The role of intermittent fasting and meal timing in weight management and metabolic health
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Proceedings of the Nutrition Society (2020), 79, 76–87 doi:10.1017/S0029665119000636
© The Authors 2019 First published online 26 April 2019
The Nutrition Society Winter Meeting was held at the Royal Society of Medicine, London on 4–5 December 2018
Conference on ‘Optimal diet and lifestyle strategies for the management of
cardio-metabolic risk’
Symposium 4: Lifestyle factors
The role of intermittent fasting and meal timing in weight management
and metabolic health
Iain Templeman, Javier T. Gonzalez , Dylan Thompson and James A. Betts*
Department for Health, University of Bath, BA2 7AY, UK
Proceedings of the Nutrition Society
Obesity remains a major public health concern and intermittent fasting is a popular strategy
for weight loss, which may present independent health benefits. However, the number of diet
books advising how fasting can be incorporated into our daily lives is several orders of mag-
nitude greater than the number of trials examining whether fasting should be encouraged at
all. This review will consider the state of current understanding regarding various forms of
intermittent fasting (e.g. 5:2, time-restricted feeding and alternate-day fasting). The efficacy
of these temporally defined approaches appears broadly equivalent to that of standard daily
energy restriction, although many of these models of intermittent fasting do not involve fed-
fasted cycles every other 24 h sleep–wake cycle and/or permit some limited energy intake
outside of prescribed feeding times. Accordingly, the intervention period therefore may
not regularly alternate, may not span all or even most of any given day, and may not
even involve absolute fasting. This is important because potentially advantageous physio-
logical mechanisms may only be initiated if a post-absorptive state is sustained by uninter-
rupted fasting for a more prolonged duration than applied in many trials. Indeed, promising
effects on fat mass and insulin sensitivity have been reported when fasting duration is rou-
tinely extended beyond sixteen consecutive hours. Further progress will require such models
to be tested with appropriate controls to isolate whether any possible health effects of inter-
mittent fasting are primarily attributable to regularly protracted post-absorptive periods, or
simply to the net negative energy balance indirectly elicited by any form of dietary
restriction.
Eating pattern: Circadian rhythms: Time-restricted feeding: Weight loss
Obesity is a prevalent health concern throughout the energy intake and/or increasing expenditure, which can
world(1,2), which arises due to chronic positive energy improve health outcomes(18,19). However, these impro-
balance(3–5). Any energy surplus is stored primarily in vements are hampered by compensatory changes in appe-
the form of TAG within adipocytes, thus leading to adi- tite and energy use(4,20–22), as well as poor adherence(23,24),
pose tissue expansion(6,7) predominantly as a result of resulting in poor long-term success rates(4,25,26).
adipocyte hypertrophy(8). If sustained over time, this Strategies that exploit nutrient timing as a means of
hypertrophic expansion can lead to adipocyte dysfunc- achieving weight loss and/or improving metabolic health
tion, hyperglycaemia, hyperlipidaemia, ectopic lipid have been the subject of considerable public interest in
deposition, chronic low-grade systemic inflammation recent years(27). Intermittent fasting is an umbrella term
and insulin resistance(9–15), thereby fostering comorbid- that may be used to describe these approaches, which
ities such as type 2 diabetes and CVD(16,17). To remedy involve a complete or partial restriction of energy within
this metabolic dysfunction, interventions often seek to defined temporal windows on a recurrent basis(27,28).
redress the underlying energy imbalance by reducing Thus far, the therapeutic potential of intermittent fasting
*Corresponding author: James A. Betts, email j.betts@bath.ac.uk
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. https://doi.org/10.1017/S0029665119000636The role of intermittent fasting and meal timing in weight management and metabolic health 77
has been largely overshadowed by direct manipulation of and utilisation of endogenous lipid reservoirs. However,
the principal components of the energy balance equa- the imbalance between the daily fasting window and
tion(29). However, advances in the understanding of cir- the daily feeding window remains largely unperturbed.
cadian rhythms suggest that this could be a particularly Comparatively, the omission of meals is typically neces-
effective approach for tackling obesity and the accom- sitated by intermittent fasting and eliminates a subset
panying dysfunction(30,31), in addition to arguably of these postprandial excursions, thereby providing
being more acceptable in practice than conventional greater equilibrium between fasting and feeding oppor-
alternatives(32–36). To explore this notion, this review tunities and a better platform for achieving energy
will consider the literature on meal timing and intermit- balance.
tent fasting as it relates to metabolic health. Further to this, the routine extension of fasting periods
has been associated with metabolic benefits which are
independent of net energy balance(27,28,47), constituting
Meal timing a secondary therapeutic dimension to these strategies.
Specifically, Anton et al.(28) argue that the depletion of
In Western cultures, consuming three or more meals hepatic glycogen reserves and the ensuing transition
daily is generally accepted as a societal norm(37,38). towards metabolism of endogenous, lipid-derived sub-
However, this typically results in an anabolic state pre- strates (i.e. NEFA, glycerol, ketone bodies) prompt a ser-
dominating each day(39,40). The postprandial metabolic ies of adaptive processes conducive to improved health
Proceedings of the Nutrition Society
response to a mixed-macronutrient meal in metabolically outcomes, including improvements in body composition
healthy participants is characterised by a peak in gly- and insulin sensitivity. Considering that this transition
caemia within the first hour followed by a steady return does not take place in most instances until the uninter-
to fasted glycaemia over the ensuing 2 h(41,42). This is rupted fasting duration proceeds beyond 12–14 h(28,48),
paralleled by an accompanying peak in insulin secretion these adaptive processes are not often invoked by the
within the first hour followed by a decrease over the next conventional meal patterns described earlier.
