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nutrients

Review
Beneficial Effects of Early Time-Restricted Feeding on
Metabolic Diseases: Importance of Aligning Food Habits with
the Circadian Clock
Anouk Charlot *, Fanny Hutt, Eugénie Sabatier and Joffrey Zoll *

CRBS, UR3072: Mitochondria, Oxidative Stress and Muscular Protection, University of Strasbourg,
1 rue Eugène Boeckel, 67000 Strasbourg, France; fanny-04@live.fr (F.H.); eugenie.sabatier@etu.unistra.fr (E.S.)
* Correspondence: anouk.charlot@etu.unistra.fr (A.C.); joffrey.zoll@unistra.fr (J.Z.)

Abstract: The importance of metabolic health is a major societal concern due to the increasing
prevalence of metabolic diseases such as obesity, diabetes, and various cardiovascular diseases. The
circadian clock is clearly implicated in the development of these metabolic diseases. Indeed, it
regulates physiological processes by hormone modulation, thus helping the body to perform them at
the ideal time of day. Since the industrial revolution, the actions and rhythms of everyday life have
been modified and are characterized by changes in sleep pattern, work schedules, and eating habits.
These modifications have in turn lead to night shift, social jetlag, late-night eating, and meal skipping,
a group of customs that causes circadian rhythm disruption and leads to an increase in metabolic
risks. Intermittent fasting, especially the time-restricted eating, proposes a solution: restraining the
feeding window from 6 to 10 h per day to match it with the circadian clock. This approach seems

 to improve metabolic health markers and could be a therapeutic solution to fight against metabolic
diseases. This review summarizes the importance of matching life habits with circadian rhythms for
Citation: Charlot, A.; Hutt, F.;
metabolic health and assesses the advantages and limits of the application of time-restricted fasting
Sabatier, E.; Zoll, J. Beneficial Effects
of Early Time-Restricted Feeding on
with the objective of treating and preventing metabolic diseases.
Metabolic Diseases: Importance of
Aligning Food Habits with the Keywords: time-restricted fasting; intermittent fasting; circadian clock; metabolic diseases; obesity;
Circadian Clock. Nutrients 2021, 13, cardiovascular disease
1405. https://doi.org/10.3390/
nu13051405

Academic Editor: Silvio Buscemi 1. Introduction


Obesity is a growing and epidemic disease, with a prevalence reaching such propor-
Received: 11 March 2021 tions that it is now considered as a pandemic. Obese people expose themselves to health
Accepted: 20 April 2021 problems. Indeed, they are more susceptible to suffering from heart attacks, strokes, and
Published: 22 April 2021
diabetes [1]. Nowadays, there is no miracle cure to treat obesity. The few pharmacologi-
cal agents available usually present side effects and need to be combined with a dietary
Publisher’s Note: MDPI stays neutral intervention, an increase of physical activity, and behavior modifications [2,3]. When
with regard to jurisdictional claims in
lifestyle and pharmacotherapy approaches result in insufficient weight loss or insufficient
published maps and institutional affil-
maintenance of weight loss, surgery may be proposed to patients with morbid obesity
iations.
or severe obesity associated with comorbidities. Bariatric surgery promotes weight loss
by reducing stomach volume to limit nutritional intake. This gastric reduction can also
be combined with a malabsorptive procedure where a part of the intestine is resected [4].
Although bariatric surgery is an effective therapeutic option for obese patients and is used
Copyright: © 2021 by the authors. with increasing frequency, this procedure is associated with serious complications, such
Licensee MDPI, Basel, Switzerland. as gastroesophageal reflux disease, hypoglycemia, osteoporosis, and nutritional deficien-
This article is an open access article
cies [5].
distributed under the terms and
Public health policies, scientific recommendations, and the guidance of health organi-
conditions of the Creative Commons
zations also try to fight against obesity with preventative care approaches [6]. For example,
Attribution (CC BY) license (https://
nutrition labeling is used on food packages to inform consumers, providing them with
creativecommons.org/licenses/by/
simplified information on the essential nutrients contained in the food products. It helps
4.0/).

Nutrients 2021, 13, 1405. https://doi.org/10.3390/nu13051405 https://www.mdpi.com/journal/nutrients


Nutrients 2021, 13, 1405 2 of 16

them to identify and promote healthy eating by choosing healthy foods [7]. Informational
campaigns, such as “five fruits and vegetables per day” or graphic images that warn about
the consequences of a poor diet, are broadcasted across a variety of media platforms to
promote healthy eating behaviors [8]. It is now inscribed in the social conscious that food
quality and dietary habits are essential to a healthy lifestyle. However, “what we eat” is
not everything; “when we eat” also has a significant role in metabolic health. The circadian
rhythms, which regulate the organism’s functions, also determine at what time of day it is
most appropriate to eat.
In this review, we discuss the importance of the circadian clock in physiologic pro-
cesses, and how disruptions of it can lead to metabolic impairments. We also focus on
the interest of using intermittent fasting to “synchronize” lifestyle habits with the cir-
cadian clock and suggest it as a therapeutic approach to fight against obesity and its
associated complications.

