increase the risk of developing type 2
diabetes, and this should be carefully considered before prescribing an increased meal frequency pattern, since the benets are
modest at best.
3. Does reduced meal frequency or time-restricted feeding

(TRF) differentially impact appetite, body weight and
metabolic health?
There are a handful of studies that have compared the impacts
of consuming 1e2 meals/day vs. 3e5 meals/d on body weight and
metabolic health in humans, but none have examined this
approach long term (Table 2). In a randomised cross-over study that
was conducted inside a metabolic chamber, reducing meal frequency from 3 to 2 meals/d (breakfast and dinner) reduced
perceived satiety acutely in lean women [42]. However, there was
no differential impact on 24-h energy expenditure, or diet induced
thermogenesis over the 36 h of assessment. In obese individuals,
consuming 1 meal/d for 1 week resulted in greater weight loss vs.
an equicaloric diet that was consumed as 5 meals/d [65]. However,
there was no difference in weight loss in obese men who were
randomly assigned to consume a hypocaloric diet as either 1, 3 or
6 meals/d for 5 weeks [74]. Further, consuming 3e5 meals/d vs.
2 meals/d (breakfast and dinner) did not differentially impact body
weight, fat mass, fat free mass or 24-h energy expenditure in obese
women following a 1000 kcal/d hypocaloric diet after 4 weeks [47].
Thus, reducing meal frequency does not appear to differentially
impact weight loss or energy expenditure in humans. It should be
noted that these studies have not generally considered meal timing,
and were of small sample size.
Time restricted feeding describes a dieting approach where food
is available ad libitum for a shortened window of time. In lean rodents, providing an 8e9 h feeding opportunity, during the active
phase, abrogated the metabolic consequences of a high fat diet,
including maintaining lean body weight and normal glucose homeostasis [75]. In diet-induced obese rodents, switching to a TRF
protocol normalised the metabolic milieu by reducing hyperinsulinemia, hepatic steatosis, and inammation [76]. Interestingly,
when lean animals were switched to a TRF high fat diet protocol,
which allowed ad libitum access to the high fat diet for 2 consecutive days per week, simulating a weekend, lean body weights
and metabolic proles were maintained [76]. These studies suggest
that following a TRF protocol is of signicant benet to prevent
Table 2
Short term studies examining the effects of 1) increased and 2) reduced meal frequency on body weight and composition, lipid proles and glycaemia in humans.
Subjects (n) Design Diet
1. Increased meal frequency

Lean men
RX
Eucaloric
(7)
Obese men
and
women
(16)
Lean men
(36)
Duration Number of meals/d Body weight and

(weeks)
composition
Lipid proles
Total-C
LDL-C
2w
3 vs. 17
RP
Hypocaloric 8 w
3 vs. 6
4 weight, FM,
FFM
RP
Hypercaloric 6 w
3 vs. 6 High Fat/

Sugar [HFHS] or
High Sugar [HS]
4 weight
[ intrahepatic
triglyceride and
abdominal fat
[ weight loss Y
nitrogen loss
RX
Hypocaloric
Obese
women
(10)
Hypocaloric
Obese men RP
and
women
(93)
Hypocaloric
Obese men RP
and
women
(51)
RX
Eucaloric
Lean
women
(15)
Hypocaloric
Overweight RP
women
(8)
RX
Eucaloric
Lean
women
(6)
RX
Hypocaloric
Obese
women
(6)
RX
Eucaloric
Lean men
and
women
(19)
RX
Eucaloric
Men and
women*
(16)
RX
Eucaloric
Lean
women
(9)
RX
Eucaloric
Obese
women
(10)
2. Reduced meal frequency
RX
Eucaloric
Lean men
and
women
(15)
RP
Hypocaloric
Obese
women
(14)
Lean men
(24)
Parallel Eucaloric
Obese men
(11)
RX
2w
3 vs. 6
52 w
3 vs. 6
4 weight and
energy intake
24 w
3 vs. nibbling
(100 kcal/2e3 h)
4 BMI and
energy intake
3w
3 vs. 6
8w
3 vs. 6
3w
2 vs. 9 (3 as control) 4 weight
Glycaemic control
HDL- TG
C
4 4 glucose
Y fasting insulin
4 glucose and insulin IVGTT
[13]
[19]
4 glucose
6 HFHS Y hepatic insulin
sensitivity; 6 HS [ insulin
4 resting
EE
4 4
[52]
[53]
4 weight
[26]
[48]
[56]
4 4 fasting glucose
[57]
3 w each 3 then 1 or 9
4 weight loss
2w
3 vs. 9
4w
3 vs. 9
2w
Irregular*** (3e9).
vs. Regular (6)
4 energy intake
Irregular Irregular 4
MF [
MF [
2w
Irregular*** (3e9).
vs. Regular (6)
Irregular MF
[ energy intake
Irregular Irregular 4
MF [
MF [
8w
3 vs. 1
Y weight
Y FM
4w
3e5 vs. 2
4 weight,
4 FM,
4 FFM
4w
3 vs. 4**
4 weight
Reducing MF [
FM
4 weight, FM
Hypocaloric 5 w each 1 vs. 3 vs. 6
Energy
Reference
metabolism
[58]
[62]
4 4 insulin: glucose ratio
[69]
4 4 postprandial insulin
[71]
4 fasting insulin and

glucose Irregular MF [
postprandial insulin AUC
4 fasting insulin and
glucose
Irregular MF [ insulin AUC
Glucose 4
[72]
Irregular
MF Y DIT
[73]
[28]
4 24 h EE, [47]
DIT
[ sleeping
metabolic
rate
Reducing
[50]
MF [ RQ
[74]
All effects are compared with 3 meal frequency. ADMR: average daily metabolic rate (basal metabolic rate diet induced thermogenesis physical activity); AUC: area under
the curve; DIT: diet-induced thermogenesis; EE: energy expenditure; FFM: fat free mass; FM: fat mass; HDL-C: high-density lipoprotein-cholesterol; IVGTT: intravenous
glucose tolerance test; LDL-C: low-density lipoprotein cholesterol; MF: meal frequency; NS: not signicant; RX: randomised crossover; RP: randomised parallel; RQ: respiratory quotient; total-C: total cholesterol; TG: triglycerides. * Hypercholesterolemic, BMI not stated; ** Habitual 4 meal/d eaters reduced meals to 3, and habitual 3 meal/
d eaters increased meals to 4; *** irregular meal pattern: 7, 4, 9, 3, 5, 8, 6, 5, 9, 8, 3, 4, 7, and 6 occasions/d on days 1e14 (average 6).
weight gain, and normalises the metabolic consequences of a dietinduced obesity, at least in rodents.
There are a very limited number of studies that have interrogated the effects of time restricted feeding in humans. Most of this
evidence is from observational studies of individuals who undertook the Islamic ritual of fasting during the month of Ramadan
[77e83]. Under these conditions, not only is a TRF protocol
implemented, but the feeding time is switched to predominantly
night time consumption of foods, which may adversely impact
health. Nonetheless, studies reporting on Ramadan fasts are supportive of improved cardiovascular health [78,82,83]. Responses
include favourable improvements in blood lipids, including reductions in total and LDL-cholesterol, triglycerides, and increases in
HDL-cholesterol in lean [78,81e83] and overweight individuals
[77]. Some of these effects are likely due a mild energy restriction,
since most have reported modest weight loss in response to
Ramadan fasting [77,78]. Of concern, some studies have noted that
fasting glucose is increased after Ramadan [78], but this is not reported universally [82].
The timing that meals are distributed across the wake cycle
likely plays a role in body weight regulation and metabolic health.
Whilst self-reported morning food intake was not associated with
obesity, consuming more than a third of daily energy intake at the
evening meal doubled the risk of obesity compared with
consuming more than a third of energy intake at, or before 12:00 h
[84]. Further, eating lunch later in the day (i.e. after 15:00 h) was
predictive of poorer weight loss during a 20-week dietary intervention, and this effect was independent from self-reported 24-h
caloric intakes [85]. Poorer insulin sensitivity by HOMA-IR was
also noted. A 12-week intervention study reported similar ndings
[86]. In that study, subjects who were assigned to consume a larger
proportion of their calories at breakfast lost signicantly more
weight than those who consumed a majority of their calories at
dinner [86]. Taken together these data suggest that under hypocaloric conditions, a larger proportion of total daily energy
consumed in the morning, as opposed to later in the day is more
benecial for weight loss. However, the mechanisms underlying
this phenomenon are unclear. In a recent study, Bandin et al. fed
normal weight women 3 standardised meals for 1 week, with
breakfast and dinner at set times, and lunch consumed either early
(13:00 h) or late (16:30), in a randomised cross-over design. Eating
lunch later resulted in decreased pre-meal resting energy expenditure, and lower pre-meal carbohydrate utilisation, although these
differences were small, and not sufcient to explain the difference
in weight loss [87]. Whether changes in appetite may also partially
explain this warrants further investigation.
To our knowledge, three randomised TRF intervention studies
have been conducted in humans [28,49,88]. The rst was a randomised controlled cross-over intervention, where lean individuals
were instructed to consume all of their calories required for weight
maintenance over a 4 h period from 17:00e21:00 h, or as 3 meals/
d for 8 weeks. Increased feelings of hunger and desire to eat were
noted prior to breaking the fast when following the TRF protocol vs.
the 3 meals/d condition [28]. However, measures of satiety and
fullness were not assessed post meal, or at other times per day.
Signicant reductions in body weight and body fat mass (as
measured by bioelectrical impedance analysis), by 1.4 and 2.1 kg
respectively, were also noted when following the TRF protocol [28].
Consumption of the evening meal was supervised within the laboratory, to ensure subjects consumed the entire meal. When on the
TRF protocol, measured food consumption was 65 kcal/d lower.
However, this small calorie discrepancy cannot fully explain the
weight loss observed, and measured physical activity levels were
unchanged. No assessments of energy expenditure were taken.
Despite a small amount of weight loss, fasting blood glucose
levels were increased, and TRF resulted in poorer glucose tolerance

