Physiology & Behavior 218 (2020) 112827

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Physiology & Behavior

journal homepage: www.elsevier.com/locate/physbeh

Intermittent fasting: What questions should we be asking? T

a,b,⁎ a,b a,b
Kai Liu , Bo Liu , Leonie K. Heilbronn
a
Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
b
Lifelong Health Theme, South Australia Health and Medical Research Institute Adelaide, South Australia, Australia

ARTICLE INFO ABSTRACT

Keywords: Obesity and overweight are contributing factors to chronic disease. Lifestyle management, which incorporates
Daily calorie restriction advice on moderate daily caloric restriction (CR) and physical activity to reduce body weight, is the cornerstone
Energy metabolism treatment in practice. Intermittent fasting (IF) is a popular alternative that cycles fasting with unrestricted eating
Intermittent fasting periods. IF appears to be an equivalent approach to CR to induce weight loss, although as yet there is limited
Meal timing
long-term evidence. Some controversy exists as to whether IF yields superior health benefits to CR. Discrepancies
Metabolic adaptation
Treatment outcome
between studies may be due to the heterogeneity in the design of IF protocols. There is also still some concerns
around the safety and feasibility of IF compared to CR, which has not been well-studied to date. Moreover, the
underlying cellular pathways that are differentially activated in IF in comparison to CR requires further in-
vestigation in humans. This review summarises trials that have compared IF with CR, and discusses evidence
from animal studies to raise questions for future research in humans.

1. Introduction
Obesity is associated with chronic diseases including type 2 diabetes
(T2DM), cardiovascular diseases (CVD) and cancer [1]. In 2017–2018,
67% of Australians were overweight or obese and 47% of Australians
suffered from at least one type of chronic disease [2]. As little as 3%
weight reduction produces clinically significant effects to attenuate risk
[3, 4]. Daily moderate (~30%) calorie restriction is the most widely
studied and recommended prescription to achieve 3–10% weight loss
[5, 6]. CR protects against insulin resistance [7, 8], CVD [9] and in-
creases life expectancy in animal models [8]. Yet CR often fails in long-
term adult weight management due to poor adherence [6, 10]. This is
partly the result of adaptive responses that increase appetite and reduce
energy expenditure, limiting further weight loss and promoting weight
regain [5, 11]. Intermittent fasting (IF) is proposed as an alternative
dieting strategy. IF includes cycles of fasting and unrestricted eating
periods, which may allow more flexibility and thereby enhance ad-
herence [12]. The term “intermittent fasting” refers to a range of
dietary regimens, of which fasting for two or three times per week and
alternate-day fasting (ADF, to fast every other day) are the most com-
monly studied in humans. Several common pathways are activated in
response to both CR and IF in animal models. These include attenuated
oxidative stress [13, 14], reduced inflammation [15, 16], enhanced
autophagy and tissue repair capacity [17], altered gut microbiota [18,
19], along with changes in gene expression and post-transcriptional
modifications [20, 21]. This review aims to update current evidence on
IF and its effectiveness in comparison with CR and raises questions for
future research in regards to the optimal design for health and safety.
This review does not include studies of “time-restricted feeding” which
promote lengthening the daily overnight fast (e.g. 12–18 h), since no
comparator studies with CR have yet been performed.
2. Benefits of IF vs CR – evidence gap and inconsistencies
2.1. Body weight and composition
Previous randomised controlled trials (RCT) that compared weight
changes between IF and CR are summarised in Table 1. The majority of
studies showed comparable weight losses with IF versus a calorie-
matched CR arm [22-29], including the long-term studies conducted to
date [24, 25, 29]. One study [30] reported slightly greater weight re-
duction after 8-week intervention in IF versus CR with 70% calorie
restriction (−5.4 ± 0.5 kg versus. 3.9 ± 0.4 kg) amongst women
with overweight and obesity. Yet this trial was a highly controlled food
provision study, rather than a free-living trial. Many of these studies
were underpowered to detect weight loss differences, since the ex-
pected standard deviation is 5 kg [31], and 90 (45/group) completers
would be required to detect a 3 kg difference between two groups. Only
one trial powered their study to detect 4–5 kg weight loss at 1 year in IF
and CR and achieved similar reduction (~9 kg) post-intervention in

⁎
Corresponding author.
E-mail address: kai.liu@adelaide.edu.au (K. Liu).

https://doi.org/10.1016/j.physbeh.2020.112827
Received 9 December 2019; Received in revised form 30 January 2020; Accepted 31 January 2020
Available online 01 February 2020
0031-9384/ Crown Copyright © 2020 Published by Elsevier Inc. All rights reserved.