2. Obesity and Diabetes Mellitus: Epidemiology and Physiopathology


In the past few decades, obesity prevalence has considerably increased: in 1975,
5% of the world population was obese, compared to 13% in 2016, according to the WHO
database [1]. Obesity is defined as an excessive fat accumulation that leads to health
complications [1].
The development of obesity is exacerbated by a modern diet rich in sugar and lipids.
This type of hypercaloric food promotes hyperglycemia and insulin secretion that induce
fat accumulation in adipose tissue [9].
Adipose tissue, in addition to its storage function, is an important endocrine organ that
releases free fatty acids (FFA) which are partly responsible for insulin resistance [10]. FFA
induces the inactivation of kinase proteins involved in the insulin signaling pathway by
phosphorylation and leads to diabetes mellitus [11]. Adipose tissue produces plasminogen
activator inhibitor type 1 (PAI-1), a protein involved in cardiovascular disease (CVD)
development, particularly in the pathogenesis of atherothrombosis. Plasminogen allows
for fibrinolysis, the mechanism that thins the blood. In the presence of PAI-1, plasminogen is
inhibited and the fibrinolytic activity decreases, which increases the risk of thrombosis [12].
Although type 2 diabetes has been accurately described as a disease of insulin resis-
tance, a large number of treatment centers around giving the patient more insulin. For
instance, drugs all work by either increasing the endogenous production of insulin or
increasing the amount of exogenous insulin received. While this works to reduce hy-
perglycemia in these patients, the concept of treating an insulin resistance disease by
increasing insulin levels may be counterproductive, as it may later necessitate an increase
in the dosage of medication over a long period of time (for review, please see: [13]). It ap-
pears that it is essential to find effective therapeutic solutions to treat obesity and diabetes
and to reduce the spread of this pandemic of the 21st century. Dietary approaches, which
are becoming increasingly popular, seem to be promising remedies to cure obesity and
its comorbidities. Some new strategies that focus on the timing of eating and duration
of fasting, rather than the type, quality, or quantity of foods, have been demonstrated to
improve metabolic health independent of weight loss [14,15]. Indeed, a systematic review
and meta-analysis concluded that intermittent fasting may provide a significant metabolic
benefit by improving glycemic control, insulin resistance, and adipokine concentration as
well as a reduction in the body mass index in adults [16].

3. Intermittent Fasting and Time-Restricted Feeding: Definition, History,


and Principle
Intermittent fasting refers to the idea of adopting alternating fasting periods, char-
acterized by a lack of food consumption, and feeding periods, during which food may
be consumed ad libitum. Different forms of fasting are ingrained as normal behavior
in animals to adapt to their ecologic and physiologic constraints, such as hibernation,
molting, reproduction, illness, or intermittent feeding habits [17]. Voluntary abstinence
from food has also been used throughout human history, especially in religious contexts
Nutrients 2021, 13, 1405 3 of 16

such as the holy fasting observed by many during Ramadan or Lent [18]. It was also
used as an epilepsy treatment in Ancient Rome, where the first mention of diet therapy
to cure seizures dates back to 500 BC [19]. Currently, intermittent fasting is becoming
increasingly popular because it seems to be an interesting clinical approach in the treatment
of several diseases such as diabetes, obesity, cancer, or neurodegeneration (for review,
please see: [20,21]). Many studies have shown the positive effects of intermittent fasting
practice in the management of obesity and diabetes, principally by improving weight loss
and metabolic markers such as the level of triglycerides, cholesterol, and glycemia, (for
meta-analysis, please see: [22–24]). Nonetheless, several other authors did not observe
any significant effects of intermittent fasting on metabolic health [25–27]. The evaluation
of fasting efficacy during a year on obese adults also did not show improvement in risk
indicators for cardiovascular disease [28]. Other studies have shown short-term effects of
intermittent fasting because the weight lost during the fasting period was quickly regained
after it [29,30].
If the effects of intermittent fasting are heterogenous, it is partly because the term
“intermittent fasting” encompasses several approaches to the regulation of eating patterns
which are not all equally effective. Some of these methods use alternation between a
fasting day and feeding day (others split weeks into five days of normal dieting and two
days of caloric restriction, known as “the 5:2 diet”, or two days of 24-h fasting, named
“eat-stop-eat”). Generally, intermittent fasting restricts the feeding window from 6 to 10 h
each day. Again, not all studies show the same positive results [31]. One of the reasons that
could explain the controversial results of the fasting practices is that these methods do not
consider the importance of matching the food intake timing with the circadian clock.
Indeed, even if fasting may appear to be a voluntary practice, linked to beliefs, culture,
or environmental restriction, it is actually a biological process present in all living organisms,
from archaea to mammals. Organisms are subject to circadian rhythms (CR—approximately
24-h oscillations) which are useful in facilitating the performance of physiological processes
at the optimal times of day. The daily rhythms of sleeping and activity depend on a complex
interaction between endogenous cell autonomous molecular oscillators and exogenous
factors such as daily exposure to light/darkness and feeding/fasting patterns [32,33]. This
circadian clock is essential for health and provides the rhythms of function for many organ
systems, such as the digestive, cardiovascular, endocrine, and reproductive systems [32].
Growing evidence shows that circadian clock disruption is the cause of many metabolic
diseases such as obesity, diabetes, or CVD [34]. A solution could be the use of “time-
restricted feeding”, which is based on a routine day pattern, with 14 to 18 h of fasting per
day and a restriction of the daily eating window of 10 to 6 h. Indeed, this approach seems
to present health benefits, when it aims to align daily food consumption with the circadian
clock [24,35].