in response to an oral glucose tolerance test (OGTT) [49]. This study
shows that limiting energy intake to late in the day is detrimental
for metabolic health in humans, although no differences in insulinemia were noted [49]. It is unclear whether limiting the calorie
allowance to the morning, or at lunch would have impacted this
outcome. Presumably, when following this TRF protocol, a greater
number of calories were consumed closer to the OGTT (i.e. 100%
calories between 1700 and 2100, vs. perhaps one third before 2000
in the 3 meals/d condition). These subjects had also likely adapted
to not having breakfast, and so performing the OGTT at a time they
were not accustomed to eating may have contributed to the poor
glucose tolerance observed. In support of this concept, a unique
study utilizing an irregular meal pattern of 7, 4, 9, 3, 5, 8, 6, 5, 9, 8, 3,
4, 7 and 6 meals/d, vs. continuing on a 6 meals/d pattern for
2 weeks, showed poorer insulin sensitivity in response to a highcarbohydrate mixed meal in both lean [72] and obese women
[73], although fasting blood glucose was not different between
dietary conditions. This study suggests that varying meal timing
each day induces inappropriate changes in carbohydrate metabolism. The effect of limiting food intake to 4-h in the evening (i.e.
from 17:00e21:00 h) on cardiovascular disease risk was also
studied. When following the TRF protocol HDL cholesterol was
increased, and triacylglycerols decreased, but total and LDLcholesterol were increased [28]. These changes were independent
of diet composition since dietary cholesterol and fatty acids were
carefully matched in each dietary condition.
To our knowledge, just one other study has performed a randomised controlled TRF protocol in humans. In this study, healthy,
lean male subjects were allowed to eat ad libitum for 13 h per day
(6 ame7 pm) for 2 weeks. Participants reported eating signicantly
less on the TRF vs. the control condition, and lost 0.4 kg compared
with a gain of 0.6 kg in the control condition [88]. Whilst this is a
minor change in body weight, this pattern is not that atypical of
modern eating patterns, and if benecial would be relatively easy to
translate into the community. The metabolic health impacts as well
as any effects on energy expenditure were not reported in that
study. Thus, the limited number of studies, with small sample sizes,
as well as the lack of data establishing the effects of TRF in obese
individuals highlights the necessity of further research in this area.
4. Considerations when designing reduced meal frequency
diets, circadian impacts
Differences in experimental design, including the number of
meals, the macronutrient composition of the meals, the timing of
meals and the study population make it difcult to draw meaningful conclusions regarding the effects of meal frequency on
appetite and energy intakes in humans. Animal studies have shown
that it is vital to consider meal timing [75,89,90] and consideration
of the degree of deviation from habitual meal patterns is also
warranted.
Circadian rhythms regulate a vast number of processes, and
current epidemiological evidence suggests that circadian rhythms
may play a unique role in nutrient metabolism in humans [91,92].
Circadian rhythms are driven by the central clock in the suprachiasmatic nuclei (SCN), which is synchronised by the ~24 h light/
dark cycle via retinal photoreceptors that project to the SCN via
the retinohypothalamic tract. The most well-known circadian
rhythm in humans is the sleepewake cycle, however many other
physiological, biochemical and behavioural responses are
controlled by the SCN, including regulation of core body temperature, blood pressure, and the release of a number of hormones
[93]. The core of the molecular clock is centred around the PERARNT-SIM domain, containing the transcription factors circadian
locomotor output cycles kaput (CLOCK) and brain and muscle

ARNT-like 1 (BMAL1), which act as positive elements in the
feedback loop. CLOCK and BMAL1 bind to the E-box promoter
element of target genes, driving the transcription of six repressor
encoding genes, three period genes (per1, per2, per3), two cryptochrome genes (cry1 and cry2), the transcription factor Rev-Erba
and one promoter gene RORa [94].
Apart from the SCN, peripheral clock systems are also found in
a number of tissues, including adipose tissue, the pancreas, liver
and the gastrointestinal tract, where they regulate local metabolic
processes, including glucose and lipid homeostasis, hormone
release, the immune response, gastrointestinal motility and
digestive processes [95]. The peripheral circadian clocks, particularly those in liver and adipose tissue are entrained by additional
zeitgebers, including nutrients, food intake and meal timing, body
temperature and physical activity, since they cannot perceive
lightedark cues directly [96,97]. Critically, these tissues are
strongly entrained by feeding patterns [96], so that alterations in
feeding time can uncouple the central and peripheral clocks,
which disrupts homeostasis and can cause disturbances in leptin
release, glucose and energy metabolism and insulin sensitivity.
Under normal conditions, metabolism and nutrient utilisation
oscillate at an optimal phase and amplitude, according to the
sleep/wake cycle, to allow temporal coordination of key physiological functions [98]. When circadian rhythms become misaligned, or the amplitude is dampened, metabolic function is also
disrupted. Importantly, while the circadian clock regulates metabolic oscillation, both metabolites, and the timing of their delivery
provide feedback which reciprocally impacts the central clock
[98]. As such, too many meals, or inappropriately timed meals may
result in circadian misalignment, or dampened circadian oscillations. Moreover, in humans, there is a time-of-day variation in
glucose and insulin release, with peak glucose tolerance occurring
in the morning, and a trough occurring in the evening and night
[99e101], independent of the sleep/wake and feeding/fasting cycles [102,103]. Hence, unusual feeding patterns can cause disruptions in both the circadian clock, and nutrient metabolism, which
ultimately result in the manifestation of disease states, including
obesity and metabolic syndrome.
An elegant study examined the effects of consuming 2, 3, 4, or
6 equally spaced meals over 24-h in mice [104]. By necessity,
mice were calorically restricted by 20% during this period, to
ensure all food was eaten within discrete time periods. In this
study, increasing meal frequency with equi-spaced meals did not
alter the phase of the peripheral clock. However, feeding mice
three discrete meals, out of phase, induced signicant changes in
peripheral clocks, as expected. Of particular interest, feeding
mice 3 meals/d in a pattern that mimicked typical human consumption (at our equivalent of 7 am, 12 pm and 8 pm, with
slightly more calories provided at lunch and dinner) was sufcient to lead to phase advancement of the peripheral clock. This
study also suggests that eating larger meals, later in the day may
be particularly detrimental to metabolic health. Unfortunately,
the impact of this feeding paradigm on energy or glucose
metabolism was not assessed, although there was no effect on
body weight. The short duration of this study, the necessity of
implementing a slight caloric restriction to ensure timely meal
completion and feeding a standard chow diet may have inuenced this response. Whether the size of the evening meal
signicantly impacts body weight and metabolic health in
humans is not yet clear, although increasing evidence indicates
this is likely.
Rodent studies have shown that, when fed in the wrong
phase (i.e. eating when the animal would normally rest) they
become obese, despite similar energy intake and expenditure.
However, the authors concede that a modest non-signicant

reduction in activity, and non-signicant increase in energy
intake may have been additive, resulting in the differences in
weight between groups [89]. Nevertheless, this data supports
additional animal studies [105], suggesting that the timing of food
intake is important in driving the obese phenotype [89]. Interestingly, when high-fat energy intake is restricted to the active
phase, the animals become obese, but do not develop the metabolic sequelae that are observed when the same foods are provided in the inactive phase [76]. As mentioned earlier, in mice,
using a time-restricted feeding protocol and restricting intake to
the active (night) phase was protective against obesity and the
metabolic consequences of a high-fat diet [75]. Hatori et al. reported that mice fed a high-fat diet, under ad libitum conditions
display dampened diurnal rhythms in food intake and resting
metabolic rate. By comparison, mice fed an isocaloric high-fat diet
under time-restricted conditions gained less weight, and diurnal
oscillations in resting energy expenditure and hepatic glucose
metabolism were restored. Moreover, these mice showed glucose
tolerance, and insulin levels, similar to those of control mice. As
such, restricting the feeding period, without reducing energy
intake, abrogated the deleterious effects of a high-fat diet [75].
In humans, night eating syndrome is characterised by late
night hyperphagia, abnormally increased food intake after the
evening meal, and nocturnal awaking for ingestion [106]. This
syndrome is associated with disruption of the sleep/wake cycle
and an increased risk of obesity [107]. Shift workers are also at
higher risks of metabolic disorders, including obesity and type 2
diabetes, possibly as a result of clock desynchronization [108,109].
Alternatively, this may be the result of mis-timing of meals. For
example, epidemiological evidence suggests that a shift toward
consuming more calories at night is more likely to result in being
overweight when compared with breakfast eaters [8], while
eating a greater proportion of calories at the dinner meal is
associated with a higher overall intake [110] and an increased risk
for obesity, metabolic syndrome and non-alcoholic fatty liver
disease [111].
Given that the sleepewake cycle and meal timing are both
disrupted in these conditions, it is not yet clear which may be the
main contributor to these poorer health outcomes. For example,
when 10 healthy adults were subjected to a 28 h day during
which they consumed 4 isocaloric meals, the resulting circadian
misalignment was associated with increased blood glucose, even
in the presence of increased insulin. Moreover, in 3 of the subjects, a postprandial glucose response was observed that would
suggest a pre-diabetic state [112]. However, a 28 h day cycle is
not entirely representative of shift-work patterns. A recent study
from the same group established that misalignment of the
endogenous circadian rhythms, and 24-h behavioural and environmental cycles impact glucose tolerance, through two distinct
mechanisms [113]. Individuals were exposed to two 8-day protocols, in a cross-over design. 1) a circadian misalignment
protocol, where they slept from 11 pm to 7 am from day 1e3, and
then were shifted 12 h to sleep from 11 am to 7 pm for days 4e8,
or 2) normal circadian alignment protocol (sleep 11 pme7 am).
Under the circadian alignment condition, glucose tolerance
declined from breakfast (i.e. 8 am) to dinner (8 pm). Under the
circadian misalignment condition, glucose tolerance was lower,
presumably as a result of lowered insulin sensitivity. Critically,
prolonged exposure to circadian misalignment also resulted in
poorer glucose tolerance [113]. These studies show that
consuming calories at night or out-of-phase will have deleterious effects on metabolic health, and clearly argue that meal
timing plays a key role in mitigating the metabolic impairment,
particularly under chronic conditions.
5. The unique case for intermittent and alternate day fasting