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 Table 1
IF diet design and outcome comparison with CR.
K. Liu, et al.

First author, year Study population, sample size (M/ IF diet design IF vs CR outcome comparison
(reference number) F)
Study design, %CR, Fasting regimen Feeding regimen Weight and body Metabolic adaptation Health risk factors
duration composition

Antoni, 2018 [32] Healthy overweight and obese 2FD/W 22% 2 consecutive fasting days ↔ weight ↔ adjusted REE ↔ post-prandial
adults CR 23% 2638kJ 100% CI ↔ median days to insulin
IF n=15 (7/8) Until 5% weight loss (∼25% CI) Self-selected 5% weight loss ↔ FBG, insulin
CR n=12 (6/6) achieved Commercially available ↔ FM, FFM ↔ HOMA-IR
formula ↔ WC, HC ↓postprandial TG
↔ TC, LDL, HDL
↓ SBP,
↔ DBP
Carter, 2016 [40] T2DM overweight and obese adults 2FD/W 23%† 2 non-specified fasting days ↔ weight ↔ subjective hunger ↔ HbA1c
IF n=31 (14/17) CR 40%† 1670-2500kJ/day Ad libitum ↔ FM, %FM, FFM ↔ subjective fullness ↔ use of OHA and
CR n=32 (16/16) 12 weeks Self-selected Self-selected insulin

Conley, 2018 [27] Healthy obese older males 2FD/W 23% † 2 non-consecutive fasting ↔ weight - ↔ FBG
IF n=11 (11/0) CR 20% † days Ad libitum ↔ WC ↔ TC, LDL, HDL, TG
CR n=12 (12/0) 6 months 600 kcal CI Self-selected ↔ SBP, DBP
Self-selected
Fitzgerald, 2018 [28] MS but otherwise healthy 2FD/W 21% † 2 consecutive fasting days ↔ weight - ↔ FBG
overweight and obese adults CR 22% 25% CI 100% CI ↔ FM ↔ TG,TC, HDL, LDL
IF n=12 (2/10) 8 weeks Meal provided Meal provided ↑ FM loss rate
CR n=12 (2/10) ↔ WC, HC, LM, VAT
Harvie, 2011 [22] Healthy premenopausal 2FD/W 25% 2 consecutive fasting days ↔ weight ↔ fasting adiponectin, leptin ↓ fasting insulin
overweight and obese females with CR 25% VLCD diet 2700kJ (∼25% 100% CI ↔ FM, FFM ↓HOMA-IR

2
breast cancer family history 6 months CI) Self-selected ↔ WC, HC ↔ FBG
IF n=53 (0/53) Self-selected ↔ TC, TG, LDL
CR n=54 (0/54) ↔ SBP, DBP
↔ BDNF
↔ CRP
Harvie, 2013 [23] Healthy overweight and obese 2FD/W + low CHO 2 consecutive fasting days ↔ weight ↔ subjective hunger score ↓ fasting insulin
females with breast cancer family 25% 2500-2717kJ CI 100% CI ↓ FM ↓ fasting leptin ↓ HOMA-IR
history CR 25% Self-selected Self-selected ↑ fasting adiponectin ↔ HbA1c, FBG
IF n=37 (0/37) 3 months ↔ TC, TG, HDL, LDL
CR n=38 (0/38) ↔ SBP, DBP
↔ IGF-1, IL-6, TNF-α

Schubel, 2018 [29] Healthy overweight and obese 2FD/W 20% 2 non-consecutive fasting ↔ weight ↔ fasting leptin, adiponectin ↑ FBG
adults CR 20% days 100% CI ↔ HOMA-IR; insulin
IF n=49 (25/24) 12 weeks 25% CI Self-selected ↔ TC, LDL, HDL, TG
CR n=49 (25/24) Self-selected ↔ CRP, IL-6
↔ BDNF
↔ % liver fat; GGT,
AST, ALT
Sundfor, 2018 [25] Healthy obese adults 2FD/W 23%† 2 non-consecutive fasting ↔ weight ↑ subjective hunger ↔ FBG, HbA1c
IF n=54 (28/26) CR 23% † days Ad libitum Mediterranean diet ↔ WC, HC ↔ unadjusted REE ↔TC, HDL, LDL, TG,

