Current research: Effect of time restricted eating on weight and cardiometabolic health

Kelsey Gabel and Krista A. Varady

Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL

Correspondence and reprint requests:

Kelsey Gabel, PhD
Postdoctoral Research Associate and Clinical Assistant Professor
Department of Kinesiology and Nutrition, University of Illinois at Chicago
1919 W Taylor, Room 506F, Chicago IL, 60612
312.413.8911
kdipma2@uic.edu

Running Head: Time restricted eating for weight loss and metabolic disease risk reduction

Key words: Intermittent fasting, time restricted eating, weight loss, metabolic disease, obesity

Ethical statements

Conflict of interest: Krista Varady is the author of the book “The Every Other Day Diet”
published by the Hachette Book Group. KG has no competing interests to disclose.

Consent for publication: All authors have approved the version of the manuscript
submitted.

This is an Accepted Article that has been peer-reviewed and approved for publication in The Journal
of Physiology, but has yet to undergo copy-editing and proof correction. Please cite this article as an
'Accepted Article'; doi: 10.1113/JP280542.

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 Kelsey Gabel obtained her PhD and RD and from the University of
Illinois at Chicago (UIC). She is currently a postdoctoral research
associate under the mentorship of Dr. Krista Varady and a clinical
assistant professor of nutrition at UIC. Her research to date has
focused on the effect of time restricted eating on weight loss and
metabolic disease risk reduction. She is also conducting research in
the area of alternate day fasting as treatment for non-alcoholic fatty
liver disease. She is interested in continuing her research in time restricted eating.
Specifically, she would like to investigate the efficacy of this diet as a nutrition therapy for
obesity related cancers.

Krista Varady obtained her PhD in human nutrition at McGill

University in Montreal, Canada. She is currently a Professor of
Nutrition at the University of Illinois at Chicago (UIC). Her
research focuses on the efficacy of intermittent fasting for weight
loss, weight maintenance, and metabolic disease risk reduction in
adults with obesity. Her work is funded by the NIH, American
Heart Association, International Life Sciences Institute, and the University of Illinois. She
has published over 80 publications on this topic and is also the author of a book for the
general public, entitled the "Every Other Day Diet".

Key Points:

 Time restricted eating produces spontaneous energy restriction and significant weight
loss.
 Time restricted eating decreases diastolic blood pressure independent of weight loss.
 Time restricted eating may improve insulin resistance and glucose regulation.

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Abstract

Intermittent fasting has grown in popularity as a weight loss strategy in recent years. In
particular, time restricted eating (TRE), has been popularized in the diet industry with dozens
of books touting its ability to promote weight loss and improve glucose regulation. TRE
involves confining the eating window to a specified number of hours per day (usually 4 to 10
h), and fasting (with zero-calorie beverages) for the remaining hours of the day. While
several studies of TRE have been performed in rodent models, human studies are only now
emerging. The goal of this review is to summarize the effects of TRE on body weight and
cardiometabolic disease risk factors in human subjects. Accumulating evidence shows that
TRE may spontaneously decrease energy intake by 20-30% under ad libitum conditions,
producing small but statistically significant weight loss of 1-4%. In addition, TRE may
significantly decrease systolic and diastolic blood pressure independent of weight loss.
Further, improvements in fasting insulin and insulin resistance have also been reported.
Taken together, these preliminary data suggest that TRE produces mild weight loss, and also
may improve some aspects of cardiometabolic health by lowering blood pressure and insulin
resistance.

Abstract Figure: Time restricted eating, current data and future directions

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Introduction

Almost three quarters of Americans over the age of 20 have overweight or obesity
(Prevention, 2017). Although almost half of US adults will try to lose weight each year,
prevalence of obesity and severe obesity continues to rise (Prevention, 2017). Daily energy
restriction, with and without exercise, is the most common treatment used to combat obesity.
However, adherence to energy restriction decreases in the first month and continues to
decline thereafter (Dansinger et al., 2005; Das et al., 2007; Sacks et al., 2009; Trepanowski et
al., 2017).