(ADF)
Interest in intermittent fasting has been steadily growing over
the past decade due to an increasing number of rodent studies
reporting benecial effects on glycaemic control, metabolism, cardiovascular risk, cancer survival and lifespan [114e121]. In rodents,
these effects have been noted without signicant weight loss [122]
suggesting that periodic cellular energy deprivation, rather than
weight loss per se is sufcient to provide the impetus to improve
metabolic health. Fasting depletes hepatic glycogen, reduces
glucose and insulin and produces a robust switch towards ketogenesis, lipolysis and lipid oxidation. As recently reviewed, fasting
also activates the cellular and metabolic processes that increase
stress resistance and autophagy and reduces oxidative and cellular
damage in animal models, all of which may contribute to the health
benets of fasting diets [123].
In humans, studies of intermittent fasting are limited to a
handful of, mostly uncontrolled, observational studies [124e132]
(Table 3). Non-obese individuals who followed a strict alternate
day fasting protocol for 22 days (24 h total fast, with ad libitum
energy intake on non-fasting days) displayed increased hunger and
reduced fullness on the rst day of fasting compared with baseline.
Hunger did not habituate over the course of the study, although
feelings of fullness increased [126]. In this study, individuals lost
~2.5 kg of body weight with signicant reductions in fat mass, and
fat-free mass [126]. This occurred despite instruction to consume
double their usual intake on feeding days to maintain body weight.
Hunger was not increased from baseline, or compared with a
control ad libitum fed group, after 12 weeks of modied-alternate
day fasting (m-ADF). In this study, the fast was broken by consumption of 25% of energy requirements between 1200 and 1400 h.
Satisfaction and feelings of fullness increased in the m-ADF group
suggesting that modied fasting may be easier for people to follow
over prolonged periods [130]. In this study, individuals lost ~6% of
their body weight [130], and similar weight losses have since been
reported in other m-ADF protocols in the obese [129,133,134], along
with reduced triacylglycerol levels and increased LDL-particle size
[128,130,131]. In support of the use of modied-fasting protocols,
mouse studies have shown that provision of 15e25% of calorie requirements during fasting days produced similar reductions in
visceral adipose tissue mass and increases in adiponectin over 4
weeks as true ADF [116,135]. However, the small amounts of food
provided during the fasting day may have been consumed relatively quickly, resulting in a prolonged fasting period. Of note, the
cellular proliferation rates were reduced in true and 85% ADF
groups only [117]. The impact of breaking up this fasting period on
longevity, autophagy, and stress resistance are not tested in mouse
models.
In a unique TRF/ADF study, healthy, lean men alternated fasting
for 20 h and consuming their habitual diet ad libitum on alternate
days (feast day) for 15 days. The prescribed fast was from 22:00 h
until 18:00 h the following day, thus re-feeding occurred later in
the day, which may not be optimal for metabolic health [28].
Despite this, ADF increased insulin-mediated glucose uptake as
assessed by euglycemic hyperinsulinemic clamp, although no
changes in body weight, fasting blood glucose or insulin were noted
[136]. To our knowledge, only one study has investigated the effects
of altering the times of caloric intake during the fasting day on
weight and compliance to the protocol for 3 months in humans. In
this study, 25% of calories were consumed at lunch (12:00e14:00 h;
ADF-L), dinner (18:00e20:00 h, ADF-D) or as 3 small meals
(100 kcal between 06:00e08:00 h, 300 kcal between
12:00e14:00 h and 100 kcal between 18:00e20:00 h) [127], and
there was no difference between groups. This study is the rst to
show that an ADF protocol may be adapted to suit individual circumstances, without compromising the magnitude of the health
benets. However, it did not test relative to true ADF. Altering the
carbohydrate and fat composition of ADF diets did not differentially
impact body weight or other outcomes in humans or animal
models [128,129].
A recent study tested the effects of a very low calorie/low protein fasting mimicking diet (FMD). This diet implemented a severe low protein energy restricted diet for 4e5 consecutive days
[137], followed by ad libitum intake. In mice, FMD was implemented for 1 day at 50% of energy intake, and a further 3 days at
10% of intake every 2 weeks. The timing of food provision to each
mouse was not made clear, but possibly the mice ate the entire
calorie allotment quickly, and so underwent prolonged fasting
periods each day. Similar to true alternate day fasting, FMD
stimulated ketogenesis, lipolysis and reduced blood glucose, insulin
and insulin-like growth factor 1 (IGF-1) [137]. Cumulative 14-day
energy intake was not different to control, although body weight
was lower in FMD mice, they were weight stable between 16 and 22
months of age. FMD mice displayed similar lean mass but reduced
visceral fat volume vs. control mice. In humans, the FMD was a low
calorie, low protein diet provided at ~1000 kcals/d for 1 day, and
then at 725 kcals/d for an additional 4 days every 4 weeks. This was
well tolerated over 3 months and resulted in minor weight loss and
signicant reductions in glucose, C-reactive protein (CRP) and IGF1
compared with controls.
Alternate day/intermittent fasting represents a feasible means
of reducing body weight that will improve metabolic health in
humans. However, the evidence is limited by the small number of
randomised, controlled trials investigating these outcomes, studies
with small sample sizes, a lack of a priori hypotheses, and multiple
hypotheses, and short study durations. Further, it is not clear
whether weight loss is necessary for these benecial effects in
humans and whether interrupting the fasting period mitigates
some of the benecial effects of ADF. Randomised controlled trials
comparing intermittent and TRF protocols with more traditional
methods of reducing energy intake (i.e. calorie restriction) are
warranted to better elucidate the mechanisms underlying the
observed benets of ADF.
6. Conclusions
Epidemiological reports have shown a favourable relationship
between increased meal frequency, weight and metabolic health
[6]. However, controlled intervention trials, whilst limited in sample size and duration, have shown little or no benecial impact of
increased meal frequency on body weight and health under either
eucaloric or hypocaloric conditions. Further, increased meal frequency was detrimental to metabolic health under conditions of
energy excess. This is of concern since the rising rates of obesity
indicate that most of the population eats to excess. The American
Dietetic Association acknowledges the limited evidence for absolute meal frequency and their position statement for weight management recommends that total caloric intake should be spread
throughout the day, with the consumption of 4e5 meals, including
breakfast. They also recognise the importance of meal timing and
suggest that consumption of more energy throughout the day may
be preferable to evening consumption [140]. Practically, dietary
adherence to any intervention remains of primary concern in the
population, and it may be that no one dietary recommendation
suits all.
Eating late in the day or at night disrupts circadian rhythms, and
may have adverse effects on weight and health. Modulating meal
patterns to best match diurnal rhythms of nutrient metabolism and
glucose tolerance may mitigate this risk, particularly in shift
Table 3
Effects of time restricted feeding (TRF) and alternate day fasting (ADF) on appetite, body weight and composition, lipid proles and glycaemia in humans.
Subjects (n)
Study Comparator Intervention

design diet
protocol
Time restricted feeding

Lean men and
RC
women (15)
Lean men and
RC
women (15)
Lean men (29)
RC
Alternate day fasting
Lean and
SA
overweight
men and
women (16)
SA
Lean and
overweight
men and
women (16)
Duration
of diet
(weeks)
Body weight and

composition
Y weight and fat

mass
3 meals/d
TRF 1700e2100*
8w
3 meals/d
TRF 1600e2000*
8w
ad libitum
TRF 0600e1900
2w
Y weight
ADF** (12 am
e12 am)
3w
Y weight and fat

mass
ADF** (12 am
e12 am)
3w
8w
m-ADF 25% as
breakfast vs. lunch
vs. 3 meals/d
m-ADF 25% high-fat 6 w
vs. low-fat
Lipid proles and cholesterol