4. Circadian Clock, a Key Regulator of the Physiological Processes


Circadian systems are composed of a biological clock network, made of a central clock
and peripherical clocks. The central clock is the hypothalamic suprachiasmatic nucleus
(SCN) and acts as a master pacemaker of circadian rhythm production and maintenance
throughout the body [36]. The most powerful regulator of the circadian rhythms is light.
The retina detects photonic inputs and transduces them to the SCN which allows for
the synchronization of tissue activities and behaviors with the day/night cycles. These
circadian oscillations are generated by proteins encoded by a set of genes (Clock, Bmal1,
Per and Cry, for example) which constitute a transcriptional-translational feedback loop
(for review, please see: [37,38]). Even if the SCN is the master regulator of the circadian
system, peripheral clocks (such as the liver, adipocyte, or pancreas clocks) can be uncoupled
from SCN control by other exogenous components, such as food intake. It appears that
alterations in normal feeding rhythm can affect the circadian system and induce metabolic
disorders [39,40].
The production of hormones such as melatonin or cortisol depends on the SCN rhythmic
activity in response to light/darkness whereas some others, known as nutrient-sensitive
hormones, oscillate following a circadian basis but are also regulated by feeding/fasting
Nutrients 2021, 13, 1405 4 of 16
cycles [41].
In human physiology, a day is split between an activity phase that begins at 10 a.m.
and ends at 10 p.m., when the resting phase starts [32]. These two phases depend on mel-
atonin, the “sleeping
Circadian hormone”,
clocks play anrenowned for its
essential role in central
glucoserole
andinlipid
the regulation
metabolism ofbecause
circadianthey
rhythms. Melatonin oscillations have a particular characteristic pattern commonly
induce variations in circulating hormone levels, according to several stimuli (Figure used 1).
to define daily cycles.
The production This hormone
of hormones suchsecretion begins
as melatonin orapproximately
cortisol depends at on
10 p.m.,
the SCNrisesrhythmic
to its
peak at 3 a.m.,
activity and finally
in response decreases to itswhereas
to light/darkness offset atsome
10 a.m. [42].known
others, Melatonin secretion de-
as nutrient-sensitive
pends on the photoperiod
hormones, and can
oscillate following be described
a circadian asbut
basis a chemical
are also expression
regulated byof feeding/fasting
the darkness
because it is
cycles [41].produced during the night in response to the lower light exposure [43,44].