4 h(42). Conversely, plasma TAG concentrations rise Based on the afore-mentioned reasoning, it is conceiv-
steadily to a peak after 3–5 h and generally remain 50 % able that intermittent fasting may constitute an effica-
higher than baseline even after 6 h(41). When a subse- cious strategy for tackling obesity and the metabolic
quent meal is ingested approximately 5 h after the first disorders associated with excess adiposity. To date, how-
(as is common in Western diets), glucose peaks at a simi- ever, studies exploring these facets of intermittent fasting
lar time after feeding, albeit an attenuated absolute are scarce and inconsistent.
peak(43). However, glucose then takes slightly longer to
return to baseline as the day progresses, a pattern that
is largely mirrored by insulin concentrations(44). Plasma Eating frequency
TAG on the other hand does not peak until shortly
after the second meal is ingested; it then falls rapidly Perhaps the most widely researched dimension of nutri-
due to the insulinaemic response to the second meal, ent timing within the context of obesity in human sub-
before peaking again about 5 h after the second meal(44). jects is eating frequency. Early work by Fabry et al.(49)
These responses suggest that, even with just two meals deployed a cross-sectional approach to explore the
daily, plasma TAG is elevated continuously for 12 h, relationship between intake frequency and metabolic
with this pattern then propagated when further extended health. Interestingly, in a cohort of 440 men, higher
to include a third meal. This is well-demonstrated by eating frequency broadly corresponded to a healthier
Ruge et al.(45), who examined the 24 h circulating profiles profile of BMI, cholesterol concentrations and fasting
of glucose, TAG and insulin in response to three succes- glucose. Contrary to this, using data from the National
sive meals at 10.00, 15.00 and 20.00 hours. Within this Health and Nutrition Examination Survey, Murakami
model, TAG remained elevated until 02.00 hours, along and Livingstone(50) observed that those eating on more
with insulin and glucose concentrations. Similarly, than four occasions daily were approximately 50 %
McQuaid et al.(46) showed that TAG extraction by adipose more likely to be overweight or obese by BMI relative
tissue in response to three meals daily is elevated for over to those eating on less than three occasions daily. Such
16 h. The net effect of this is that the majority of each 24 h discrepancies are a consistent theme throughout these
day is spent in a postprandial and lipogenic state, which is cross-sectional studies; a recent systematic review by
conducive to fat accretion(39,40). By extension, this pro- Canuto et al.(51) analysed data from thirty-one such stud-
vides fewer opportunities for net lipolysis and the predom- ies containing a collective sample of over 130 000 partici-
inance of lipid-derived substrates in energy metabolism, pants. Of these thirty-one studies, fourteen established an
thereby favouring positive fat balance. inverse association, ten showed no association and seven
Ultimately, this results in a scenario wherein those revealed a positive association, which the authors ascribe
adhering to conventional dietary meal timing patterns to the spectrum of approaches employed.
are attempting to achieve energy balance using a feeding Upon shifting to prospective methodologies, the pat-
schedule that is inherently biased towards fat accretion. tern appears to be largely the same; two recent systematic
Conventional diet and exercise interventions aim to reviews conclude that the majority of studies reveal no
reduce the amplitude of postprandial excursions in association between eating frequency and subsequent
order to provide more opportunities for the liberation obesity(52,53). The review of Raynor et al.(52) makes a
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. https://doi.org/10.1017/S002966511900063678 I. Templeman et al.
particularly strong case, given that these authors only feeding restrictions, nominally categorised as: the 5:2
included human studies in which food was provided or diet, modified alternate-day fasting, time-restricted feed-
intake monitored in a laboratory setting. However, of ing and complete alternate-day fasting(27). Irrespective
the studies covered in these reviews, most evaluated the of the rationale for each, such approaches have been sub-
impact of increased meal frequency on metabolic health, ject to growing popularity in recent years, yet experimen-
wherein three meals daily is used as the reference for tal data to support their application are comparatively
lower frequency. Therefore, upon framing these studies sparse(27,36). Bluntly, the number of diet books advising
within the context of the 24 h metabolite profiles dis- how intermittent fasting can be incorporated into our
cussed previously, the lack of a consensus is perhaps daily lives is several orders of magnitude greater than
not surprising. In fact, only one of the studies reported the number of scientific papers examining whether inter-
is likely to have resulted in the predominance of a fasting mittent fasting should be encouraged at all(27).
state over the course of 24 h(54).