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CR n=58 (28/30) 6 months 400/600 kcal (female/male) Self-selected apoB
CI ↔ SBP, DBP, heart
Self-selected rate
↔ CRP
Bowen, 2018 [41] Healthy overweight and obese 3FD/W + CR 54%† 3 non-consecutive fasting 3 non-consecutive CR days ↔ weight - ↔ FBG, fasting
adults CR 50%† days 5000 kJ CI ↔ VAT insulin
IF n=67 (12/55) 16 weeks 2400kJ CI Commercially available ↔ LM ↔ TC, HDL, LDL
CR n=65 (13/52) Commercially available formula + self-selected foods
(continued on next page)
Physiology & Behavior 218 (2020) 112827
 Table 1 (continued)

First author, year Study population, sample size (M/ IF diet design IF vs CR outcome comparison
K. Liu, et al.

(reference number) F)
Study design, %CR, Fasting regimen Feeding regimen Weight and body Metabolic adaptation Health risk factors
duration composition

formula, consumed for 1 ad libitum day ↔ SBP, DBP

breakfast and lunch ∼10,000 kJ CI ↔ CRP
Self-selected
Coutinho, 2017 [26] Healthy obese adults 3FD/W 33% 3 non-consecutive fasting ↔ weight ↔ fasting and postprandial ↔ fasting and
IF n=14 (4/10) CR 33% days 100% CI ↔ FM, FFM subjective appetite rating postprandial insulin
CR n=14 (2/12) 12 weeks VLCD (550kcal for women, Self-selected ↔ fasting and postprandial
660kcal for men), 3 meals+1 ghrelin, PYY, CCK, GLP-1
snack ↔ unadjusted REE
Commercially available diet ↔ adjusted REE

Hutchison, 2019 [30] Healthy overweight and obese 3FD/W 30% 3 non-consecutive fasting ↓ weight ↓ subjective hunger rating one ↔ FBG, insulin
females CR 30% days 100% CI ↓ FM week during intervention ↓ HOMA-IR (fasting
IF n=25 (0/25) 8 weeks 32% CI Meal provided ↔ FFM day)
CR n=26 (0/26) consumed before 8am ↔ insulin sensitivity
Meal provided ↓ TC, LDL, TG
↔ FGF21
↔ AST
Beaulieu, 2019 [33] Healthy, overweight or obese ADF 38%† Fast every other day ↔ weight ↔ subjective hunger, dietary -
female adults CR 25% 25% CI no time restrictions Ad libitum ↔ FM, %FM, FFM, restraint, susceptibility to
IF n=12 (0/12) 12 weeks Commercially available diet Self-selected WC, HC hunger, binge eating, cravings
CR n=18 (0/18) ↑disinhibition, craving for
savoury food
↔ unadjusted REE

3
Catenacci, 2016 [45] Healthy obese adults ADF 47% Fast every other day 100% CI + ad libitum access to 5-7 ↔ weight ↔ fasting leptin, ghrelin ↔ FBG, fasting
IF n=13 (3/10) CR 28% Zero CI snacks (200kcal/serve) ↔ total FM, %FM, ↔ unadjusted REE insulin
CR n=12 (3/9) 8 weeks 24-hour fasting started after Meal provided trunk FM, %trunk ↔ adjusted REE ↔ TC, LDL, HDL, TG
evening meal FM ↔BDNF
↔ LM, %LM

Trepanowski, 2017 Healthy, overweight and obese ADF 25% Fast every other day ↔ weight - ↔ FBG, insulin,
[24] adults CR 25% ∼25% CI 12-2pm 125% CI ↔ body composition HOMA-IR
IF n= 34 (4/30) 24 weeks Month 1-3: Month 1-3: ↔ TC, LDL
CR n= 35 (6/29) Meal provided Meal provided ↑ HDL
Month 4-6: Month 4-6: ↔ SBP, DBP
Self-selected Self-selected ↔ CRP
Varady, 2011 [58] Healthy, overweight and obese ADF 38% † Fast every other day ↔ weight - ↓ TG
adults CR 25% ∼25% CI 12-2pm Ad libitum ↔ LDL
IF n=13 (3/10) 12 weeks Meal provided Self-selected ↔ LDL particle size
CR n=12 (2/10)