Intermittent fasting has emerged as a promising alternative to daily energy restriction. These
diets involve voluntary abstinence from food, alternated with periods of ad libitum eating.
Intermittent fasting is an umbrella term for three different diets: alternate day fasting (ADF),
the 5:2 diet, and time restricted eating (TRE).

ADF consists of a “fast day”, where 0-500 kcal are consumed, alternated with a “feast day”,
where one is permitted to eat ad libitum. The 5:2 diet is similar to ADF, however, fasting
occurs only two days each week. ADF and the 5:2 diet have been shown to produce moderate
weight loss (4-7%) in 3 to 6 months and reduce systolic and diastolic blood pressure (Varady
et al., 2009; Harvie et al., 2011; Varady et al., 2011b; Eshghinia & Mohammadzadeh, 2013;
Klempel et al., 2013; Hoddy et al., 2014; Varady et al., 2015; Carter et al., 2016; Catenacci
et al., 2016). The 5:2 diet and ADF may also reduce LDL cholesterol and triglyceride
concentrations when weight loss reaches 5% or more (Harvie et al., 2011; Varady et al.,
2011a; Klempel et al., 2013; Varady et al., 2013; Carter et al., 2016; Catenacci et al., 2016).
Further, it appears that ADF may improve insulin resistance more effectively than daily
energy restriction (Gabel et al., 2019).

TRE is the newest form of intermittent fasting that is being examined in humans. TRE
involves confining the eating window to a specified number of hours per day (usually 4 to 10
h), and fasting with zero-calorie beverages for the remaining hours of the day. During the
eating window, individuals do not need to count calories or monitor food intake in any way
(Figure 1). Interest in TRE emerged because humans and other living organisms are
influenced by the daily 24h light/dark cycle known as the circadian rhythm (Longo & Panda,
2016). These rhythms affect almost every region in the body including the brain and
peripheral organs (Chaix et al., 2019). The circadian rhythm oscillates between activity and

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rest, feeding and fasting, nutrient utilization and nutrient storage, and many other cellular
processes (Longo & Panda, 2016; Chaix et al., 2019). These physiological rhythms are
synchronized with behavioral and environmental patterns as well. Disruptions in these
patterns, such as extended exposure to light or eating during the night, may negatively impact
brain and organ processes (Chaix et al., 2019). For instance, glucose storage and insulin
sensitivity decrease throughout the day, especially at the onset of melatonin release prior to
sleep (Chaix et al., 2019). Eating later at night has been linked to higher rates of metabolic
disease and insulin resistance (Kutsuma et al., 2014). Further, shift workers who often eat and
work during the circadian rest phase, report higher rates of obesity, metabolic disease, and
cancer (Arble et al., 2009).

The majority of TRE research to date has been conducted in rodent models (Longo & Panda,
2016; Chaix et al., 2019). In rodents, the term “time restricted feeding” (TRF) is used instead
of TRE, to describe the diet. Several metabolic benefits of TRF have been reported in
animals. For instance, mice fed an isocaloric diet during the 12-h dark phase (their normal
circadian feast phase) weighed 19% less than those fed during the light (sleep) phase (Arble
et al., 2009). It has also been shown that 9-h, 12-h, and 15-h TRF reduced weight gain, fat
deposition, and insulin resistance caused by an ad libitum high fat diet in rodents (Chaix et
al., 2014). These findings have been replicated by several other groups as well (Hatori et al.,
2012; Sherman et al., 2012; Chaix et al., 2014; Duncan et al., 2016; Sundaram & Yan, 2016;
Olsen et al., 2017).

Whether or not the same body composition and metabolic improvements seen in rodents can
be mimicked in humans, remains unresolved. Accordingly, the goal of this review is to
summarize the effects of TRE on body weight, body composition, glycemic control, plasma
lipids, and blood pressure in human subjects.