Specifically, the study of Stote et al.(54) explored the
impact of reducing meal frequency to one meal daily The 5:2 diet
under conditions of energy balance. Briefly, fifteen Amongst the most coveted forms of intermittent fasting
normal-weight participants completed two 8-week inter- is the 5:2 diet, wherein severe energy restriction is
vention periods in a randomised crossover design with imposed on 2 d/week with ad libitum consumption on
an 11-week washout interval. In one treatment, all energy the remaining five. The study of Carter et al.(58) rando-
Proceedings of the Nutrition Society
was consumed in a single meal between 17.00 and 21.00 mised sixty-three adults with overweight or obesity and
hours, whilst the other treatment separated the same type 2 diabetes to 12 weeks of either daily energy restric-
foods into a conventional breakfast, lunch and dinner for- tion or a 5:2 approach. The 5:2 group reduced their
mat. To facilitate compliance, the dinner in both condi- intake to 1674–2510 kJ (400–600 kcal) for two non-
tions was consumed under supervision and all foods consecutive days per week and followed their habitual
were provided. The diets were matched for both energy diet on the remaining five, whilst the daily restriction
and macronutrient content and targeted weight mainten- group simply reduced their intake to 5021–6485 kJ
ance, with daily adjustment of prescribed intake based (1200–1550 kcal) every day. Although the extent to
on body weight measurements, which were then mirrored which prescriptions were achieved was not reported,
in the opposing trial. No differences in body mass, body main effects of time but not group were seen for reduc-
composition or health markers were apparent at the outset tions in body mass, fat mass and fat-free mass, as well
of each treatment and no differences in energy intake, as improvements in glycated Hb concentration and the
macronutrient balance or physical activity were noted use of diabetic medications. Similar conclusions were
between the two conditions. Despite these null findings, also drawn by two recent studies which compared this
body mass and fat mass (as assessed by bioelectrical 5:2 approach (i.e. 1674–2510 kJ (400–600 kcal) on two
impedance) were reduced by 1·4 and 2·1 kg, respectively, non-consecutive days per week) against daily energy
following the one meal daily condition but not the three restriction over 6 months(59,60).
meals daily condition. However, the reduction in adiposity This pattern of results indicates a broad equivalency
was not accompanied by improvements in lipid profile or between the metabolic impacts of the 5:2 diet and daily
glycaemia(55). This is consistent with the prior suggestion energy restriction, arguing against any special properties
that extending the daily fasting period may result in of the fasting element per se. However, this is not a con-
increased utilisation of lipid-derived substrates in energy sistent finding throughout the literature. Upon compar-
metabolism and favourable effects on fat balance(28). ing the 5:2 approach (requiring two consecutive days of
The afore-mentioned interpretation suggests that, in 75 % energy restriction per week) against daily energy
much the same way as a protracted daily feeding window restriction (requiring 25 % energy restriction every day)
may be conducive to an energy surplus, prolonged fast- over 6 months, Harvie et al.(61) observed differential
ing on a routine basis could be an effective strategy to changes in fasting insulin and fasting indices of insulin
counter fat accretion. However, what is particularly resistance. Despite similar reductions in body mass and
interesting here is that this observation was made under fat mass, the modest reductions in fasting insulin and
carefully matched conditions. Whilst this does not insulin resistance seen in both groups were more pro-
exclude any possibility of some amalgamation of nounced with the 5:2 method. Although this may
undetectable changes in the various components of reflect a more potent influence of using two consecutive
energy balance(56), it is also plausible that the protracted days of severe energy restriction (as opposed to non-
fasting period is exerting impacts on energy metabolism consecutive), there were also greater reductions in energy
that are independent of net energy balance(28,57). The cur- and carbohydrate intake in this group, which complicate
rent literature on intermittent fasting provides a useful the interpretation.
platform for exploring this notion further. Using a similar approach, Antoni et al.(62) sought to
compare the effects of intermittent energy restriction
(implemented using the 5:2 approach) against daily
Intermittent fasting energy restriction when matched for net energy balance
and thus weight losses, in order to minimise the con-
The umbrella term intermittent fasting refers to a series founding influence of such factors on metabolic health.
of therapeutic interventions which target temporal Furthermore, this study featured dynamic indices of
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. https://doi.org/10.1017/S0029665119000636The role of intermittent fasting and meal timing in weight management and metabolic health 79
metabolic control, building upon the prior studies which where twelve obese participants completed 8 weeks of
only featured fasted measures. Briefly, twenty-seven par- modified alternate-day fasting. Reported adherence to
ticipants with overweight or obesity were randomised to the fasting protocol remained high throughout, with
undertake either an intermittent or a continuous energy energy intake averaging 26 % of habitual(32,35).
restriction diet. The 5:2 condition restricted participants Comparatively, intake on feeding days reached 95 % of
to 2636 kJ (630 kcal)/d for two consecutive days each the habitual level, resulting in a 37 % net energy restric-
week, with a self-selected euenergetic diet on the remain- tion on average. This led to body mass losses of 5·6 kg,
ing five. Comparatively, the continuous restriction imple- 5·4 kg of which was accounted for by decreases in fat
mented a self-selected diet intended to reduce energy mass(32). Total cholesterol, LDL-cholesterol and TAG
intake by 2510 kJ (600 kcal)/d. As opposed to returning were also reduced by at least 20 %, effects which were
to the laboratory after a fixed period, participants were associated with improvements in adipokine profile(63).