Figure
Figure 1. Time-of-day-dependent
1. Time-of-day-dependent patterns
patterns of of circulating
circulating hormonelevels
hormone levelsvariation.
variation.Circadian
Circadian rhythms
rhythms are driven
are driven by oscillations
by oscillations of endocrine
of endocrine factor during
factor levels levels during
the day.the day.variations
These These variations are
are important to
important to perform physiological processes at the optimal time of the day. Melatonin induces
perform physiological processes at the optimal time of the day. Melatonin induces the resting phase
the whereas
resting phase whereas
cortisol cortisol
prepares prepares
the body for thethe body phase.
activity for the The
activity
otherphase. The other
hormones drivehormones
modifications of
drive modifications of glucose and lipid metabolism, promoting either catabolism with fatty acid
glucose and lipid metabolism, promoting either catabolism with fatty acid oxidation and glycolysis
oxidation and glycolysis (FGF21, adiponectin, leptin) or anabolism with lipogenesis and glycogen-
(FGF21, adiponectin, leptin) or anabolism with lipogenesis and glycogenesis (insulin).
esis (insulin).
In human physiology, a day is split between an activity phase that begins at 10 a.m. and
Between
ends 7 andwhen
at 10 p.m., 8 a.m.,theatresting
the beginning of the
phase starts day’s
[32]. Theseactivity, the body
two phases is prepared
depend to
on melatonin,
wake up due to a cortisol peak. This hormone prepares the body for the increase
the “sleeping hormone”, renowned for its central role in the regulation of circadian rhythms. in ener-
getic demandsoscillations
Melatonin induced byhave activity [45]. Cortisol
a particular production
characteristic is linked
pattern to the diminution
commonly of
used to define
melatonin secretion, which normally inhibits cortisol secretion. Thus, the cortisol
daily cycles. This hormone secretion begins approximately at 10 p.m., rises to its peak at secretion
cycle is theand
3 a.m., opposite
finallyof the melatonin
decreases one [46].
to its offset at 10In the[42].
a.m. morning, another
Melatonin hormone,
secretion ghrelin,
depends on the
is secreted
photoperiod and can be described as a chemical expression of the darkness becauseatit is
following a pulsatile rhythm. It has three peaks of secretion, approximately
8 a.m., 1 p.m.,during
produced and 6 p.m. [47,48].
the night Ghrelin regulates
in response energy
to the lower lighthomeostasis by increasing ap-
exposure [43,44].
petite and food intake.
Between 7 and 8 a.m., at the beginning of the day’s activity, the body is prepared to
At 10
wake upa.m.,
due toadiponectin begins
a cortisol peak. Thissecretion
hormoneand ends the
prepares at 8body
p.m.,for
with a peak secretion
the increase in energetic
level attainedinduced
demands at 11 a.m. byAdiponectin
activity [45].is Cortisol
an important regulator
production of glucose
is linked and
to the lipid me- of
diminution
tabolism.
melatoninIt improves
secretion,glycolysis and fatty
which normally acid cortisol
inhibits oxidation via the Thus,
secretion. activation of AMPK,
the cortisol a
secretion
kinase involved in the support of energetic homeostasis, and which also
cycle is the opposite of the melatonin one [46]. In the morning, another hormone, ghrelin,reduces hepatic
is secreted following a pulsatile rhythm. It has three peaks of secretion, approximately
at 8 a.m., 1 p.m., and 6 p.m. [47,48]. Ghrelin regulates energy homeostasis by increasing
appetite and food intake.
At 10 a.m., adiponectin begins secretion and ends at 8 p.m., with a peak secretion level
attained at 11 a.m. Adiponectin is an important regulator of glucose and lipid metabolism.
It improves glycolysis and fatty acid oxidation via the activation of AMPK, a kinase
involved in the support of energetic homeostasis, and which also reduces hepatic glucose
Nutrients 2021, 13, 1405 5 of 16

production. These mechanisms increase glucose use and insulin sensitivity and prevent fat
accumulation [45,49].
During the afternoon, from 2 to 6 p.m. and especially at the 4 to 5 p.m. peak, insulin
is produced by pancreatic islets and induces metabolic changes: the catabolic reactions
mediated by adiponectin become anabolic processes [50]. Insulin stimulates substrate
storage by activating fatty acid synthesis genes (such as acetyl-CoA carboxylase) and
glycogenesis genes, and by inhibiting gluconeogenesis gene transcription and fatty acid
oxidation [9].
Furthermore, leptin peaks at approximately 7 p.m., after rising 3 h earlier (4 p.m.), and
later declines back to baseline levels at 2 a.m. It removes food intake, increases lipolysis,
and inhibits fat accumulation [45].
Finally, melatonin is once again produced at 10 p.m., marking the beginning of the
resting phase. During this stage at 4 a.m., another hormone, the fibroblast growth factor
(FGF)-21 is secreted by the liver. It peaks at 6 a.m. and declines back to nadir at 9 a.m.
FGF21 is a key regulator of energetic homeostasis, it promotes AMPK activation, leading
to fatty oxidation, glycolysis increasing, and substrates stockage inhibition [51–53]. All of
these hormones regulate an alternating between catabolic and anabolic stages, essential to
performing physiological processes at the optimal time of the day. For example, digestion
and metabolization of nutrients are more efficient when the food is consumed earlier in the
day during the active phase rather than during the resting phase [54,55].
If we refer to the 24-h hormone oscillations, we hypothesize that food intake should
begin at 8 a.m., after the cortisol peak when the activity phase started, and should end
no later than 6 p.m., during the ghrelin and insulin peak. Indeed, between 8 a.m. and
4 p.m., FGF21 and adiponectin are produced and promote fatty acid oxidation, glycolysis,
and inhibit fat accumulation [53,56]. The consumption of food should not occur during
the insulin peak because it induces fat storage, nor should it occur at night when leptin is
produced, since it normally induces satiety [9,57]. Several hormone levels peak during the
activity phase, suggesting early daytime is more optimal for food intake than evening [58].
Thereby, the optimal time for food intake seems to be during the morning and the early
afternoon. This proposal needs to be confirmed by additional scientific studies carried out
with animal and human protocols.
Melatonin secretion (and consequently cortisol production) depends on the photope-
riods which are modified according to seasonal variations. At the European latitude, the
duration of melatonin secretion is longer in winter, which causes the resting phase to
extend, and is shorter in summer when the duration of the activity phase increases [59].
In theory, food intake should be adapted to seasonal variations to match the change in
the duration of the activity period. A reduction in the feeding time should occur during
the winter to correspond with the decrease in duration of the activity phase; the inverse is
true during the summer. This phenomenon is observed in mammals inhabiting temperate
latitudes where seasonal variations occur. They present a winter phenotype with a food
intake reduction during short photoperiods and a summer phenotype with increased
food consumption during long photoperiods [60]. However, an abundance of evidence
has shown that the Homo sapiens is also a seasonal species, with an annual pattern of
susceptibility to illness or mood changes, so it appears relevant to suppose that humans
have to adapt their food intake to the seasonal variations [61–64].
Globally, metabolic hormones, circulating nutrients, and visceral neural inputs trans-
mit rhythmic cues that permit brain and peripheral organs to be synchronized to feeding
time. However these chrono-disruptions, mistimed eating, coupled with food abundance
and electrical lighting have clearly deleterious effects on metabolic health [65]. Indeed,
everyone has their own habits and is able to change their circadian rhythm by adopting
an abnormal eating routine, bad sleep pattern, night shift, or jet lag [55]. This circadian
misalignment can often increase the risk of developing obesity, diabetes, and cardiovascular
disease [34,66,67].
Nutrients 2021, 13, 1405 6 of 16