IF intermittent fasting; CR daily calorie restriction; 2FD/W 2 fasting days per week; 3FD/W 3 fasting days per week; ADF alternate day fasting; CI calorie intake; CHO carbohydrate; T2DM type 2 diabetes; MS multiple
sclerosis; VLCD very low calorie diet; FM fat mass; VAT visceral adipose tissue; FFM fat free mass; LM lean mass; REE resting energy expenditure; WC waist circumference; HC hip circumference; SBP systolic blood
pressure; DBP diastolic blood pressure; FBG fasting blood glucose; TC total cholesterol; TG triglyceride; LDL low-density lipoproteins; HOMA-IR Homeostatic model assessment of insulin resistance; HbA1c glycated

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hemoglobin; BNDF Brain-derived neurotrophic factor; SHBG sex hormone binding globulin; OHA oral hypoglycaemic agent; CRP C-reactive protein; apoB apolipoprotein B; PYY peptide YY; CCK cholecystokinin; GLP-1

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glucagon-like peptide 1; IGF-1 insulin-like growth factor 1; IL-6 interleukin 6; IL-8 interleukin 8; FGF21 fibroblast growth factor 21 AST aspartate transaminase; GGT gamma glutamyltransferase ; ALT alanine
aminotransferase
† ER estimated by the author according to the description in the paper; otherwise assuming ad libitum as 100% CI, 2400kJ (∼600kcal) as 20% CI in people with overweight and obesity
↔ No significant difference between IF and CR
↑ IF significantly higher than CR
↓IF significantly lower than CR
Physiology & Behavior 218 (2020) 112827
K. Liu, et al.
both groups [25]. However, some studies suggested the rate of weight
loss may be increased in IF versus CR. A median of 59 days was required
in IF versus 73 days in CR to achieve 5% weight loss, but this difference
was at trend level only [32]. Harvie et al. [23] also reported 65%
women achieved 5% weight loss at 3 months in IF versus 40% in CR,
but there was no statistical difference between groups. In contrast,
Fitzgerald et al. [28] reported slightly greater rates of weight loss in CR
than IF amongst people diagnosed with multiple sclerosis. Beaulieu
et al.[33]. reported that the CR group achieved 5% weight loss sooner
than the ADF group, although this was not significant (57 ± 16 days
versus 67 ± 13 days) in women with overweight and obesity. Further,
the number of completers who achieved 5% weight loss was sig-
nificantly higher in CR (n = 18) than IF (n = 12).
A handful of short-term uncontrolled ADF trials reported no sig-
nificant change in fat free mass (FFM) with overall weight losses of
3–7 kg [34-37]. This led Varady to propose that IF may preserve FFM
[38]. Mechanistically, this could be explained if the catabolic phase of
fasting was entirely compensated by the anabolic processes during
complete refeeding. In animal models, fasting triggered fatty acid-de-
rived ketone production and gluconeogenesis from amino acids, once
liver glycogen was depleted [39]. Conversely, resumption of calorie
intake on non-fasting days to energy balance or above, increased cir-
culating amino acids and insulin activating mTOR complex 1 pathways
to promote muscle protein synthesis in rodents [39]. As shown in
Table 1, larger controlled trials of IF did not differentially alter muscle
losses versus CR [22, 26, 28, 33, 40, 41] in people with obesity. Simi-
larly, IF did not differentially alter fat mass losses, except in two studies
conducted in women with overweight and obesity where greater re-
ductions were observed in IF versus CR [23, 30].
2.2. Adaptive responses to weight loss
Metabolic adaptations to preserve energy and promote appetite are
known to occur in response to caloric restriction [42]. For example,
total energy expenditure was −135 ± 42 kcal/day lower than expected
in response to 6 months of CR [5]. In contrast, IF increased body
temperature, energy expenditure and promoted adipose tissue
browning in mice [18, 43]. Two trials reported no change in resting
energy expenditure (REE) following IF with 3% weight loss in in-
dividuals without obesity [12, 44], and one study reported no change in
unadjusted REE following 6% weight loss following IF or CR in women
with overweight and obesity [33]. Other studies in people with over-
weight and obesity have shown similar reductions in adjusted REE in
both IF and CR with ≥5% weight loss [25, 26, 32, 45]. IF also did not
alter markers of white adipose tissue browning in women [43]. Further
research is required to study the effects of IF on energy expenditure,
diet-induced thermogenesis and adipose tissue browning in humans,
and in comparison with CR.
Appetite regulation is a complex process that involves interaction
between the hypothalamus and peripheral tissues through secretion of
orexgenic and anorexigenic hormones [46]. For example, the orexi-