reassessed upon achieving a 5 % weight loss. Despite lar- Subsequent work by the same group neatly demonstrates
ger reductions in energy intake in the intermittent condi- that these outcomes are similar when applied to cohorts
tion, the design meant that changes in body mass were of adults who are overweight(64), when meal timing on
similar between groups. Body composition and fasting the fasting day is varied(65), and that concurrent macro-
biochemical outcomes were also similarly affected by the nutrient manipulation does not exert additive effects(66).
two diets, showing good agreement with previous studies. Collectively, these data suggest that modified alternate-
However, the intermittent diet resulted in significant day fasting may be a viable means of improving cardio-
Proceedings of the Nutrition Society
reductions in postprandial TAG concentrations relative metabolic health in adults who are overweight or obese.
to daily energy restriction, whilst postprandial C-peptide However, without a comparative daily energy restriction
concentration also showed a tendency for greater reduc- group, it is difficult to isolate any independent effects of
tions in the intermittent feeding group. The authors con- the fasting periods from the effects of energy restriction
cluded that this highlights a potential superiority of and/or associated weight loss. This was addressed
intermittent relative to continuous energy restriction. recently by a comparison of the two methods under iso-
Based on the afore-mentioned studies of the 5:2 energetic conditions relative to a no intervention control
approach to intermittent fasting, it seems that the manner group(67,68). Briefly, sixty-nine adults with obesity were
in which the fast is applied is a key determinant of the randomised to undertake 6 months of modified alternate-
impacts on metabolic health. When the fast is undertaken day fasting or daily energy restriction. The alternate-day
on consecutive days, there is an apparent superiority rela- fasting diet restricted participants to a single meal con-
tive to daily energy restriction(61,62), whilst applying the taining 25 % of their measured energy requirements
fast on non-consecutive days results in broadly equivalent between 12.00 and 14.00 hours during fasting periods,
effects(58–60). Upon considering this in terms of the result- but prescribed 125 % of energy requirements on feeding
ant uninterrupted fasting duration, this would appear to days. Conversely, the daily energy restriction diet pre-
fit with the proposition of Anton et al.(28), as fasting on scribed a 25 % reduction in energy intake every day,
consecutive days is more likely to result in an uninter- resulting in an equivalent reduction in energy intake of
rupted fast of over 12–14 h when compared with fasting 25 % in both groups. Macronutrient balance was pre-
on non-consecutive days. However, as these interventions served in both instances and the attained energy restric-
do not confine the permitted intake during fasting to a tion was 21 and 24 % for alternate-day fasting and
specific time window (e.g. 1674–2510 kJ (400–600 kcal) daily energy restriction, respectively. The observed
consumed between 12.00 and 14.00 hours on fasting body mass loss of 6·8 % was also similar between the
days), this makes it difficult to establish the exact duration two groups, a pattern driven by changes in both fat
of absolute fasting achieved. mass and lean mass. Fasted markers of metabolic health
were also largely unaffected by either intervention,
including lipid profile, inflammatory markers, adipo-
Modified alternate-day fasting kines, glucose concentration and insulin resistance(67,68).
The majority of human studies which examine intermit- Furthermore, few differences emerged during an ensuing
tent fasting have centred upon a strategy referred to as 6-month weight maintenance period in which the feeding
modified alternate-day fasting(27). It differs from the 5:2 patterns were maintained but the prescriptions modified
diet in two key regards: the severe restriction is applied to fulfil energy requirements (i.e. no energy deficit).
during alternating days (nominally 24 h, although prac- This once again indicates that intermittent fasting and
tically more varied to accommodate sleep); and any per- daily energy restriction exert similar effects on most
mitted energy during fasting is provided in a single meal health outcomes, as concluded previously for the 5:2
(thereby ensuring a tangible extension of the typical over- approach. However, during the modified alternate-day
night fast). Much of the work undertaken in this field ori- fasting intervention, participants consistently over-
ginates from pioneering experiments by Varady et al., in consumed on fasting days and under-consumed on fed
which participants were required to alternate between 24 days, in what the authors describe as de facto energy
h periods of fasting and ad libitum feeding, with a single restriction(67). Consequently, over the duration of the
2510–3347 kJ (600–800 kcal) meal permitted between study, the difference in reported energy intake between
12.00 and 14.00 hours on non-feeding days. feeding and fasting days was80 I. Templeman et al.
those who lost more or less than 5 % body mass, those breakfast did result in improved insulinaemic responses
closest to the prescribed intake targets showed larger during an oral glucose tolerance test relative to the fast-
decreases in body mass despite consuming more energy ing condition. However, this test was aligned for circa-
overall(69). Unfortunately, the mechanisms underpinning dian cycle rather than feeding cycle, so the observed
this are unclear. The observation could reflect increased finding could simply reflect better alignment with antici-
use of lipid-derived substrates or lower levels of adaptive pated events in the breakfast condition.