5. Modern Lifestyle and Circadian Disruption: Leaving the Door Open to


Metabolic Diseases
Modernization of human life refers to the transition from a “traditional” society to a
“modern” society. It is deeply linked to industrialization and urbanization processes. It
began in the 19th century when the First Industrial Revolution hallmarked a boom mechan-
ical invention, allowing for production optimization and cost reduction. The invention of
the steam machine gave birth to factory development that rapidly invaded the countryside,
transforming the rural environment into an urban one [68]. Other industrial revolutions
came after the first one and lead to considerable changes to human life. Electrical lighting
was invented by Thomas Edison in 1879; vehicles such as trains, cars, and boats were mod-
ernized; agriculture became mechanized and the invention of fertilizers increased farming
production after the 2nd World War. At the same time, the food industry experienced a
boom in the 1970s with the arrival of large retailers, a success that was further accelerated
by the mass shift to household fridges and the expansion of the frozen food market [69].
Finally, all these revolutions led to a new age of globalization in the 21st century,
characterized by a rapid growth of the global economy, increasingly faster means of
transport, and the emergence of new technologies such as satellites for telecommunication,
television, computers, internet, or smartphones [70].
Although these industrial revolutions have driven progress in many sectors, they have
also caused substantial changes to the human routine, especially human circadian rhythms.
Firstly, the invention of the electric light had major consequences on the way people
worked and lived because they were now able to work at night. Globalization and techno-
logical advances also promote night shift because many companies relocate to countries
situated in different time zones, forcing company employees to synchronize their tasks with
the work schedule of the countries they operate for [71]. Almost 30% of adult employees
work outside daytime hours (between 9 a.m. and 5 p.m.) and 19% of European workers
reportedly work at least 2 h between 10 p.m. and 5 a.m. [72].
Being awake at night leads to circadian disruption by modifying hormone levels.
Several studies have focused on the hormone variations experienced by night workers, and
have provided evidence of melatonin and cortisol changes: melatonin levels are lower in
the night worker groups [73,74], and the total levels of cortisol production are reduced in
shift workers [75,76].
There is evidence that circadian rhythm disturbances induced by changes in night-time
and day-time patterns are a risk factor for cardiovascular diseases. Shift work is associated
with a higher risk of coronary heart diseases and vascular events such as myocardial
infarction or ischemic stroke, in comparison to day work [77,78].
These observations have also been noted in animal models: circadian rhythm disor-
ganization induces cardiomyopathy in hamsters and cardiac dysfunction in mice [79,80].
Artificial lighting has also changed human lifestyles by interfering considerably with indi-
vidual sleep preferences among the population. Most people accumulate a lack of sleep
during the work/school days and compensate by extending sleep duration on weekends.
This mismatch between weekday and weekend times of sleep duration leads to a circadian
clock disordering known as “Social Jetlag”, where the endogenous circadian clock does not
match with actual sleep times [81]. This phenomenon is associated with cardiovascular
risk factors, with higher triglyceride and fasting insulin levels and lower high-density
lipoprotein (HDL) cholesterol. These components predispose one to the development of
obesity, diabetes mellitus, and atherosclerotic cardiovascular disease [82–84].
Furthermore, changes and progress induced by industrial revolutions have modified
the food habits of people by impacting their timing of eating, the number of meals per day,
and the qualitative aspect of the consumed food [85]. Artificial lighting, night shift, social
jetlag, and later bedtimes tend to postpone mealtimes (especially the evening dinner), induce
meal omission (usually breakfast), or increase snacking between regular meals [86,87].
The time at which one eats is really important for metabolic health because late-night
eating (defined as eating dinner within 2 h of bedtime) is associated with increased body
Nutrients 2021, 13, 1405 7 of 16