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Figure 1: Time restricted eating pattern

Types of time restricted eating

Current research in TRE has been separated into two factions. The first group of research
examines TRE independent of weight loss, i.e. during isocaloric conditions. Participants are
either fed at a research center or asked to consume sufficient energy at home, to maintain
their baseline weight. The second group of research examines TRE with weight loss, under
free-living ad libitum intake conditions.

Body weight and body composition

Seven studies have examined the effect of TRE on body weight under isocaloric conditions
(independent of an energy deficit) (Table 1) (Carlson et al., 2007; Stote et al., 2007;
Kahleova et al., 2014; Moro et al., 2016; Tinsley et al., 2017; Martens et al., 2020;
McAllister et al., 2020). In these isocaloric TRE human trials, subjects were prescribed an
energy goal for weight maintenance. It should be noted that, if researchers do not supply food
to participants, there is a chance that spontaneous energy restriction will occur due to the
shortened eating window during TRE (Gill & Panda, 2015; Antoni, 2018; Gabel et al., 2018;
Cienfuegos et al., 2020). In the studies by Stote et al. (Stote et al., 2007) and Carlson et al.
(Carlson et al., 2007), participants consumed isocaloric diets as either 1 meal/d (during a 4-h

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window), or 3 meals/d (with no timing restrictions). Participants lost significant body weight
(-2%) and fat mass after 8 weeks in the 1 meal/d group when compared to 3 meals/d group
(Carlson et al., 2007; Stote et al., 2007). In a similar meal frequency trial, Kahelova et al.
(Kahleova et al., 2014) reported significant weight loss in subjects eating 2 meals/d when
compared to subjects eating 6 meals/d. McAllister et al. (McAllister et al., 2020) compared 8-
h isocaloric TRE to 8-h ad libitum TRE. Both TRE groups had significant weight loss, but
there was no difference between groups (McAllister et al., 2020). Martens et al. (Martens et
al., 2020) examined the effect of 8-h isocaloric TRE in older adults. The participants were
normal weight at baseline and were asked to monitor their weight twice per week to ensure
weight stability. After 6 weeks of TRE, body weight did not change. Taken together, it
appears that under isocaloric conditions, TRE may occasionally produce mild weight loss in
human subjects.

The effect of isocaloric TRE combined with exercise on body weight has also been evaluated.
In the studies by Tinsley et al. (Tinsley et al., 2017) and Moro et al. (Moro et al., 2016),
subjects participated in an isocaloric TRE intervention combined with resistance training,
versus resistance training alone. After 8-weeks, neither group reported a change in body
weight or fat free mass (Moro et al., 2016; Tinsley et al., 2017). However, Moro et al. (Moro
et al., 2016) observed a significant decrease in fat mass in the TRE group when compared to
the usual diet group. This difference in fat mass reduction could be due differences in study
design. Tinsley et al. (Tinsley et al., 2017) prescribed a 4-h TRE intervention for only 4
days/week (on the days participants abstained from resistance training). Participants could
choose their eating window any time between 16:00-0:00 h and resistance training was not
supervised. In contrast, Moro et al. (Moro et al., 2016) prescribed an 8-h TRE window
between 13:00-21:00 h daily and all resistance training sessions were supervised. Further,
adherence to resistance training could also explain the differences in fat mass loss as
participants in the Tinsley et al. study (Tinsley et al., 2017) were not supervised during the
exercise intervention. These preliminary findings show that resistance training combined
with TRE may result in a greater loss of fat mass than resistance training with a usual diet,
but further studies are warranted.

Figure 2: TRE vs the current American eating pattern

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Nine ad libitum TRE studies (Gill & Panda, 2015; Arnason et al., 2017; Antoni, 2018; Gabel
et al., 2018; Anton et al., 2019; Hutchison et al., 2019; Kesztyus et al., 2019; Chow, 2020;
Wilkinson et al., 2020) and three energy deficit (250-500kcal) studies (Tinsley et al., 2019;
Karras et al., 2020a; Karras et al., 2020b) (Table 1) have examined the effect of this diet on
body weight and body composition. Gill and Panda (Gill & Panda, 2015) examined the eating
pattern of 156 adults with overweight and found that subjects ate within a 15 h median
window. They also found that foods consumed after 18:30 h contributed to excess energy
intake above daily weight maintenance requirements (Gill & Panda, 2015). These findings
suggest that decreasing the eating window may spontaneously decrease excess energy intake
(Figure 2).