genic hormone ghrelin increases before meals and decreases in response
to feeding [47], whereas anorexigenic hormones such as peptide YY
(PYY) and cholecystokinin (CCK) increase in response to meal, in-
creasing feelings of satiety [46]. In response to CR, elevated ghrelin,
together with reduced PYY, CCK and amylin were reported, which in-
creased the drive to eat and reduced feelings of fullness [5, 11, 48].
These changes in appetite regulation persisted for one year post-inter-
vention [11], and likely contributed to weight regain following CR.
The effects of IF on appetite regulation are poorly studied to date.
Reductions in perceived hunger [12, 36, 49] and increases in perceived
fullness and satisfaction [12, 37, 49] were observed in response to IF as
compared to baseline. But this was not significantly different when
compared to calorie-matched CR [23, 25, 26, 33]. Four studies mea-
sured hormones that can affect appetite including ghrelin, leptin and
adiponectin but solely in the fasting state, and showed no difference
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Physiology & Behavior 218 (2020) 112827
between IF and CR (Table 1). Only one study has assessed both fasting
and postprandial hormone response and showed no difference between
IF and CR after 12 weeks [26]. It should be noted that this study pre-
scribed three small meals across the fasting day, which would limit
reductions in insulin, and suppress the rise of ketone and fatty acids that
typically occur in IF trials.
A distinct feature of IF versus CR is the metabolic switch that occurs
between fast and feast cycles [50]. Prolonged fasting (>18 h) results in
a transient increase in lipolysis increasing blood non-esterified fatty
acids (NEFA) and ketone body production to preserve blood glucose
[30, 51, 52]. Ketogenic diets, such as very low calorie diet (VLCD) and
low carbohydrate diets, increase perceived fullness and satiety [53].
Raising blood ketones by exogenous ketone ester consumption also
reduced subjective hunger and ghrelin AUC compared to placebo [54].
The mechanism of action through which ketones impact appetite re-
mains unclear. Although recently β-hydroxybutyrate (a ketone body)
was shown to antagonise G protein-coupled receptor 41 on murine
enteroendocrine cells and altered gut hormone secretion [54, 55].
There is some indication that IF is associated with spontaneous re-
ductions in calorie intake on refeeding days [30, 32, 56]. For example,
Hutchison et al. [30] found 9% less food consumption than prescribed
on non-fasting days. Secondary data analysis on two of Harvie's trials
reported 19% spontaneous restriction of the intake on refeeding days
[56]. These findings likely contributed to the greater changes in body
weight, fat mass and improvements in glycaemic control that were re-
ported in these studies. In the only long-term study assessing calorie
intake during both weight loss and follow-up phases, a trend of in-
creased calorie intake on both fasting and non-fasting days during the
6-month follow up in the IF group was reported [24]. It should be noted
that current dietary assessments are highly reliant on self-reported
questionnaires and food diaries, and under-reporting is commonly ob-
served [57]. Whether spontaneous reductions in calorie intake occur or
persist longer term (>6 months) requires further study with objective
assessments through doubly labelled water.
2.3. Metabolic health
IF reduces risk markers for T2DM and CVD. However, whether the
health benefits of IF outweigh the benefits observed during CR is con-
troversial. Of the 15 IF versus CR trials discussed in this review
(Table 1), two reported greater reductions in insulin sensitivity by
homoeostatic model assessment of insulin resistance (HOMA-IR) [22,
23]. Three studies reported better outcome in CVD risks in IF versus CR
including reduced blood pressure [32], lower blood triglyceride [30,
32, 58] and lower total cholesterol and LDL levels [30]. Four out of
these five studies reported similar weight losses between the IF and CR
groups [22, 23, 32, 58], and the fifth showed the improvement was
independent of weight loss [30]. These studies suggest that IF may
provide greater improvements in metabolic health independently from
weight reductions.
2.4. Psychological, cognitive and neurological benefits
The psychological impact of cycles of fasting and feasting on mood,
emotional wellbeing and quality of life are commonly studied using
validated questionnaires. Generally, both IF and CR improved overall
psychological health amongst study volunteers [22, 27, 28, 41, 59].
However, IF was associated with minor adverse cognitive effects such