fat, leading to a high risk of obesity [88,89]. Moreover, the authors observed that people
with late dinner habits are more susceptible to consume larger portion sizes, second rounds,
and energy-rich foods; these people also present a high fat mass, insulin resistance, and
cardiovascular risks [90,91]. In animal studies, authors showed that food availability during
the day (where rodents are normally supposed to sleep) induced circadian clock disruption
and thus metabolic disorders [92–94].
Late-night eating is also a risk factor for insulin resistance development. Glucose
tolerance, for an identical meal, is higher in the morning (8 a.m.) than in the evening
(8 p.m.), and similar rhythms have been observed in rodent models [95,96]. During the
resting phase, insulin levels are reduced to the offset and beta-cell responsivity to glucose
is lower. If glucose consumption occurs during the evening, the body will not be able to
process it properly, leading to lower insulin sensitivity [96,97].
In addition, processed and ultra-processed foods enriched in fats, salt, and sugar,
are positively associated with being overweight and obese [98]. Foods with added sugar,
sweeteners, and/or saturated fats raise blood levels of low-density lipoprotein (LDL), glu-
cose, and insulin, and these level profiles are associated with an increased risk of coronary
heart diseases, glucose intolerance, and insulin resistance [99,100]. The consumption of
these types of food associated with late-night dinner could be an aggravating risk factor of
obesity, CVD, and diabetes [101].
In the same way that eating at an inappropriate time promotes metabolic risks, missing
meals normally consumed during the activity phase can have consequences on the health.
Numerous studies highlight an association between skipping breakfast and weight gain,
cardiovascular risks, and diabetes, supporting the fact that breakfast consumption is essen-
tial to a healthy eating regimen [102]. Breakfast skippers are associated with a higher body
mass indices and higher levels of hemoglobin A1C (HbA1C), another marker for glucose
metabolism dysfunction), leading to an increased risk of obesity and diabetes [103,104].
They also present elevated blood pressure and increased levels of LDL which indicate a
higher risk for CVD [105,106].
In light of these elements, it is clear that circadian clock disruption, caused by changes
in work schedules and food habits, has significant effects on metabolic health. A solu-
tion to reduce the risks of developing metabolic disease could be the implementation of
intermittent fasting to realign lifestyle behaviors with the biological circadian rhythms.

6. Association between Time-Restricted Feeding and Normal Circadian Rhythms:


A Relevant Approach for the Fight against Metabolic Diseases
The hypothesis regarding the effectiveness of time-restricted feeding in metabolic
disorders is that imposing eating/fasting cycles will restore robust circadian rhythms and
improve metabolic homeostasis. Several clinical studies as well as studies with animal mod-
els were carried out to investigate metabolic disorders [14,15,27,107–117]. Some reviews
evaluated the metabolic effects of time-restricted feeding in both animal and human studies;
without focusing exclusively on the populations with metabolic syndrome [24,118–120].
Regarding the animal models, it has been shown in rodents that time-restricted feed-
ing during the animal activity phase, significantly protects the mice from diet-induced
obesity and associated metabolic complications, while also improving glucose tolerance
and reducing liver weight [121]. Indeed, it induced a significant decrease in body weight,
associated with a loss of fat mass in C57BL6/J mice [122–125]. The reduction of fat mass
could be explained by an increased AMP-activated protein kinase (AMPK) activity induced
by fasting, because its kinases promote fatty acid oxidation and inhibit acetyl CoA carboxy-
lase (ACC), one of the enzymes involved in fat storage [122]. The mice also experienced
decreased levels of insulin and fasting glucose levels, suggesting an improved glucose
metabolism and insulin sensitivity [122–126]. Time-restricted feeding revealed beneficial
effects in rat models as well [127,128]. The authors observed that it induced weight loss
due to a significant reduction of visceral and subcutaneous adipose tissues and a better
activation of PGC1α, a transcriptional coactivator involved in mitochondrial biogenesis
Nutrients 2021, 13, 1405 8 of 16