thermogenesis with intermittent methods, or perhaps it Other studies have applied time-restricted feeding
simply reflects poorer dietary reporting by those with under euenergetic conditions, much like the study of
lower adherence. Stote et al.(54). Focusing on energy metabolism, Moro
Nonetheless, data emerging from studies of modified et al.(75) randomised thirty-four men to 8 weeks of time-
alternate-day fasting do not allude to a superiority rela- restricted feeding or a control diet. Diets were matched
tive to daily energy restriction. Although, the use of for energy and macronutrient content and aimed to pro-
single-arm trials and poor adherence to fasting prescrip- vide 100 % of energy requirements across three meals in
tions leave this question open to further study. both conditions. In the control condition, meals were
consumed at 08.00, 13.00 and 20.00 hours, whilst in the
experimental condition, meals were consumed at 13.00,
Time-restricted feeding 16.00 and 20.00 hours to give a 16 h fast. The time-
Ironically, the adherence issues that appear common to restricted approach resulted in reductions in fat mass
Proceedings of the Nutrition Society
modified alternate-day approaches may lie in the impos- relative to controls, which were partnered by decreases
ition of a severe restriction as opposed to a complete fast, in RER, indicating a shift towards fat oxidation.
which in being an absolute (albeit more severe) could in Interestingly, however, despite accompanying reductions
fact facilitate compliance(32,33,36). Drawing from this in leptin and hypothalamic–pituitary–thyroid signalling,
premise, time-restricted feeding is another method of resting energy expenditure was maintained. This rein-
intermittent fasting which has emerged recently(27) and forces the notion that nutrient timing impacts upon nutri-
requires no knowledge of food composition or restraint ent metabolism, whilst also highlighting that this appears
at eating occasions, only awareness of the time at to occur to a greater degree with a 16 h fast relative to a
which eating occasions are permitted at all. This 12 h fast. Considering this in light of the typical post-
approach aims to restrict food intake to a temporal win- prandial nutrient profile discussed previously, the
dow (typically ≤10 h) within the waking phase, thereby increase in fasting duration may provide more opportun-
reducing feeding opportunities and extending the over- ities for the metabolism of substrates derived from
night fast to at least 14 h daily(70). endogenous lipids. This again points to the possibility
Work in our laboratory explored the impact of extend- that routine extension of the fasting period beyond 12–
ing the overnight fast on energy balance and nutrient 14 h may be key to these benefits, which was not neces-
metabolism, thereby providing several insights regarding sarily achieved by the 5:2 or modified alternate-day
the effects of such strategies(71–74). Initially, thirty-three methods discussed earlier. The pivotal question is
adults who were of healthy weight were randomised to whether these improvements are enhanced with even
6 weeks of either consuming breakfast, defined as at longer durations of complete fasting.
least 2929 kJ (700 kcal) before 11.00 hours daily (with More prolonged and complete fasting was recently
half consumed within 2 h of waking), or extended examined by Sutton et al.(70), who hypothesised that cir-
morning fasting up until 12.00 hours(73). Interestingly, cadian rhythms in energy metabolism would potentiate
improvements in anthropometric parameters and fasting the effects of time-restricted feeding when eating times
health markers were not meaningfully different between are confined to earlier stages of the waking phase.
interventions. In agreement, a panel of hormones impli- Using a repeated-measures crossover design, they com-
cated in the regulation of energy balance showed little pared the effect of consuming all daily energy within a
change following the two interventions, although specific 6 h window and a 12 h window over 5 weeks in men
measures of adipose tissue insulin sensitivity suggested an with pre-diabetes. The diets were prescribed based on
improvement in the breakfast group only(71). energy requirements to maintain energy balance and
These largely null findings relative to prior research were also matched for energy and macronutrient content.
could be explained by the free-living approach used to Compliance to the two conditions was high and the
study compensatory changes in components of energy extended fasting period was accompanied by reductions
balance. The fasting group consumed less energy than in fasting insulin, peak insulin and insulin resistance dur-
the breakfast group when averaged throughout each ing an oral glucose tolerance test. However, it appears
24 h period, but this was compensated for by lower phys- the magnitude and persistence of any treatment effects
ical activity thermogenesis. Upon applying this protocol may have required a longer wash-out interval between
to a cohort of adults with obesity(72), extended fasting repeated treatments, as the impacts on insulinaemia
resulted in a slightly greater compensatory increase in were seemingly affected by baseline differences arising
energy intake following fasting (although still not from a trial order effect. Combined with the fact that
adequate to offset the energy consumed or omitted at the fasting duration preceding post-intervention measure-
breakfast), whilst daily fasting was again causally related ments was not standardised across trials, further investi-
to lower physical activity energy expenditure in the gations are warranted to verify these intriguing
morning. Interestingly, in this cohort with obesity possibilities.
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. https://doi.org/10.1017/S0029665119000636The role of intermittent fasting and meal timing in weight management and metabolic health 81
Based on all the afore-mentioned findings, the evi- measures crossover study. This compared the effects of 2
dence does point to an effect of extended fasting intervals weeks of a standard weight maintenance diet against 2
on fat mass independent of energy balance, particularly weeks of an intermittent fasting diet, using the same fast-
when the fasting interval is extended to at least 16 h, as ing protocol as Halberg et al.(47). In this instance, a more
shown by Stote et al.(54) and Moro et al.(75). In both prescriptive approach was adopted to the feeding cycles,
cases, this produced significant reductions in fat mass with liquid meals used to bolster intake and adjustment
relative to a routine 12 h fast, which implicates extended of prescriptions in the event of meaningful weight change.
fasting beyond 12 h as a key factor. However, the import- Accordingly, body mass and composition were unaltered,
ance of such changes for metabolic health is less clear yet there were no significant changes in glucose, lipid or
due to a series of confounding influences. protein kinetics in the basal state, or during a two-stage
euglycaemic–hyperinsulinaemic clamp. In actuality, the
only difference was a slight decrease in resting energy
Complete alternate-day fasting expenditure following the intermittent fasting arm.