The effects of shorter ad libitum eating windows (4-6 h) during TRE have been evaluated in
two recent trials (Arnason et al., 2017) (Cienfuegos et al., 2020). Arnason et al. (Arnason et
al., 2017) examined the effect of 4-6-h TRE in participants with non-insulin dependent
diabetes. These participants lost 1% body weight in two weeks (Arnason et al., 2017).
Cienfuegos et al. (Cienfuegos et al., 2020) investigated the effect of 4-h TRE and 6-h TRE
versus a control group in adults with obesity. Both the 4-h and 6-h TRE groups lost
significantly more body weight (3% and 3% respectively) and fat mass, relative to the control

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group (Cienfuegos et al., 2020). The 6-h TRE group lost significantly more lean mass than
the control group and the 4-h group; though it is unclear why this difference occurred
(Cienfuegos et al., 2020).

The effects of longer ad libitum eating windows (8-10 h) during TRE have also been
examined. Hutchinson et al. (Hutchison et al., 2019) compared the effects of early 9-h TRE
(8:00-17:00 h) versus late 9-h TRE (12:00-21:00 h) in men with pre-diabetes. After 1-week,
weight loss was 1% from baseline, and did not differ between the early versus late TRE
interventions. Anton et al. (Anton et al., 2019) reported 3% weight loss in older adults after 4
weeks of 8-h TRE. Karras et al. (Karras et al., 2020a) compared 8-h TRE to Orthodox fasting
(a low energy pescatarian diet) for 7 weeks. Both groups were prescribed a 500-750 kcal
energy deficit, which resulted in significant weight loss (Karras et al., 2020a). Karras et al.
(Karras et al., 2020b) then followed up with the same participants 6 weeks after the
completing the intervention, and found that weight loss had been maintained in both groups.
However, the TRE group had significantly lower body fat percentage at follow-up when
compared to the Orthodox fasting group (Karras et al., 2020b). Six studies have examined
the efficacy of ad libitum TRE with the feeding window ranging from 8-10-h (Gill & Panda,
2015; Gabel et al., 2018; Kesztyus et al., 2019; Chow, 2020; Wilkinson et al., 2020). All
studies reported a weight loss of 2-4% (Gill & Panda, 2015; Gabel et al., 2018; Kesztyus et
al., 2019; Chow, 2020; Wilkinson et al., 2020) except the trial by Antoni et al. (Antoni, 2018)
which reported decreased fat mass, but no significant reductions in body weight. In a study
by Chow et al. (Chow, 2020) participants significantly decreased fat mass and fat free mass.
Further, this group reported a 18% decrease in visceral fat mass indicating possible protection
against cardiometabolic disease (Chow, 2020). Tinsley et al. (Tinsley et al., 2019) examined
the effects of 8-h TRE combined with resistance training, versus resistance training alone.
Both groups were prescribed a 250 kcal energy deficit. Lean mass increased in both groups,
but significantly larger decreases in fat mass were noted in the TRE group (Tinsley et al.,
2019). These results are promising, and show that with a larger sample size, TRE combined
with resistance training may preserve fat free mass while decreasing fat mass.

Taken together, data from ad libitum TRE trials show that this fasting regimen produces mild
to moderate weight loss (1-4%) in adults with obesity. These findings also show that body

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composition may be improved when TRE is combined with resistance training under both
isocaloric and ad libitum conditions.