and fatty acid oxidation. Rats improved glucose tolerance and had lower LDL levels and
higher HDL levels, showing an improvement in CVD risk markers [127,128].
Beneficial results regarding obesity were also observed in human studies when this
nutritional strategy was applied during the activity phase. This strategy could be divided
into early and late time-restricted feedings with different results. Indeed, the early time-
restricted feeding, where the food intake occurs between 8 a.m. and 6 p.m., facilitated
weight loss and appetite reduction in overweight and obese people [14,111,114,115]. Pre-
diabetic and diabetic patients, characterized by an impaired glucose tolerance, presented
lower insulin levels and a better insulin sensitivity when they restrained their daily eating
window to 8 h per day [14,15,115]. Moreover, it induced changes in cardiovascular mark-
ers by decreasing blood pressure and LDL levels [14,111]. The changes observed among
the participants of these studies are beneficial for their metabolic health. A decrease in
bodyweight and loss of fat mass are associated with an improvement in health-related
quality of life, reduction in obesity risks, and comorbidity development [129]. Moreover, it
is well known that a decrease in blood pressure and LDL levels is associated with better
cardiovascular health, whereas a higher insulin sensitivity reduction decreases the risk of
insulin resistance and diabetes [130]. The global mechanism behind the beneficial effects
of early time-restricted feeding involved the central and peripheral circadian oscillators.
Indeed, when food is consumed between 8 a.m. and 6 p.m., the secretion of hormones
from the peripheral oscillators are in phase with the central mechanism of synchronization
emerging from the suprachiasmatic nucleus [131–133]. These mechanisms should opti-
mize the functioning of the peripheral organs involved in the metabolism regulation thus
preventing the development of type 2 diabetes, as it can be observed when food intake
is matched with metabolic hormones’ oscillations [14,15,115]. It will be an interesting
challenge to identify the signal transduction pathways participating in the impulsion of
peripheral clocks by the central clock in the case of early time-restricted feeding.
All of these elements highlight the importance of an alignment between food intake
and circadian rhythms to improve cardiometabolic health. Indeed, several studies used late
time-restricted feeding where subjects were allowed to eat until the evening and showed
reduced beneficial effects. Results on weight loss are mixed, showing a weight loss [116]
or no significant change in weight or whole-body fat mass [27,117]. They also showed no
significant effects on fasting glucose, HbA1C, triglycerides, total cholesterol, blood pressure,
LDL, or HDL levels [27,116,117]. These outcomes demonstrate how important matching
the eating window and circadian rhythms is to optimize the effects of time-restricted
feeding and, therefore, to provide health benefits.
However, it would be more relevant to compare the effects of early time-restricted
feeding with those of late time-restricted feeding to give a better understanding of the
importance of the daily eating window moment for the favorable outcome of this strategy.
For the moment, only one study has compared early (8 a.m. to 5 p.m.) versus late (12 to
9 p.m.) time-restricted feeding on glucose tolerance [113]. Authors demonstrate that
time-restricted feeding improves glycemic responses, regardless of meal timing (late or
early), although the early time-restricted feeding group has presented a lower mean fasting
glucose than the late group [113]. Even if these results tend to discredit the idea of the
importance of an early food intake during a time-restricted feeding, this study presents
several limits. Only men were included so these findings cannot be extended to women.
The number of participants is small (only fifteen), and the early and late time-restricted
feeding groups were tested during a short period of time (one week).
More randomized clinical trials with larger cohorts and longer durations of time-
restricted feeding treatment will be required to conclude on the most efficient differences
strategy, especially between early and late time-restricted feeding. Despite the fact that
more and more authors investigate the metabolic effects of fasting, a significant limitation
persists. In most of the studies, participants had an imposed fasting duration, but they
were free to choose the time frame that best fit their eating habits [107–110,112]. Some
of these studies showed beneficial effects of fasting with a significant weight loss, waist
Nutrients 2021, 13, 1405 9 of 16

circumference and blood pressure reduction, and lower LDL level [107–109]. Others
presented less positive results, where time-restricted fasting did not confer significant
effects on glucose or insulin levels [107,110,112], blood pressure [112], or weight loss [110].
These mixed results are most likely caused by a lack of control on the timing of
participants’ feeding windows, which are spread over the day. As we have described
previously, the timing of food intake is essential to obtain beneficial metabolic effects, so it
is difficult to draw a real conclusion on the outcomes of time-restricted feeding based on
these studies which do not impose a precise feeding window on their subjects. The lack of
protocol standardization is a major gap in time-restricted feeding research.

7. Warnings and Limits of the Association between Intermittent Fasting and Normal
Circadian Rhythms
Despite its numerous health benefits, intermittent fasting has its disadvantages and
limits, which constrain its application. One of the most restrictive points is the daily eating
window of 10 to 6 h, because it can be hard to observe while maintaining a family, social,
or work life. Indeed, night shift work makes intermittent fasting difficult to respect due
to desynchronized work schedules that disturb the everyday life routine [72]. Family life
can also be a brake for time-restricted feeding because family mealtimes usually adhere
to the common eating patterns of modern society (breakfast, lunch, and dinner). Dinner
is actually the most important meal in family environments. It facilitates communication
between family members and favors socio-emotional development and mental health [134].
Eating is a social activity and promotes socialization by meeting friends, colleagues, or
relatives. Commensality, defined by the act of eating with others, provides opportunities
for social integration, social support, and companionship [135]. Therefore, following a
different feeding pattern than that of one’s entourage can be a hurdle to social and family
development and can drive isolation, loneliness, or depression [136,137].
Another limit of intermittent fasting is the lack of protocol standardization. There is
no consensus about the ideal timing for eating/fasting pattern or the optimal duration of
each window. Studies use different durations for the feeding period, from 8 to 10 h, and
recommend diverse time slots for time-restricted feeding [14,109,111,114]. Although there
is no evidence of serious adverse effects of intermittent fasting when it is aligned with the
circadian clock [109], several authors did observe the importance of timing when choosing
the eating window. Indeed, time-restricted feeding increases metabolic health only when
the eating window is matched with earlier hours. Intermittent fasting that situates the
eating window during the evening is associated with a significant increase in bodyweight,
fat mass, and glycemic levels. These values are associated with a higher risk of obesity and
insulin resistance [138,139]. Unfortunately, research on time-restricted feeding is limited,
and clear conclusions cannot be made at present.
Moreover, seasonal changes are not taken into consideration in the selection of the
eating window whereas the activity phase is dependent on it. Eating hours should be
adapted to the season and the length of days to match hormone oscillations and optimize
physiological processes [60,140,141].
In spite of its positive results, the application of intermittent fasting needs to be
rigorously supervised. Even if the timing of the feeding window is hard to respect because
it interferes with social and family lives, it is essential to follow an early eating pattern. A
desynchronization of time-restricted eating and the circadian clock with the evening meal
window can reverse the beneficial effects of fasting.