Total-C
LDL-C
HDL-C TG
Reference
4 glucose
[28]
[ fasting glucose, Y
morning glucose
tolerance.
[49]
[88]
[
Y men
women
Y weight, fat mass

and visceral fat
similarly
Y weight, fat mass,
4 lean mass
similarly
Y weight, Y body
fat
4 lean mass
[ Particle
size
similarly
Y
4
similarly
Obese men and

women (74)
RP
No control
Obese men and

women (32)
RP
No control
Lean and
overweight
men and
women (32)
Obese men and
women (16)
RP
ad libitum
m-ADF 25% TDE
12 w
SA
m-ADF 25% TDE
8w
Y weight, Y waist
Obese men and

women (10)
Obese men and
women (16)
Obese men and
women (64)
SA
m-ADF <20% TDE
8w
Y weight
SA
m-ADF 25%
8w
RC
ad libitum,
usual
activity
m-ADF 25%
/ Exercise (EX)
12 w
Y weight, Y body
fat
Y weight (both)
Y fat mass (EX)
4 lean mass
Lean men (8)
SA
2w
Overweight and
obese women
(15)
Overweight and
obese women
(107)
SA
20 h ADF** (2200
e1800)
m-ADF 25%
6w
Y Weight, Y waist Y
RP
No control
IER 25% vs. 25% daily 24 w

CR
Glycaemic control and

energy metabolism
4
[ LDL
4
Particle
size
Y Particle
size
[ LDL
Glucose 4
Fasting insulin Y
RMR and RQ 4
[126]
Men: 4 glucose
response to a meal, Y
insulin response
Women: Y glucose
response, 4 insulin
response.
4 fasting glucose,
insulin and HOMA-IR
[125]
Y
similarly
[129]
[130]
[131]
[132]
[133]
[ particle [ EX
size
(both)
Y LDL
(EX)
Y weight similarly Y
Y
similarly similarly
[127]
[134]
[ insulin stimulated
glucose uptake
Y fasting glucose
[136]
[138]
Y
Y fasting insulin, insulin [139]
similarly resistance (greater Y in
IER)
m-ADF: modied-ADF (allows 15e25% of total daily energy intake during a fasting day); IER: 2 consecutive d/week of 25% of total daily energy requirements 5-days ad
libitum intake; AUC: area under the curve; DIT: diet-induced thermogenesis; EE: energy expenditure; HDL-C: high-density lipoprotein-cholesterol; LDL-C: low-density lipoprotein cholesterol; MF: meal frequency; NS: not signicant; OGTT: oral glucose tolerance test; RC: randomised controlled; RP: randomised parallel; RMR: resting metabolic
rate; RQ: respiratory quotient; SA: single arm; total-C: total cholesterol; TG: triglycerides; * subjects consumed all food intake for weight maintenance between the specied
times. ** Participants were instructed to consume sufcient food to maintain weight.
workers. Alternate day fasting, where calories are restricted to a

single small meal for a few days each week, and interspersed with
ad libitum consumption days, may provide a new strategy for weight
loss and improved metabolic health in humans. However, whether
individuals can adhere to this type of dietary pattern, long term, is
unknown. Time restricted feeding has also shown great promise as a
tool to mitigate the metabolic sequelae of diet induced obesity in
rodents, and further suggests that reducing fasting periods to as
little as 13e16 h, overnight, may be of benet. Evidence for this type
of dietary approach, in humans, is currently lacking, although it is
clear that time restricting energy intake to later in the day is not
optimal for metabolic health. In light of the limited available evidence, randomised, controlled trials are now required to interrogate
the effects of ADF and TRF, and their practicality long-term.
Acknowledgements
LKH is funded by a Futures Fellowship, Australian Research
Council (FT120100027).
References
[1] World Health Organisation, in: World Health Organisation (Ed.), Obesity and
Overweight e Fact Sheet 311, 2015.
[2] T. Kelly, W. Yang, C.S. Chen, K. Reynolds, J. He, Global burden of obesity in
2005 and projections to 2030, Int. J. Obes. (Lond) 32 (2008) 1431e1437,
http://dx.doi.org/10.1038/ijo.2008.102.
[3] Diabetes Prevention Program Research Group, The diabetes prevention
program (DPP): description of lifestyle intervention, Diabetes Care 25 (2002)
2165e2171.
[4] Clinical guidelines on the identication, evaluation, and treatment of
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
overweight and obesity in adults e the evidence report. National Institutes of

Health, Obes. Res. 6 (Suppl. 2) (1998) 51Se209S.
J. Louis-Sylvestre, A. Lluch, F. Neant, J.E. Blundell, Highlighting the positive
impact of increasing feeding frequency on metabolism and weight management, Forum Nutr. 56 (2003) 126e128.
P. Fabry, Z. Hejl, J. Fodor, T. Braun, K. Zvolankova, The frequency of meals. Its
relation to overweight, hypercholesterolaemia, and decreased glucosetolerance, Lancet 2 (1964) 614e615.
H.L. Metzner, D.E. Lamphiear, N.C. Wheeler, F.A. Larkin, The relationship
between frequency of eating and adiposity in adult men and women in the
Tecumseh Community Health Study, Am. J. Clin. Nutr. 30 (1977) 712e715.
Y. Ma, E.R. Bertone, E.J. Stanek 3rd, G.W. Reed, J.R. Hebert, N.L. Cohen,
P.A. Merriam, I.S. Ockene, Association between eating patterns and obesity in
a free-living US adult population, Am. J. Epidemiol. 158 (2003) 85e92.
D.P. Speechly, R. Buffenstein, Greater appetite control associated with an
increased frequency of eating in lean males, Appetite 33 (1999) 285e297,
http://dx.doi.org/10.1006/appe.1999.0265.
J. LeBlanc, I. Mercier, A. Nadeau, Components of postprandial thermogenesis
in relation to meal frequency in humans, Can. J. Physiol. Pharmacol. 71
(1993) 879e883.
M.R. Rashidi, S. Mahboob, R. Sattarivand, Effects of nibbling and gorging on
lipid proles, blood glucose and insulin levels in healthy subjects, Saudi Med.
J. 24 (2003) 945e948.
S.L. Edelstein, E.L. Barrett-Connor, D.L. Wingard, B.A. Cohn, Increased meal
frequency associated with decreased cholesterol concentrations; Rancho
Bernardo, CA, 1984e1987, Am. J. Clin. Nutr. 55 (1992) 664e669.
D.J. Jenkins, T.M. Wolever, V. Vuksan, F. Brighenti, S.C. Cunnane, A.V. Rao,
A.L. Jenkins, G. Buckley, R. Patten, W. Singer, et al., Nibbling versus gorging:
metabolic advantages of increased meal frequency, N. Engl. J. Med. 321
(1989) 929e934, http://dx.doi.org/10.1056/NEJM198910053211403.
M.A. Taylor, J.S. Garrow, 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 (2001) 519e528.
G.A. Bray, Lipogenesis in human adipose tissue: some effects of nibbling and
gorging, J. Clin. Invest. 51 (1972) 537e548, http://dx.doi.org/10.1172/
JCI106842.
M. Shahraki, S. Mahboob, M.R. Rashidi, M. Majidi, M. Mesgari, Z.T. Shahraki,
Effect of nibbling and gorging dietary regimens on weight and lipid prole in
rat, Pak. J. Biol. Sci. 10 (2007) 4444e4448.
N. Baker, R.J. Huebotter, Lipogenic activation after nibbling and gorging in
mice, J. Lipid Res. 14 (1973) 87e94.
J.T. Powell, P.J. Franks, N.R. Poulter, Does nibbling or grazing protect the
peripheral arteries from atherosclerosis? J. Cardiovasc. Risk 6 (1999) 19e22.
J.D. Cameron, M.J. Cyr, E. Doucet, Increased meal frequency does not promote
greater weight loss in subjects who were prescribed an 8-week equienergetic energy-restricted diet, Br. J. Nutr. 103 (2010) 1098e1101, http://
dx.doi.org/10.1017/S0007114509992984.
D.J. Jenkins, A. Khan, A.L. Jenkins, R. Illingworth, A.S. Pappu, T.M. Wolever,
V. Vuksan, G. Buckley, A.V. Rao, S.C. Cunnane, et al., Effect of nibbling versus
gorging on cardiovascular risk factors: serum uric acid and blood lipids,
Metabolism 44 (1995) 549e555.
C. Juhel, Y. Pafumi, M. Senft, H. Lafont, D. Lairon, Chronically gorging v.
nibbling fat and cholesterol increases postprandial lipaemia and atheroma
deposition in the New Zealand white rabbit, Br. J. Nutr. 83 (2000) 549e559.
C. Hartmann, M. Siegrist, K. van der Horst, Snack frequency: associations
with healthy and unhealthy food choices, Public Health Nutr. 16 (2013)
1487e1496, http://dx.doi.org/10.1017/S1368980012003771.
M.A. Palmer, S. Capra, S.K. Baines, Association between eating frequency,
weight, and health, Nutr. Rev. 67 (2009) 379e390, http://dx.doi.org/10.1111/
j.1753-4887.2009.00204.x.
H. Berteus Forslund, A.K. Lindroos, L. Sjostrom, L. Lissner, Meal patterns and
obesity in Swedish women-a simple instrument describing usual meal types,
frequency and temporal distribution, Eur. J. Clin. Nutr. 56 (2002) 740e747,
http://dx.doi.org/10.1038/sj.ejcn.1601387.
S. Drummond, N. Crombie, T. Kirk, A critique of the effects of snacking on
body weight status, Eur. J. Clin. Nutr. 50 (1996) 779e783.
K.E. Koopman, M.W. Caan, A.J. Nederveen, A. Pels, M.T. Ackermans, E. Fliers,
S.E. la Fleur, M.J. Serlie, Hypercaloric diets with increased meal frequency,
but not meal size, increase intrahepatic triglycerides: a randomized
controlled trial, Hepatology 60 (2014) 545e553, http://dx.doi.org/10.1002/
hep.27149.
M.J. Munsters, W.H. Saris, Effects of meal frequency on metabolic proles
and substrate partitioning in lean healthy males, PLoS One 7 (2012) e38632,
http://dx.doi.org/10.1371/journal.pone.0038632.
K.S. Stote, D.J. Baer, K. Spears, D.R. Paul, G.K. Harris, W.V. Rumpler, P. Strycula,
S.S. Najjar, L. Ferrucci, D.K. Ingram, et al., A controlled trial of reduced meal
frequency without caloric restriction in healthy, normal-weight, middleaged adults, Am. J. Clin. Nutr. 85 (2007) 981e988.
C.M. Kroeger, M.C. Klempel, S. Bhutani, J.F. Trepanowski, C.C. Tangney,
K.A. Varady, Improvement in coronary heart disease risk factors during an
intermittent fasting/calorie restriction regimen: relationship to adipokine
modulations, Nutr. Metab. (Lond) 9 (2012) 98, http://dx.doi.org/10.1186/
1743-7075-9-98.
V.D. Dixit, H. Yang, K.S. Sayeed, K.S. Stote, W.V. Rumpler, D.J. Baer, D.L. Longo,
M.P. Mattson, D.D. Taub, Controlled meal frequency without caloric
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
restriction alters peripheral blood mononuclear cell cytokine production,