Thus far, the intermittent fasting strategies discussed typ- Contrary to the studies of Halberg et al.(47) and Stote
ically permit the consumption of energy within each 24 h et al.(54), the afore-mentioned findings suggest that recur-
cycle to some degree, meaning that the fasting interval is rent extension of the fasting period exerts no influence on
only extended by a few hours(76). This is primarily to energy or nutrient metabolism, aside from a possible
facilitate adherence(32,34) but it also replenishes hepatic decline in resting energy use. Whilst there are some dis-
Proceedings of the Nutrition Society
glycogen stores and reduces the utilisation of lipid- crepancies in terms of the approach to feeding cycles
derived substrates (i.e. ketone bodies), which may mask and assessment of nutrient metabolism under dynamic
several proposed benefits of intermittent fasting(28). conditions, attributing to such factors would suggest
Furthermore, this disruption is profoundly asymmetric, the effect is unlikely to be clinically meaningful.
in that even a short feeding occasion immediately sup- However, work by Heilbronn et al. provides interesting
presses lipolysis and ketogenesis, which then do not insights that could explain such stark contrasts between
return for a number of hours(41,42). It is worthy of note ostensibly similar approaches(34,78). Their study applied
at this juncture that the inclusion of physical activity or an intermittent fasting intervention to a cohort of sixteen
exercise during the fasted period may serve to accelerate adults who were not obese which involved fasting from
the restoration of these pathways to some degree, midnight to midnight on alternating days for 3 weeks,
although the concurrent application of intermittent fast- with fasting periods only permitting energy-free drinks
ing alongside exercise interventions is beyond the scope and sugar-free gum (fed periods were ad libitum).
of this review. Nonetheless, the 20 h fasting interval Assessments of body composition, a mixed-meal test
used by Stote et al.(54) is likely to have led to a greater and muscle biopsies were carried out at baseline and
reliance on these lipid-derived substrates over the course follow-up, with an additional set of measurements col-
of 24 h, which may explain the reduction in fat mass des- lected after a 36 h fast to explore the physiological impact
pite euenergetic intake. of individual fasting periods on energy metabolism.
Building upon this premise, Halberg et al.(47) applied a Although energy intake was not reported, the interven-
20 h fast on alternate days from 22.00 to 18.00 hours, tion reduced body mass by 2·5 %, approximately
representing an integration of the strategies employed two-thirds of which was accounted for by reduced fat
by Stote et al.(54) and Varady et al.(32). Fasting prohibited mass. However, the majority of fasting parameters,
all intake with the exception of water, whilst during the including plasma glucose concentration, RMR, substrate
intervening feeding periods, participants were told to oxidation and muscle GLUT4 content showed no not-
double their habitual intake to maintain body mass. able change(34,78). Key exceptions were sex-specific
Although dietary intake was not monitored, blood sam- alterations in cholesterol profile, with women experien-
ples collected in a subset of fasting periods confirmed cing an increase in HDL-cholesterol concentration and
compliance with the fasting protocol, with corresponding men exhibiting reductions in fasting TAG. Values col-
changes in systemic concentrations of glucose, NEFA, lected after 36 h of fasting confirmed increased fatty
glycerol, adiponectin and leptin. Although both body acid oxidation, raising the question of why the routine
mass and fat mass were unchanged, the glucose infusion up-regulation of fat metabolism combined with body
rate during a euglycaemic–hyperinsulinaemic clamp mass losses resulted in no consistent changes in metabolic
increased in the final 30 min of the sampling period, sug- health. However, this pattern of sexual dimorphism con-
gesting enhanced insulin sensitivity following complete tinued into postprandial outcomes, with increases in glu-
alternate-day fasting. Accordingly, this was accompanied cose area under curve for females and reductions in
by more rapid suppression of adipose tissue lipolysis dur- insulin area under curve for males(78).
ing the insulin infusion. While the lack of an effect on It might then be suggested that males and females
body mass and fat mass relative to prior studies may respond differently to complete alternate-day fasting.
reflect the disparity in cumulative fasting time, the authors However, there were a number of baseline differences
were nonetheless able to conclude that this approach to between men and women in that study which should be
intermittent fasting can improve metabolic health even considered in this interpretation, with men exhibiting
in the absence of detectable changes in body mass. higher glucose, insulin and TAG concentrations in the
Employing a similar approach, Soeters et al.(77) fasted state(34). Upon contextualising this in the physiology
recruited eight males of healthy weight to a repeated- of insulin resistance(9–14), it seems plausible that the
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. https://doi.org/10.1017/S002966511900063682 I. Templeman et al.