as lack of concentration, bad temper and preoccupation with food,
despite overall improvement in quality of life after 6 months [22].
Appleton et al. [60] observed significant lower positive mood, higher
negative mood as well as lower level of perceived work performance on
fasting days in a pilot study on 16 individuals.
Animal models have shown neuroprotective effect of IF through
inducing autophagy, inhibiting the formation of reactive oxygen spe-
cies, as well as increased brain-derived neurotrophic factor (BDNF)
K. Liu, et al.
signalling [61, 62]. Reduced BDNF was observed in IF and CR after 8-
and 12-week intervention in men and women with overweight and
obesity [29, 45]. Significant reductions in BDNF were also reported in
women after a 12-week CR intervention (8-week VLCD + 4-week
weight maintenance) [63], but this was not associated with changes in
cognitive function. To our knowledge, only one pilot study has tested
the effect of a combination of IF and ketogenic diet in children who
underwent seizure control [64]. Improved seizure control compared to
baseline was reported by four families but only three children adhered
to the combined diet for two months or longer. Whether IF will be
beneficial to reduce the risk of developing neurological disorders such
as Alzheimer's disease and Parkinson's disease warrants further study to
investigate whether the neuroprotective effects described in animals
translates to humans.
3. Potential risks and adverse events of IF
Current evidence supports that IF is a safe dietary approach to un-
dertake for up to 12 months, although only three long-term trials have
been conducted [24, 25, 29]. Of the 15 IF versus CR trials listed in
Table 1, only 7 reported adverse events (AE) and none compared the
incidence of AE between the two groups, which makes it hard to de-
termine whether IF is as safe as CR. However, in all studies only minor
physical symptoms such as hunger, lack of energy, headaches, light-
headedness, constipation, bad breath, and feelings of cold, together
with minor cognitive adverse effects including lack of concentration
were reported over 1–6 months as a result of IF or CR [22, 23, 25, 27-
29, 37, 60, 65]. In a trial conducted amongst people with T2DM, the
study protocol for oral hypoglycaemic agent (OHA) dosage was
changed mid-way during the trial due to incidences of hypoglycaemia
[40]. Medications were discontinued for participants with glycated
haemoglobin (HbA1c) <7%. For people with HbA1c level between
7–10%, medications were discontinued on fasting days only. No further
hypoglycaemic incidences were reported following this change in pro-
tocol.
There is also some concern amongst health professionals that fasting
could encourage disordered eating. The majority of RCT trials to date
have screened out people who had a medical history of eating disorder
[25, 28-30, 33, 41, 45] and psychiatric conditions [22, 23, 27] and did
not measure risks of disordered eating during the trial. Only one IF
study (no CR comparator) assessed signs of disordered eating during the
intervention period through a self-report inventory, Multidimensional
Assessment of Eating-Disorder Symptoms (MAEDS) [65]. Reduced signs
of depression and binge eating together with less concerns about body
size/shape were reported post-intervention which indicates a reduced
likelihood of developing disordered eating following IF.
Fasting for several days a week could also induce micronutrient
deficiencies. Only one study has assessed calcium and sodium with IF in
comparison to CR using a food frequency questionnaire and found si-
milar reductions in sodium and adequate calcium intake during the
intervention period [27]. Calcium intake was particularly of interest for
this study as it was conducted amongst older male participants (average
age 68 years old), and individuals older than 70 years of age are known
to have higher calcium [27, 66]. In future trials, assessment of micro-
nutrients through self-report and blood would provide insight on the
safety of IF and to generate recommendations for clinical practice.
4. IF design for optimal effectiveness
4.1. Time to fast
IF trials demonstrate great heterogeneity in design, with fasting
periods initiated at different times of the day (e.g. 20 hour fasts from
10pm to 6pm [51, 67], 24-hour fasts from midnight [12] or 8am [30] or
~18 hour fasts broken by small meals consumed at lunch or dinner [24,
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Physiology & Behavior 218 (2020) 112827
27, 58, 68]). The optimal time to initiate the fasting period has not been
studied. Metabolism and gut physiological processes demonstrate cir-
cadian rhythmicity across the day and glucose tolerance is lowest in the