J. Inamm. (Lond) 8 (2011) 6, http://dx.doi.org/10.1186/1476-9255-8-6.
J.B. Ruidavets, V. Bongard, V. Bataille, P. Gourdy, J. Ferrieres, Eating frequency
and body fatness in middle-aged men, Int. J. Obes. Relat. Metab. Disord. 26
(2002) 1476e1483, http://dx.doi.org/10.1038/sj.ijo.0802143.
M.A. McCrory, N.C. Howarth, S.B. Roberts, T.T. Huang, Eating frequency and
energy regulation in free-living adults consuming self-selected diets, J. Nutr.
141 (2011) 148e153, http://dx.doi.org/10.3945/jn.109.114991.
S.W. Lichtman, K. Pisarska, E.R. Berman, M. Pestone, H. Dowling,
E. Offenbacher, H. Weisel, S. Heshka, D.E. Matthews, S.B. Heymseld,
Discrepancy between self-reported and actual caloric intake and exercise in
obese subjects, N. Engl. J. Med. 327 (1992) 1893e1898, http://dx.doi.org/
10.1056/NEJM199212313272701.
X. Meng, D.A. Kerr, K. Zhu, A. Devine, V.A. Solah, J. Wright, C.W. Binns,
R.L. Prince, Under-reporting of energy intake in elderly Australian women is
associated with a higher body mass index, J. Nutr. Health Aging 17 (2013)
112e118, http://dx.doi.org/10.1007/s12603-012-0382-8.
D.A. Schoeller, D. Thomas, E. Archer, S.B. Heymseld, S.N. Blair, M.I. Goran,
J.O. Hill, R.L. Atkinson, B.E. Corkey, J. Foreyt, et al., Self-report-based estimates
of energy intake offer an inadequate basis for scientic conclusions, Am. J.
Clin. Nutr. 97 (2013) 1413e1415, http://dx.doi.org/10.3945/ajcn.113.062125.
X. Allirot, L. Saulais, K. Seyssel, J. Graeppi-Dulac, H. Roth, A. Charrie, J. Drai,
J. Goudable, E. Blond, E. Disse, et al., An isocaloric increase of eating episodes
in the morning contributes to decrease energy intake at lunch in lean men,
Physiol. Behav. 110e111 (2013) 169e178, http://dx.doi.org/10.1016/
j.physbeh.2013.01.009.
X. Allirot, K. Seyssel, L. Saulais, H. Roth, A. Charrie, J. Drai, J. Goudable,
E. Blond, E. Disse, M. Laville, Effects of a breakfast spread out over time on the
food intake at lunch and the hormonal responses in obese men, Physiol.
Behav. 127 (2014) 37e44, http://dx.doi.org/10.1016/j.physbeh.2014.01.004.
T.D. Heden, Y. Liu, L.J. Sims, A.T. Whaley-Connell, A. Chockalingam,
K.C. Dellsperger, J.A. Kanaley, Meal frequency differentially alters postprandial triacylglycerol and insulin concentrations in obese women, Obesity
(Silver Spring) 21 (2013) 123e129, http://dx.doi.org/10.1002/oby.20247.
J.L. Kinabo, J.V. Durnin, Effect of meal frequency on the thermic effect of food
in women, Eur. J. Clin. Nutr. 44 (1990) 389e395.
H.J. Leidy, C.L. Armstrong, M. Tang, R.D. Mattes, W.W. Campbell, The inuence of higher protein intake and greater eating frequency on appetite
control in overweight and obese men, Obesity (Silver Spring) 18 (2010)
1725e1732, http://dx.doi.org/10.1038/oby.2010.45.
K. Ohkawara, M.A. Cornier, W.M. Kohrt, E.L. Melanson, Effects of increased
meal frequency on fat oxidation and perceived hunger, Obesity (Silver
Spring) 21 (2013) 336e343, http://dx.doi.org/10.1002/oby.20032.
A.J. Smeets, M.S. Westerterp-Plantenga, Acute effects on metabolism and
appetite prole of one meal difference in the lower range of meal frequency,
Br.
J.
Nutr.
99
(2008)
1316e1321,
http://dx.doi.org/10.1017/
S0007114507877646.
T.P. Solomon, E.S. Chambers, A.E. Jeukendrup, A.A. Toogood, A.K. Blannin, The
effect of feeding frequency on insulin and ghrelin responses in human
subjects, Br. J. Nutr. 100 (2008) 810e819, http://dx.doi.org/10.1017/
S000711450896757X.
D.P. Speechly, G.G. Rogers, R. Buffenstein, Acute appetite reduction associated with an increased frequency of eating in obese males, Int. J. Obes. Relat.
Metab. Disord. 23 (1999) 1151e1159.
M.M. Tai, P. Castillo, F.X. Pi-Sunyer, Meal size and frequency: effect on the
thermic effect of food, Am. J. Clin. Nutr. 54 (1991) 783e787.
W.P. Verboeket-van de Venne, K.R. Westerterp, Inuence of the feeding
frequency on nutrient utilization in man: consequences for energy metabolism, Eur. J. Clin. Nutr. 45 (1991) 161e169.
W.P. Verboeket-van de Venne, K.R. Westerterp, Frequency of feeding, weight
reduction and energy metabolism, Int. J. Obes. Relat. Metab. Disord. 17
(1993) 31e36.
J.M. Antoine, R. Rohr, M.J. Gagey, R.E. Bleyer, G. Debry, Feeding frequency and
nitrogen balance in weight-reducing obese women, Hum. Nutr. Clin. Nutr. 38
(1984) 31e38.
O. Carlson, B. Martin, K.S. Stote, E. Golden, S. Maudsley, S.S. Najjar, L. Ferrucci,
D.K. Ingram, D.L. Longo, W.V. Rumpler, et al., Impact of reduced meal frequency without caloric restriction on glucose regulation in healthy, normalweight middle-aged men and women, Metabolism 56 (2007) 1729e1734.
D. Chapelot, C. Marmonier, R. Aubert, C. Allegre, N. Gausseres, M. Fantino,
J. Louis-Sylvestre, Consequence of omitting or adding a meal in man on body
composition, food intake, and metabolism, Obesity (Silver Spring) 14 (2006)
E. Huseinovic, A. Winkvist, F. Bertz, H. Berteus Forslund, H.K. Brekke, Eating
frequency, energy intake and body weight during a successful weight loss
trial in overweight and obese postpartum women, Eur. J. Clin. Nutr. 68
(2014) 71e76, http://dx.doi.org/10.1038/ejcn.2013.200.
H. Berteus Forslund, S. Klingstrom, H. Hagberg, M. Londahl, J.S. Torgerson,
A.K. Lindroos, Should snacks be recommended in obesity treatment? A 1year randomized clinical trial, Eur. J. Clin. Nutr. 62 (2008) 1308e1317,
http://dx.doi.org/10.1038/sj.ejcn.1602860.
J.L. Bachman, H.A. Raynor, Effects of manipulating eating frequency during a
behavioral weight loss intervention: a pilot randomized controlled trial,
Obesity (Silver Spring) 20 (2012) 985e992, http://dx.doi.org/10.1038/
oby.2011.360.
10
[54] H. Kahleova, L. Belinova, H. Malinska, O. Oliyarnyk, J. Trnovska, V. Skop,