metabolic state of male participants at baseline may stand is the confinement of energy restriction to a specified tem-
to benefit more from the routine extension of fasting (not- poral window, be that 16 h each day(75), every other
withstanding the possibility of statistical regression). In day(32,34) or just 2 d per week(61,62). Across these various
these individuals, the shift toward fat oxidation seen in models, intermittent fasting can elicit reductions in body
response to prolonged fasting could help to clear lipid inter- mass and improvements in metabolic health, effects
mediaries from non-adipose tissues, thereby enhancing which appear broadly comparable to standard daily
insulin sensitivity. This is supported by the reported energy restriction(82). However, because the therapeutic
increase in carnitine palmitoltransferase-1 protein content potential of these temporal strategies may lie in routinely
in muscle tissue after the intervention(78,79). extending catabolic periods, thereby increasing reliance
Extending this premise to the studies of Halberg et al.(47) on lipid-derived substrates(28), the similar efficacy in rela-
and Soeters et al.(77), the average body fat percentage of tion to standard approaches could instead reflect a failure
their cohorts was 20·1 and 14·8 %, respectively. This may to meaningfully extend the post-absorptive period. The
therefore support the notion that those with lower levels 5:2 diet and modified alternate-day fasting rarely omit
of adiposity may not benefit from such interventions. more than one meal in sequence and therefore this tran-
Consequently, it is imperative to consider the seemingly sition to lipid-derived substrates may scarcely be
distinct responses seen between leaner and more over- made(58–60,67,68). Conversely, if applying approaches
weight cohorts when interpreting the results of similar stud- that extend the fasting interval towards 20 h and beyond
ies. This is not only because the potential for weight loss (e.g. consecutive fasting days in the 5:2 diet or time-
Proceedings of the Nutrition Society
and health gain may vary, but also because the presenta- restricted feeding), this transition to lipid-derived sub-
tion as lean or obese at baseline may be symptomatic of strates is likely to be made more frequently, perhaps
a predisposition towards various compensatory adjust- explaining the proposed superiority of these
ments that predict responsiveness to treatment(5,72–74,80). approaches(54,61,62,75). Unfortunately, whilst the latter
Furthering this line of enquiry, Catenacci et al.(81) studies of complete alternate-day fasting offer amongst
undertook a randomised controlled trial of complete the longest uninterrupted fasting periods, the true effects
alternate-day fasting in a sample of adults with obesity. of this are difficult to isolate due to metabolically diverse
Briefly, twenty-six participants were randomised to samples and the use of single-arm trials. Consequently,
undertake 8 weeks of either daily energy restriction there remains an urgent need for well-designed,
(requiring a reduction in energy intake of 1674 kJ randomised-controlled trials of this commonly adopted
(400 kcal)/d) or a complete alternate-day fast. The inter- approach.
mittent fasting condition imposed a fast on every other
day and provided a diet to meet estimated daily energy
requirements during feeding periods, with a series of Future directions
837 kJ (200 kcal) optional food modules to permit ad
libitum intake. All foods were provided and diets were Identifying more effective strategies for managing obesity
matched for macronutrient balance rather than energy and associated metabolic disorders remains a public
intake. Consequently, energy intake across the interven- health challenge and intermittent fasting may represent
tion was lower with the intermittent fasting approach, a potent tool. However, research to support this is scarce
averaging 53 % of weight maintenance requirements and a number of important facets have been overlooked.
compared with 72 % for daily energy restriction. This Further research is therefore warranted to establish
was accompanied by a trend for greater reductions in whether intermittent fasting is simply an alternative
body mass with intermittent fasting relative to energy means of achieving energy restriction(76), or a dietary
restriction, with 8·8 and 6·2 % reductions seen in the strategy which offers a favourable method for maintain-
respective conditions. Despite this, fat mass and lean ing/improving metabolic health.
mass decreased to a similar degree in both groups, a pat-
tern mirrored by improvements in fasted lipid profile.
Only intermittent fasting produced improvements in Body composition
fasted glucose concentration from baseline to follow-up, Whilst much investigation has been devoted to the effects
yet responses to a dynamic test of insulin sensitivity were intermittent fasting exerts on fat balance, routinely
unaltered. Conversely, RMR was reduced by daily extending catabolic periods also carries implications for
energy restriction only, following correction for body fat-free mass. Anton et al.(28) argue that the increased
composition changes, with a trend for a between-group reliance on lipid-derived substrates during prolonged
difference. However, between-group comparisons were fasting serves to minimise deteriorations in muscle mass
compromised by baseline differences, with those in the and function, although this does not negate these dete-
daily energy restriction group presenting with higher riorations all together. Mechanistically, net protein bal-
body mass and fasting insulin concentrations on average. ance is a product of constant interactions between
protein synthesis and breakdown(83). Following an over-
night fast (approximately 8–12 h), there is an increase in
Summary amino acid efflux from muscle tissue(84), suggesting a
shift in favour of net muscle protein breakdown(85–87).