evening as compared to the same meal consumed in the morning [69].
In the last decade, it has become apparent that peripheral tissue clocks
are strongly entrained by fasting/feeding cycles as shown in animal
models [70]. Thus, eating out of phase with the biological clock induces
circadian misalignment and impairs glucose control.
During CR, consuming 50% of a hypocaloric intake at breakfast
(6–9am) led to greater reductions in body weight, waist circumference,
insulin resistance (HOMA-IR), triglyceride and total cholesterol than
consuming 50% of calories at dinner time (6–9pm) in women with
obesity [71]. As such, optimising the fasting/feeding time in the context
of IF may generate greater health outcomes by synchronising with
normal circadian rhythm. Two IF trials prescribed 20-hours of fasting
from 10pm to 6pm, promoting late night eating every other day [51,
67]. Despite this, Halberg et al. [51] reported significant improvements
in insulin sensitivity by hyperinsulinemic clamp in lean men. But Soeter
et al. [67] showed no improvement in glucose and insulin concentra-
tions. Eating one meal a day between 5–9pm impaired glucose toler-
ance and increased CVD risk markers versus eating the same foods as 3
meals per day in humans [72, 73]. In mice, initiating IF at the start of
the inactive phase (i.e. at dinner in humans) dampened the expression
of clock genes inducing circadian misalignment, whereas initiating IF at
the start of the active phase did not (i.e. at breakfast in humans) [74]. In
humans, skipping breakfast acutely affected clock gene expression and
increased postprandial blood glucose and insulin levels in a healthy
population and people with T2DM [75]. Of note, Hutchison et al. [30]
initiated a 24-hour fast at 8am after breakfast, and observed greater
reductions in weight, HOMA-IR and blood lipids versus CR.
To date, only one human study directly compared the effect of
different meal time during IF [68]. In that study, 500 kcal were pre-
scribed during the fasting day as lunch, dinner or as three small snacks
across the day but did not differentially alter weight loss and CVD risk
factors including blood pressure and lipid profiles. However, there was
no IF-breakfast group for comparison. Whether aligning the fasting/
feeding time with circadian rhythms during IF protocols requires fur-
ther research.
4.2. How long and how often?
Significant improvements in markers of metabolic health have been
observed across IF protocols, despite differences in the duration and
frequency of fasting. Interestingly, greater benefits versus CR were
found in three trials that prescribed two consecutive fasting days [22,
23, 32] and one trial that prescribed 24 h of fasting on three non-
consecutive days in a week [30]. The majority of trials have prescribed
small amounts of calories during the fasting day as shown in Table 1.
Yet prolonged fasting is necessary to elevate blood ketones [30, 51, 62,
76] and may differentially activate nutrient signalling pathways. As
discussed earlier, ketones may promote feelings of satiety [53, 54], but
have more recently been recognised as signalling molecules that inhibit
reactive oxygen species production and class I histone deacetylase
(HDAC) in animal models [77]. Ketones can thus maintain histone
hyperacetylation and activate gene transcription, including forkhead
box O3 and the mammalian orthologue of the stress-responsive tran-
scriptional factor DAF16 which are associated with lifespan extension
in model organisms [78]. To our knowledge, no studies have directly
compared how many fasting days per week are necessary to optimise
health. More frequent fasting would likely result in greater energy
deficit and weight loss. Alternatively, compensatory over-eating or
poorer adherence to repeated days of fasting may undermine this result.
Further long-term studies to identify the optimal fasting frequency to
maximise adherence and health benefits are required.
K. Liu, et al.
4.3. Is calorie restriction required in IF interventions?
The evidence from animal models suggests that the fasting period
itself brings health benefits independently of weight loss, since minimal
differences in body weight were observed [79, 80]. Metabolic benefits
of IF in model organisms include reduced cancer, improved insulin
signalling, reduced incidence of stroke, neuroprotection, and increased
lifespan [79-81]. In healthy lean men, improved insulin sensitivity
without weight or fat mass loss was also observed in response to IF
[51]. However, this was not observed in women with obesity [30]. We
also recently tested whether calorie restriction was necessary to im-
prove health in women with obesity. Prescribing IF in overall energy