L. Kazdova, M. Dezortova, M. Hajek, A. Tura, et al., Eating two larger meals a
day (breakfast and lunch) is more effective than six smaller meals in a
reduced-energy regimen for patients with type 2 diabetes: a randomised
crossover study, Diabetologia 57 (2014) 1552e1560, http://dx.doi.org/
10.1007/s00125-014-3253-5.
[55] J. LeBlanc, P. Diamond, Effect of meal size and frequency on postprandial
thermogenesis in dogs, Am. J. Physiol. 250 (1986) E144eE147.
[56] M.I. Irwin, R.M. Feeley, Frequency and size of meals and serum lipids, nitrogen and mineral retention, fat digestibility, and urinary thiamine and
riboavin in young women, Am. J. Clin. Nutr. 20 (1967) 816e824.
[57] B. Finkelstein, B.A. Fryer, Meal frequency and weight reduction of young
women, Am. J. Clin. Nutr. 24 (1971) 465e468.
[58] Y.E. Swindells, S.A. Holmes, M.F. Robinson, The metabolic response of young
women to changes in the frequency of meals, Br. J. Nutr. 22 (1968) 667e680.
[59] C.M. Young, D.L. Frankel, S.S. Scanlan, V. Simko, L. Lutwak, Frequency of
feeding, weight reduction, and nutrient utilization, J. Am. Diet. Assoc. 59
(1971) 473e480.
[60] E. Spangler, D.E. Johnson, Inuence of feeding pattern on energy balance and
activity in rats, J. Nutr. 111 (1981) 1297e1304.
[61] J.O. Hill, J.C. Anderson, D. Lin, F. Yakubu, Effects of meal frequency on energy
utilization in rats, Am. J. Physiol. 255 (1988) R616eR621.
[62] W.M. Bortz, A. Wroldsen, B. Issekutz Jr., K. Rodahl, Weight loss and frequency
of feeding, N. Engl. J. Med. 274 (1966) 376e379, http://dx.doi.org/10.1056/
NEJM196602172740703.
[63] W.S. Poston, C.K. Haddock, M.M. Pinkston, P. Pace, N.D. Karakoc, R.S. Reeves,
J.P. Foreyt, Weight loss with meal replacement and meal replacement plus
snacks: a randomized trial, Int. J. Obes. (Lond) 29 (2005) 1107e1114.
[64] B. Jon Schoenfeld, A. Albert Aragon, J.W. Krieger, Effects of meal frequency on
weight loss and body composition: a meta-analysis, 2015, http://dx.doi.org/
10.1093/nutrit/nuu017.
[65] J.S. Garrow, M. Durrant, S. Blaza, D. Wilkins, P. Royston, S. Sunkin, The effect
of meal frequency and protein concentration on the composition of the
weight lost by obese subjects, Br. J. Nutr. 45 (1981) 5e15.
[66] P.J. Arciero, M.J. Ormsbee, C.L. Gentile, B.C. Nindl, J.R. Brestoff, M. Ruby,
Increased protein intake and meal frequency reduces abdominal fat during
energy balance and energy decit, Obesity (Silver Spring) 21 (2013)
1357e1366.
[67] S. Iwao, K. Mori, Y. Sato, Effects of meal frequency on body composition
during weight control in boxers, Scand. J. Med. Sci. Sports 6 (1996) 265e272.
[68] N.A. Schwarz, B.R. Rigby, P. La Bounty, B. Shelmadine, R.G. Bowden, A review
of weight control strategies and their effects on the regulation of hormonal
balance, J. Nutr. Metab. 2011 (2011) 237932, http://dx.doi.org/10.1155/2011/
237932.
[69] L.M. Arnold, M.J. Ball, A.W. Duncan, J. Mann, Effect of isoenergetic intake of
three or nine meals on plasma lipoproteins and glucose metabolism, Am. J.
Clin. Nutr. 57 (1993) 446e451.
[70] L. Arnold, J.I. Mann, M.J. Ball, Metabolic effects of alterations in meal frequency in type 2 diabetes, Diabetes Care 20 (1997) 1651e1654.
[71] L. Arnold, M. Ball, J. Mann, Metabolic effects of alterations in meal frequency
in hypercholesterolaemic individuals, Atherosclerosis 108 (1994) 167e174.
[72] H.R. Farshchi, M.A. Taylor, I.A. Macdonald, Regular meal frequency creates
more appropriate insulin sensitivity and lipid proles compared with
irregular meal frequency in healthy lean women, Eur. J. Clin. Nutr. 58 (2004)
1071e1077, http://dx.doi.org/10.1038/sj.ejcn.1601935.
[73] H.R. Farshchi, M.A. Taylor, I.A. Macdonald, Benecial metabolic effects of
regular meal frequency on dietary thermogenesis, insulin sensitivity, and
fasting lipid proles in healthy obese women, Am. J. Clin. Nutr. 81 (2005)
16e24.
[74] C.M. Young, S.S. Scanlan, C.M. Topping, V. Simko, L. Lutwak, Frequency of
feeding, weight reduction, and body composition, J. Am. Diet. Assoc. 59
(1971) 466e472.
[75] M. Hatori, C. Vollmers, A. Zarrinpar, L. DiTacchio, E.A. Bushong, S. Gill,
M. Leblanc, A. Chaix, M. Joens, J.A. Fitzpatrick, et al., Time-restricted feeding
without reducing caloric intake prevents metabolic diseases in mice fed a
high-fat diet, Cell Metab. 15 (2012) 848e860, http://dx.doi.org/10.1016/
j.cmet.2012.04.019.
[76] A. Chaix, A. Zarrinpar, P. Miu, S. Panda, Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges, Cell Metab. 20 (2014) 991e1005, http://dx.doi.org/10.1016/
j.cmet.2014.11.001.
[77] M. Nematy, M. Alinezhad-Namaghi, M.M. Rashed, M. Mozhdehifard,
S.S. Sajjadi, S. Akhlaghi, M. Sabery, S.A. Mohajeri, N. Shalaey, M. Moohebati,
et al., Effects of Ramadan fasting on cardiovascular risk factors: a prospective
observational study, Nutr. J. 11 (2012) 69, http://dx.doi.org/10.1186/14752891-11-69.
[78] A. Temizhan, I. Tandogan, O. Donderici, B. Demirbas, The effects of Ramadan
fasting on blood lipid levels, Am. J. Med. 109 (2000) 341e342.
[79] F.B. Aksungar, A. Eren, S. Ure, O. Teskin, G. Ates, Effects of intermittent fasting
on serum lipid levels, coagulation status and plasma homocysteine levels,
Ann. Nutr. Metab. 49 (2005) 77e82, http://dx.doi.org/10.1159/000084739.
[80] V. Ziaee, M. Razaei, Z. Ahmadinejad, H. Shaikh, R. Youse, L. Yarmohammadi,
F. Bozorgi, M.J. Behjati, The changes of metabolic prole and weight during
Ramadan fasting, Singap. Med. J. 47 (2006) 409e414.
[81] A. Zare, M. Hajhashemi, Z.M. Hassan, S. Zarrin, Z. Pourpak, M. Moin,
[82]
[83]
[84]
[85]
[86]
[87]
[88]
[89]
[90]
[91]
[92]
[93]
[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102]
[103]
[104]
[105]
[106]
S. Salarilak, S. Masudi, S. Shahabi, Effect of Ramadan fasting on serum heat