Intermittent fasting clearly encompasses a broad spec- Whilst there are limited data to support an exaggeration
trum of dietary interventions. The defining characteristic of this catabolic state when the fasting duration is
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. https://doi.org/10.1017/S0029665119000636The role of intermittent fasting and meal timing in weight management and metabolic health 83
extended to 24 h, a recent study by Vendelbo et al.(88) conclusions being drawn. There is therefore a definite
showed that fasting for 72 h doubled the rate of amino need to examine the cumulative impact of intermittent
acid efflux from skeletal muscle when compared with a fasting on the components of energy balance in a reliable
10 h fast. Accordingly, it would be reasonable to antici- and well-controlled manner, not least physical activity
pate a greater decline in fat-free mass in response to inter- thermogenesis.
mittent fasting when compared with daily energy
restriction. Postprandial nutrient metabolism
Contrary to this mechanistic perspective, however, a sys-
tematic review of randomised-controlled trials by An opportunity arising from the pre-existing literature
Varady(89) concluded that intermittent fasting may in fact stems from the fact that the majority of studies have
offer enhanced retention of fat-free mass when compared focused on fasting measures of glucose, insulin and
with daily energy restriction. A similar conclusion was TAG, with very few studies employing dynamic tests.
also drawn by a more recent review comparing intermit- The relevance of this is well-illustrated by the impact of
tent approaches with very-low energy dieting(90). Whilst intermittent fasting on insulin; improvements in fasting
the predominance of modified alternate-day fasting studies insulin have been consistently shown in a number of stud-
in the former review may help to explain this, it is worthy ies as reviewed by Barnosky et al.(82). They also show
of note that the complete alternate-day studies of both that in a subset of these studies, fasting indices of insulin
Halberg et al.(47) and Heilbronn et al.(34) were included. resistance such as the homeostasis model generally
Proceedings of the Nutrition Society
If verified, enhanced retention of fat-free mass relative to improve following a period of intermittent fasting.
daily energy restriction would be a potent asset considering However, it is important to note that while these fasting
its association with RMR(91–93). Consequently, clarifying indices are useful in easing experimental demands, there
the effect of complete alternate-day fasting on fat-free are several limitations. For instance, Borai et al.(97) sug-
mass should be a central research priority. gest it is possible for a participant to be insulin resistant
without demonstrating fasting hyperinsulinaemia.
The same inconsistencies emerge when examining
Energy expenditure postprandial glycaemia, whilst postprandial lipaemia
A key (but often overlooked) issue with conventional has been largely ignored. On an acute basis, Antoni
obesity management approaches is compensatory et al.(98) demonstrate that a day of 100 % energetic
changes in other dimensions of energy balance, particu- restriction results in enhanced suppression of postpran-
larly decreased energy expenditure with daily energy dial TAG and NEFA concentrations, relative to habitual
restriction(21,22,94). It is not clear from the existing body intake and partial energy restriction. Extending this to
of intermittent fasting research whether such compensa- the 5:2 approach, a similar pattern emerged for improve-
tory changes may be invoked. Focusing initially on ments in postprandial TAG concentrations with the
RMR, both Heilbronn et al.(34) and Catenacci et al.(81) intermittent condition relative to continuous restric-
reported no detectable change in response to complete tion(62). Such effects are also consistent with the
alternate-day fasting, whilst Soeters et al.(77) suggest a enhanced suppression of adipose tissue lipolysis reported
decline in resting energy use of 247 kJ (59 kcal)/d. by Halberg et al.(47). Given the importance of these out-
Conversely, physical activity energy expenditure has comes in the context of obesity and the associated
not been thoroughly and objectively examined in comorbidities, closer examination is warranted.
response to complete alternate-day fasting. Klempel
et al.(35) observed no changes in daily step counts during Comparative designs
8 weeks of modified alternate-day fasting, despite clinic- Despite being proposed as an alternative approach to
ally meaningful weight losses, and ensuing studies weight loss, few human trials to date have directly com-
employing accelerometers have verified this out- pared complete alternate-day fasting against standard
come(95,96). However, it should be noted that these stud- daily energy restriction. Although it is generally reported
ies all employed modified alternate-day fasting that the outcomes are similar, the broad spectrum of
approaches, which can reasonably be expected to differ cohorts and experimental protocols employed confounds
in their effects on voluntary behaviour relative to com- reliable comparisons against the pre-existing litera-
plete alternate-day methods. ture(89). The study of Catenacci et al.(81) is certainly an
In the absence of objective measures of energy expend- exception to this pattern, as they directly compared com-
iture, Sutton et al.(70) argue that energy expenditure is not plete alternate-day fasting and daily energy restriction;
affected by temporal restrictions of energy intake based however, the two conditions were not matched for the
on the absence of significant differences in body mass degree of energy restriction imposed. For this reason,
in their euenergetic time-restricted feeding study. reaching a consensus on the relative merits of intermit-
However, Dhurandhar et al.(56) highlight that accurate tent fasting is not possible without further studies with
determination of energy balance necessitates measure- appropriate controls.
ment of all aspects of the equation. While it does then
remain a distinct possibility that typical compensatory
responses to an energy deficit are blunted when intermit- Fasting-dependent effects
tent fasting, a lack of evidence about isolated dimensions Lastly, and perhaps most importantly, is the possibility
of energy expenditure currently prevents reliable that remaining in a post-absorptive state for prolonged
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periods (i.e. fasting) may impart independent health ben- Technical Report Series 894. Geneva: World Health
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