balance transiently increased glucose and insulin and when considered
overall, and did not improve markers of cardiovascular disease risk
[30]. This study contrasts mouse trials and suggests that moderate
overall calorie restriction is required to improve health in humans.
4.4. Macronutrient composition and dietary quality
Limited studies have assessed the effects of varying macronutrient
composition of IF diets. Klempel et al. [36] prescribed two diets dif-
fering in total fat and carbohydrate but matched in protein and fibre.
The ADF high fat (HF) group was provided a diet that contained 45%
fat, 40% carbohydrate (CHO) and low fat (LF) group was provided a
diet that contained 25% fat, 60% CHO on both fasting and feeding days.
Similar weight losses, fat losses and comparable improvements in blood
lipid profiles were observed in both ADF-HF and ADF-LF groups after 8
weeks. This study suggests that reducing fat content may not be ne-
cessary during IF.
Whether or not people make poorer food choices in response to
refeeding during IF diets is unknown. From Table 1, 10 out of 15 trials
tested IF under free-living conditions [22, 23, 25-27, 29, 32, 33, 40,
58]. Three IF studies did not provide any dietary recommendations to IF
participants on non-fasting days beyond “eat your regular diet” [27, 33,
40], but did provide routine dietary education on healthy eating for the
CR group by fortnightly visits with dietitians. All studies reported si-
milar improvements in health markers between IF and CR. Only two of
these trials reported macronutrient intakes and neither IF nor CR al-
tered macronutrient composition of the diet from baseline [27, 33].
Five trials recommended IF participants to consume a Mediterranean
style diet [22, 23, 25, 29, 32] and two recommended a healthy eating
pattern on non-fasting days [26, 58]. Participants from six of these trials
were assisted in meeting diet prescriptions by a study dietitian [22, 23,
25, 26, 29, 32]. Two of these studies did not report macronutrient in-
takes [25, 58]. Four studies showed there was no difference in mac-
ronutrient composition overall between IF and CR groups, but did not
divide this into fed and fasted day [22, 23, 26, 29]. Antoni et al. [32]
was the only study that reported the feeding days separately, and re-
assuringly, reported macronutrients were only marginally different
than prescribed. Based on current evidence, it is hard to draw a con-
clusion on whether prescribing macronutrients in line with the Medi-
terranean diet or healthy eating provides any extra benefit to the IF
approach.
4.5. The use of behaviour change techniques
Behaviour change techniques (BCT) have been identified as one of
the main contributors to lifestyle changes which have been associated
with the success of dietary interventions [82]. A range of techniques
that can be used in lifestyle modification was summarised by previous
reviews [82, 83]. Common ones used in IF interventions including goal
setting, motivational interviews, self-monitoring, peer/family support,
as well as stimulus control, but only by a small number of trials [22, 23,
25]. Routine dietary counselling was highly recommended by previous
IF trials to explain expected mild symptoms and strategies on fasting
days, which can reassure people to stay compliant to the diet [22]. This
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Physiology & Behavior 218 (2020) 112827
is particularly important for people with extra needs on dietary mon-
itoring (e.g. people with T2DM) to assess the likelihood of adverse
events, such as hypoglycaemia incidence when following IF diet [40,
59]. Apart from educating on nutrition knowledge, behavioural coun-
selling has been used as opportunities to implement BCTs which could
increase the effectiveness of IF, including setting realistic weight loss
goals, trouble-shooting and managing dieting with daily lifestyle [22,
23, 41]. The effectiveness of this should be studied in future IF trials.
5. Recommendation for future IF trials
This review focused on raising unsolved questions in relation to
intermittent fasting. The design of IF in terms of calorie restriction,
dietary quality and macronutrient composition, as well as optimising
the fasting/feeding time should be investigated further to maximise its
effectiveness and dietary adherence in people at high risk of chronic
lifestyle-related disease. Potential mechanisms including differential
activation of nutrient signalling and stress resistance pathways, appetite
regulation require in IF versus CR also require further investigation.
Acknowledgement
This research was supported by National Health and Medical
Research Council (NHMRC) Project grant APP1143092.
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