shock protein 70 and serum lipid prole, Singap. Med. J. 52 (2011) 491e495.
H. Fakhrzadeh, B. Larijani, M. Sanjari, R. Baradar-Jalili, M.R. Amini, Effect of
Ramadan fasting on clinical and biochemical parameters in healthy adults,
Ann. Saudi Med. 23 (2003) 223e226.
A. Adlouni, N. Ghalim, A. Benslimane, J.M. Lecerf, R. Saile, Fasting during
Ramadan induces a marked increase in high-density lipoprotein cholesterol
and decrease in low-density lipoprotein cholesterol, Ann. Nutr. Metab. 41
(1997) 242e249.
J.B. Wang, R.E. Patterson, A. Ang, J.A. Emond, N. Shetty, L. Arab, Timing of
energy intake during the day is associated with the risk of obesity in adults,
J. Hum. Nutr. Diet. 27 (Suppl. 2) (2014) 255e262, http://dx.doi.org/10.1111/
jhn.12141.
M. Garaulet, P. Gomez-Abellan, J.J. Alburquerque-Bejar, Y.C. Lee,
J.M. Ordovas, F.A.J.L. Scheer, Timing of food intake predicts weight loss
effectiveness, Int. J. Obes. 37 (2013) 604e611.
D. Jakubowicz, M. Barnea, J. Wainstein, O. Froy, High caloric intake at
breakfast vs. dinner differentially inuences weight loss of overweight and
obese women, Obesity (Silver Spring) 21 (2013) 2504e2512, http://
dx.doi.org/10.1002/oby.20460.
C. Bandin, F.A. Scheer, A.J. Luque, V. Avila-Gandia, S. Zamora, J.A. Madrid,
P. Gomez-Abellan, M. Garaulet, Meal timing affects glucose tolerance, substrate oxidation and circadian-related variables: a randomized, crossover
trial, Int. J. Obes. (Lond) 39 (2015) 828e833, http://dx.doi.org/10.1038/
ijo.2014.182.
J.D. LeCheminant, E. Christenson, B.W. Bailey, L.A. Tucker, Restricting nighttime eating reduces daily energy intake in healthy young men: a shortterm cross-over study, Br. J. Nutr. 110 (2013) 2108e2113, http://
dx.doi.org/10.1017/S0007114513001359.
D.M. Arble, J. Bass, A.D. Laposky, M.H. Vitaterna, F.W. Turek, Circadian timing
of food intake contributes to weight gain, Obesity (Silver Spring) 17 (2009)
Y. Satoh, H. Kawai, N. Kudo, Y. Kawashima, A. Mitsumoto, Time-restricted
feeding entrains daily rhythms of energy metabolism in mice, Am. J. Physiol.
Regul. Integr. Comp. Physiol. 290 (2006) R1276eR1283, http://dx.doi.org/
10.1152/ajpregu.00775.2005.
F. Tuchsen, H. Hannerz, H. Burr, A 12 year prospective study of circulatory
disease among Danish shift workers, Occup. Environ. Med. 63 (2006)
451e455, http://dx.doi.org/10.1136/oem.2006.026716.
M. Ha, J. Park, Shiftwork and metabolic risk factors of cardiovascular disease,
J. Occup. Health 47 (2005) 89e95.
M.H. Hastings, A.B. Reddy, E.S. Maywood, A clockwork web: circadian timing
in brain and periphery, in health and disease, Nat. Rev. Neurosci. 4 (2003)
649e661, http://dx.doi.org/10.1038/nrn1177.
M. Garaulet, J.M. Ordovas, J.A. Madrid, The chronobiology, etiology and
pathophysiology of obesity, Int. J. Obes. 34 (2010) 1667e1683, http://
dx.doi.org/10.1038/ijo.2010.118.
M. Garaulet, J.A. Madrid, Chronobiological aspects of nutrition, metabolic
syndrome and obesity, Adv. Drug Deliv. Rev. 62 (2010) 967e978, http://
dx.doi.org/10.1016/j.addr.2010.05.005.
U. Schibler, J. Ripperger, S.A. Brown, Peripheral circadian oscillators in
mammals: time and food, J. Biol. Rhythms 18 (2003) 250e260.
S.A. Brown, G. Zumbrunn, F. Fleury-Olela, N. Preitner, U. Schibler, Rhythms of
mammalian body temperature can sustain peripheral circadian clocks, Curr.
Biol. 12 (2002) 1574e1583.
B. Marcheva, K.M. Ramsey, C.B. Peek, A. Afnati, E. Maury, J. Bass, Circadian
clocks and metabolism, Handb. Exp. Pharmacol. (2013) 127e155, http://
dx.doi.org/10.1007/978-3-642-25950-0_6.
A. Saad, C. Dalla Man, D.K. Nandy, J.A. Levine, A.E. Bharucha, R.A. Rizza,
R. Basu, R.E. Carter, C. Cobelli, Y.C. Kudva, et al., Diurnal pattern to insulin
secretion and insulin action in healthy individuals, Diabetes 61 (2012)
2691e2700, http://dx.doi.org/10.2337/db11-1478.
K.F. Carroll, P.J. Nestel, Diurnal variation in glucose tolerance and in insulin
secretion in man, Diabetes 22 (1973) 333e348.
E. Van Cauter, D. Desir, C. Decoster, F. Fery, E.O. Balasse, Nocturnal decrease
in glucose tolerance during constant glucose infusion, J. Clin. Endocrinol.
Metab. 69 (1989) 604e611, http://dx.doi.org/10.1210/jcem-69-3-604.
E. Van Cauter, J.D. Blackman, D. Roland, J.P. Spire, S. Refetoff, K.S. Polonsky,
Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep, J. Clin. Invest. 88 (1991) 934e942, http://dx.doi.org/
10.1172/JCI115396.
E. Van Cauter, K.S. Polonsky, A.J. Scheen, Roles of circadian rhythmicity and
sleep in human glucose regulation, Endocr. Rev. 18 (1997) 716e738, http://
dx.doi.org/10.1210/edrv.18.5.0317.
H. Kuroda, Y. Tahara, K. Saito, N. Ohnishi, Y. Kubo, Y. Seo, M. Otsuka, Y. Fuse,
Y. Ohura, A. Hirao, et al., Meal frequency patterns determine the phase of
mouse peripheral circadian clocks, Sci. Rep. 2 (2012) 711, http://dx.doi.org/
10.1038/srep00711.
A. Kohsaka, A.D. Laposky, K.M. Ramsey, C. Estrada, C. Joshu, Y. Kobayashi,
F.W. Turek, J. Bass, High-fat diet disrupts behavioral and molecular circadian
rhythms in mice, Cell Metab. 6 (2007) 414e421, http://dx.doi.org/10.1016/
j.cmet.2007.09.006.
J. Cleator, J. Abbott, P. Judd, C. Sutton, J.P. Wilding, Night eating syndrome:
implications for severe obesity, Nutr. Diabetes 2 (2012) e44, http://
dx.doi.org/10.1038/nutd.2012.16.

[107] M.J. Howell, C.H. Schenck, S.J. Crow, A review of nighttime eating disorders,
Sleep.
Med.
Rev.
13
(2009)
23e34,
j.smrv.2008.07.005.
[108] A. Knutsson, Health disorders of shift workers, Occup. Med. (Lond) 53 (2003)
103e108.
[109] A. Lowden, C. Moreno, U. Holmback, M. Lennernas, P. Tucker, Eating and shift
work e effects on habits, metabolism and performance, Scand. J. Work Environ. Health 36 (2010) 150e162.
[110] J.M. de Castro, The time of day and the proportions of macronutrients eaten
are related to total daily food intake, Br. J. Nutr. 98 (2007) 1077e1083, http://
dx.doi.org/10.1017/S0007114507754296.
[111] S. Bo, G. Musso, G. Beccuti, M. Fadda, D. Fedele, R. Gambino, L. Gentile,
M. Durazzo, E. Ghigo, M. Cassader, Consuming more of daily caloric intake at
dinner predisposes to obesity. A 6-year population-based prospective cohort
study, PLoS One 9 (2014) e108467, http://dx.doi.org/10.1371/
journal.pone.0108467.
[112] F.A. Scheer, M.F. Hilton, C.S. Mantzoros, S.A. Shea, Adverse metabolic and
cardiovascular consequences of circadian misalignment, Proc. Natl. Acad. Sci.
U. S. A. 106 (2009) 4453e4458, http://dx.doi.org/10.1073/pnas.0808180106.
[113] C.J. Morris, J.N. Yang, J.I. Garcia, S. Myers, I. Bozzi, W. Wang, O.M. Buxton,
S.A. Shea, F.A. Scheer, Endogenous circadian system and circadian
misalignment impact glucose tolerance via separate mechanisms in humans,
Proc. Natl. Acad. Sci. U. S. A. 112 (2015) E2225eE2234, http://dx.doi.org/
10.1073/pnas.1418955112.
[114] K.A. Varady, D.J. Roohk, M. Bruss, M.K. Hellerstein, Alternate-day fasting
reduces global cell proliferation rates independently of dietary fat content in
mice,
Nutrition
25
(2009)
486e491,
j.nut.2008.10.017.
[115] K.A. Varady, D.J. Roohk, M.K. Hellerstein, Dose effects of modied alternateday fasting regimens on in vivo cell proliferation and plasma insulin-like
growth factor-1 in mice, J. Appl. Physiol. (1985) 103 (2007) 547e551,
http://dx.doi.org/10.1152/japplphysiol.00209.2007.
[116] K.A. Varady, D.J. Roohk, Y.C. Loe, B.K. McEvoy-Hein, M.K. Hellerstein, Effects
of modied alternate-day fasting regimens on adipocyte size, triglyceride
metabolism, and plasma adiponectin levels in mice, J. Lipid Res. 48 (2007)
2212e2219, http://dx.doi.org/10.1194/jlr.M700223-JLR200.
[117] K.A. Varady, D.J. Roohk, B.K. McEvoy-Hein, B.D. Gaylinn, M.O. Thorner,
M.K. Hellerstein, Modied alternate-day fasting regimens reduce cell proliferation rates to a similar extent as daily calorie restriction in mice, FASEB J.
22 (2008) 2090e2096, http://dx.doi.org/10.1096/fj.07-098178.
[118] D.E. Mager, R. Wan, M. Brown, A. Cheng, P. Wareski, D.R. Abernethy,
M.P. Mattson, Caloric restriction and intermittent fasting alter spectral
measures of heart rate and blood pressure variability in rats, FASEB J. 20
(2006) 631e637, http://dx.doi.org/10.1096/fj.05-5263com.
[119] R. Wan, I. Ahmet, M. Brown, A. Cheng, N. Kamimura, M. Talan, M.P. Mattson,
Cardioprotective effect of intermittent fasting is associated with an elevation
of adiponectin levels in rats, J. Nutr. Biochem. 21 (2010) 413e417, http://
dx.doi.org/10.1016/j.jnutbio.2009.01.020.
[120] I. Ahmet, R. Wan, M.P. Mattson, E.G. Lakatta, M. Talan, Cardioprotection by
intermittent fasting in rats, Circulation 112 (2005) 3115e3121, http://
dx.doi.org/10.1161/CIRCULATIONAHA.105.563817.
[121] I. Siegel, T.L. Liu, N. Nepomuceno, N. Gleicher, Effects of short-term dietary
restriction on survival of mammary ascites tumor-bearing rats, Cancer
Invest. 6 (1988) 677e680.
[122] C.L. Goodrick, D.K. Ingram, M.A. Reynolds, J.R. Freeman, N. Cider, Effects of
intermittent feeding upon body weight and lifespan in inbred mice: interaction of genotype and age, Mech. Ageing Dev. 55 (1990) 69e87.
[123] V.D. Longo, M.P. Mattson, Fasting: molecular mechanisms and clinical applications, Cell Metab. 19 (2014) 181e192, http://dx.doi.org/10.1016/
j.cmet.2013.12.008.
[124] S. Bhutani, M.C. Klempel, R.A. Berger, K.A. Varady, Improvements in coronary
heart disease risk indicators by alternate-day fasting involve adipose tissue
modulations, Obesity (Silver Spring) 18 (2010) 2152e2159, http://
dx.doi.org/10.1038/oby.2010.54.
[125] L.K. Heilbronn, A.E. Civitarese, I. Bogacka, S.R. Smith, M. Hulver, E. Ravussin,
[126]
[127]
[128]
[129]
[130]
[131]
[132]
[133]
[134]
[135]
[136]
[137]
[138]
[139]
[140]
11
Glucose tolerance and skeletal muscle gene expression in response to