8. Conclusions
Circadian rhythms play an essential role in regulating physiological processes (Figure 2).
It accurately regulates several hormone levels 24 h a day, inducing a balance between catabolic
and anabolic processes that are crucial to perform physiological activity at the optimal time
of day [32]. However, modern habits, especially food habits such as skipping breakfast
or late-night eating, are involved in circadian clock disorders that have major impacts on
8. Conclusions
Circadian rhythms play an essential role in regulating physiological processes (Figure 2).
Nutrients 2021, 13, 1405 It accurately regulates several hormone levels 24 h a day, inducing a balance between 10 of 16
catabolic and anabolic processes that are crucial to perform physiological activity at the
optimal time of day [32]. However, modern habits, especially food habits such as skipping
breakfast or late-night eating, are involved in circadian clock disorders that have major
metabolic
impacts onhealth. Indeed,
metabolic circadian
health. disruption
Indeed, leads
circadian to an increase
disruption leads in
to metabolic complications,
an increase in metabolic
such as obesity, CVD, or insulin resistance [101,102].
complications, such as obesity, CVD, or insulin resistance [101,102].

Figure 2. Impacts
Figure 2. Impacts ofof food
foodhabits
habitson
onmetabolism
metabolismare areconnected
connectedwith
withthe
thecircadian
circadianclock. The
clock. Theway
waythat
people eat is essential for metabolic health. When food habits (timing and number of
that people eat is essential for metabolic health. When food habits (timing and number of meals meals per day)
are
per misaligned with the with
day) are misaligned circadian clock, they
the circadian prevent
clock, an increased
they prevent risk of obesity,
an increased cardiovascular
risk of obesity, cardio-
vascular disorders,
disorders, and diabetes.
and diabetes. On the On thehand,
other other practicing
hand, practicing time-restricted
time-restricted fasting
fasting wherewhere the
the eating
eating window
window is aligned
is aligned with circadian
with circadian rhythmsrhythms
improves improves metabolic
metabolic health. health.

The
The time-restricted
time-restrictedfeeding
feedingapproach
approach appears
appears as as
a relevant
a relevantsolution to restore
solution metabolic
to restore meta-
health only when
bolic health the feeding
only when pattern
the feeding is aligned
pattern withwith
is aligned the circadian clock,
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is dur-
the
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the activity Early
phase. time-restricted
Early time-restricted eating,
eating,based
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feedingwindow
windowper per
day,
day,reduces
reducescardiometabolic
cardiometabolicrisks risksbybyinducing
inducingweight
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andbyby decreasing
decreasingmarkers
markersof of
cardiovascular and diabetes risks [14,109,111,114].
cardiovascular and diabetes risks [14,109,111,114].
The
The assembly
assembly of of the
the presented
presented results
results suggests
suggests that
that time-restricted
time-restricted feeding
feeding could
could bebe
an alternative non-pharmacological strategy that could prevent obesity
an alternative non-pharmacological strategy that could prevent obesity and its associated and its associated
metabolic
metabolicdisorders.
disorders.AsAs research
researchon time-restricted
on time-restricted feeding is limited,
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is limited, future should
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clearly established the time
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duration of the eating
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in order to propose safe and efficient time-restricted feeding protocols.
window in order to propose safe and efficient time-restricted feeding protocols.

Author Contributions: A.C.


Author Contributions: A.C. conducted
conducted the
the review
review and
and wrote
wrote the
the manuscript.
manuscript. F.H.
F.H.and
andE.S.
E.S.assisted
assisted
the
the author
author inin manuscript
manuscriptwriting.
writing.J.Z.
J.Z. assisted
assisted in in manuscript
manuscript writing
writing andand supervised
supervised the whole
the whole pro-
project.
ject. All All authors
authors have
have readread
andand agreed
agreed to the
to the published
published version
version of the
of the manuscript.
manuscript.
Funding: Research
Funding: Research ofof the
the J.Z.
J.Z. team
team is
is supported
supported in
in part
part by
by funding
funding from
from the
the STEPAN
STEPAN company
companyand
and
the University of Strasbourg.
the University of Strasbourg.
Acknowledgments: We
Acknowledgments: Weare
aregrateful
gratefulto
toBella
BellaDally-Steele
Dally-Steelefor
forher
herassistance
assistancein
inlanguage
languageediting.
editing.
Conflicts
Conflictsof Interest:The
ofInterest: Theauthors
authorsdeclare
declareno
noconflict
conflictof
ofinterest.
interest.

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