alternate day fasting, Obes. Res. 13 (2005) 574e581, http://dx.doi.org/
10.1038/oby.2005.61.
L.K. Heilbronn, S.R. Smith, C.K. Martin, S.D. Anton, E. Ravussin, Alternate-day
fasting in nonobese subjects: effects on body weight, body composition, and
energy metabolism, Am. J. Clin. Nutr. 81 (2005) 69e73.
K.K. Hoddy, C.M. Kroeger, J.F. Trepanowski, A. Barnosky, S. Bhutani,
K.A. Varady, Meal timing during alternate day fasting: impact on body
weight and cardiovascular disease risk in obese adults, Obesity (Silver
M.C. Klempel, C.M. Kroeger, K.A. Varady, Alternate day fasting increases LDL
particle size independently of dietary fat content in obese humans, Eur. J.
Clin. Nutr. 67 (2013) 783e785, http://dx.doi.org/10.1038/ejcn.2013.83.
M.C. Klempel, C.M. Kroeger, K.A. Varady, Alternate day fasting (ADF) with a
high-fat diet produces similar weight loss and cardio-protection as ADF with
a low-fat diet, Metabolism 62 (2013) 137e143, http://dx.doi.org/10.1016/
j.metabol.2012.07.002.
K.A. Varady, S. Bhutani, M.C. Klempel, C.M. Kroeger, J.F. Trepanowski,
J.M. Haus, K.K. Hoddy, Y. Calvo, Alternate day fasting for weight loss in
normal weight and overweight subjects: a randomized controlled trial, Nutr.
J. 12 (2013) 146, http://dx.doi.org/10.1186/1475-2891-12-146.
K.A. Varady, S. Bhutani, M.C. Klempel, B. Lamarche, Improvements in LDL
particle size and distribution by short-term alternate day modied fasting in
obese adults, Br. J. Nutr. 105 (2011) 580e583, http://dx.doi.org/10.1017/
S0007114510003788.
J.B. Johnson, W. Summer, R.G. Cutler, B. Martin, D.H. Hyun, V.D. Dixit,
M. Pearson, M. Nassar, R. Telljohann, S. Maudsley, et al., Alternate day calorie
restriction improves clinical ndings and reduces markers of oxidative stress
and inammation in overweight adults with moderate asthma, Free Radic.
Biol.
Med.
42
(2007)
665e674,
j.freeradbiomed.2006.12.005.
K.A. Varady, S. Bhutani, E.C. Church, M.C. Klempel, Short-term modied
alternate-day fasting: a novel dietary strategy for weight loss and cardioprotection in obese adults, Am. J. Clin. Nutr. 90 (2009) 1138e1143, http://
dx.doi.org/10.3945/ajcn.2009.28380.
S. Bhutani, M.C. Klempel, C.M. Kroeger, J.F. Trepanowski, K.A. Varady,
Alternate day fasting and endurance exercise combine to reduce body
weight and favorably alter plasma lipids in obese humans, Obesity (Silver
K.A. Varady, C.A. Allister, D.J. Roohk, M.K. Hellerstein, Improvements in body
fat distribution and circulating adiponectin by alternate-day fasting versus
calorie restriction, J. Nutr. Biochem. 21 (2010) 188e195, http://dx.doi.org/
10.1016/j.jnutbio.2008.11.001.
N. Halberg, M. Henriksen, N. Soderhamn, B. Stallknecht, T. Ploug,
P. Schjerling, F. Dela, Effect of intermittent fasting and refeeding on insulin
action in healthy men, J. Appl. Physiol. (1985) 99 (2005) 2128e2136, http://
dx.doi.org/10.1152/japplphysiol.00683.2005.
S. Brandhorst, I.Y. Choi, M. Wei, C.W. Cheng, S. Sedrakyan, G. Navarrete,
L. Dubeau, L.P. Yap, R. Park, M. Vinciguerra, et al., A periodic diet that mimics
fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan, Cell Metab. 22 (2015) 86e99, http://dx.doi.org/
10.1016/j.cmet.2015.05.012.
S. Eshghinia, F. Mohammadzadeh, The effects of modied alternate-day
fasting diet on weight loss and CAD risk factors in overweight and obese
women, J. Diabetes Metab. Disord. 12 (2013) 4, http://dx.doi.org/10.1186/
2251-6581-12-4.
M.N. Harvie, M. Pegington, M.P. Mattson, J. Frystyk, B. Dillon, G. Evans,
J. Cuzick, S.A. Jebb, B. Martin, R.G. Cutler, et al., The effects of intermittent or
continuous energy restriction on weight loss and metabolic disease risk
markers: a randomized trial in young overweight women, Int. J. Obes. (Lond)
35 (2011) 714e727, http://dx.doi.org/10.1038/ijo.2010.171.
H.M. Seagle, G.W. Strain, A. Makris, R.S. Reeves, American Dietetic A, Position
of the American Dietetic Association: weight management, J. Am. Diet. Assoc.
109 (2009) 330e346.

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Contents lists available at ScienceDirect

Metabolic impacts of altering meal frequency and timing e Does when

Discipline of Medicine, The University of Adelaide, Australia

A.T. Hutchison, L.K. Heilbronn / Biochimie xxx (2015) 1e11

either withheld, or minimal calories are consumed typically at 1

A.T. Hutchison, L.K. Heilbronn / Biochimie xxx (2015) 1e11

Meal energy and composition (P: %

Lean men (8)

33% TDE (15P, 15F, 70C)

2866 kcal (15P, 30F, 55C)

Lean men (20)

675 kcal (6P, 37F,57C)

Lean women (18)

1200 kcal (HCLF: 11P, 19F, 70C)

RMR 1.5 (15P, 30F, 55C)

of a meal into smaller portions reduces the insulin excursion in

3. Does reduced meal frequency or time-restricted feeding

A.T. Hutchison, L.K. Heilbronn / Biochimie xxx (2015) 1e11

1. Increased meal frequency

Duration Number of meals/d Body weight and

3 vs. 6 High Fat/

2 vs. 9 (3 as control) 4 weight

Hypocaloric 5 w each 1 vs. 3 vs. 6

4 4 insulin: glucose ratio

4 fasting insulin and

A.T. Hutchison, L.K. Heilbronn / Biochimie xxx (2015) 1e11

levels were increased, and TRF resulted in poorer glucose tolerance

A.T. Hutchison, L.K. Heilbronn / Biochimie xxx (2015) 1e11

locomotor output cycles kaput (CLOCK) and brain and muscle

However, the authors concede that a modest non-signicant

A.T. Hutchison, L.K. Heilbronn / Biochimie xxx (2015) 1e11

5. The unique case for intermittent and alternate day fasting

A.T. Hutchison, L.K. Heilbronn / Biochimie xxx (2015) 1e11

Study Comparator Intervention

Time restricted feeding

Body weight and

Y weight and fat

Y weight and fat

Lipid proles and cholesterol

Y weight, fat mass

Obese men and

Obese men and

m-ADF 25% TDE

m-ADF 25% TDE

Obese men and

m-ADF <20% TDE

Lean men (8)

IER 25% vs. 25% daily 24 w

Glycaemic control and

workers. Alternate day fasting, where calories are restricted to a

A.T. Hutchison, L.K. Heilbronn / Biochimie xxx (2015) 1e11

overweight and obesity in adults e the evidence report. National Institutes of

restriction alters peripheral blood mononuclear cell cytokine production,

A.T. Hutchison, L.K. Heilbronn / Biochimie xxx (2015) 1e11

[54] H. Kahleova, L. Belinova, H. Malinska, O. Oliyarnyk, J. Trnovska, V. Skop,

S. Salarilak, S. Masudi, S. Shahabi, Effect of Ramadan fasting on serum heat

A.T. Hutchison, L.K. Heilbronn / Biochimie xxx (2015) 1e11

Glucose tolerance and skeletal muscle gene expression in response to

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