Energy intake
Moderate daily energy restriction has been shown to improve cardiometabolic risk factors
and extend longevity (Longo & Panda, 2016; Kraus et al., 2019). One of the most interesting
findings for TRE is that participants seem to spontaneously consume less energy during these
diets. For instance, in a study by Cienfuegos et al. (Cienfuegos et al., 2020) participants in
both the 4-h and 6-h TRE groups decreased their energy intake by 30%. Similarly, reductions
in energy intake (-30% from baseline) were noted by Antoni et al. (Antoni, 2018). Likewise,
participants in the 10-h TRE study by Gill and Panda (Gill & Panda, 2015) and the 8-h TRE
study by Gabel et al. (Gabel et al., 2018) spontaneously decreased their caloric intake by
20%. The study by Chow et al. (Chow, 2020) did not measure caloric intake, however, they
did measure eating occasions. By the end of the 12-week study, the number of eating
occasions was reduced by 20% when subjects ate within an 8-h window (Chow, 2020). These
data suggest that limiting the eating window to 4-10-h during the day, may produce a
spontaneous energy restriction of 20-30%.

No studies to date have examined the effect of chronic TRE on appetite regulation. However
data from ADF trials suggest that subjective hunger and fullness do not change (Heilbronn et
al., 2005; Johnson et al., 2007; Klempel et al., 2010; Bhutani et al., 2013) and compensatory
eating does not occur following the fast day (Coutinho et al., 2017; Trepanowski et al.,
2017). In continuous energy restriction trials, ghrelin and leptin significantly decrease with
weight loss. However, after 8 weeks of ADF, these hunger hormones remained unchanged
(Hoddy et al., 2016). It will be of interest for future trials in this area to examine how TRE
impacts subjective hunger and fullness and hormones that regulate appetite.

Adherence
The ability of humans to adhere to TRE regimens has been evaluated in several recent
studies. Gabel et al. (Gabel et al., 2018) and Cienfuegos et al. (Cienfuegos et al., 2020)
reported excellent adherence to the 4-h, 6-h, and 8-h TRE interventions, i.e. subjects ate
within their prescribed window on 80-90% of days over 8-12 weeks. Similarly, participants
in a trial by Kesztyus et al. (Kesztyus et al., 2019) were adherent with the 8-9-h TRE window

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on 85% of days. In the study by Martens et al. (Martens et al., 2020) participants reported
85% adherence to the 8-h TRE window, and 95% adherence to the 8.5-h TRE window over 6
weeks. In line with these findings, older adults with overweight and obesity had a self-
reported adherence rate of 84% to 8-h TRE (Anton et al., 2019). Further, all nine participants
in the 10-h TRE Gill and Panda trial (Gill & Panda, 2015) showed interest in continuing the
time restricted diet. When these researchers followed up with the participants one year after
the intervention, they found that all subjects had maintained their weight loss of 4% (Gill &
Panda, 2015). Thus, adherence to TRE appears to be quite high over short durations (<12
weeks). Future trials should investigate whether this level of adherence can be maintained
during longer TRE interventions periods.

Glucoregulatory Factors

Fasting glucose
Elevated blood glucose concentrations are a key factor in the diagnosis of metabolic disease.
Consistently high concentrations of glucose can damage blood vessels and lead to increased
heart disease risk and insulin resistance. In mice, glucose tolerance and insulin resistance
were improved with TRE (Hatori et al., 2012; Chaix et al., 2014; Sundaram & Yan, 2016).
Further, in a recent secondary analysis, ADF lowered fasting insulin and insulin resistance
almost three times more than daily energy restriction, despite similar weight loss (Gabel et
al., 2019). The effect of TRE on fasting glucose, fasting insulin, and insulin resistance has
been examined in several recent trials (Table 2).

Nine studies have examined the effect of isocaloric TRE on fasting glucose levels (Carlson et
al., 2007; Stote et al., 2007; Kahleova et al., 2014; Moro et al., 2016; Sutton et al., 2018;
Jamshed et al., 2019; Martens et al., 2020; McAllister et al., 2020; Parr et al., 2020). Jamshed
et al. (Jamshed et al., 2019) compared 6-h TRE versus a 12-h control group and found that
mean 24-h glucose decreased significantly in both groups after just 4 days. The improvement
in both groups could be due to the possibility that the 12-h eating window may still have been
smaller than the baseline eating window. In the trials by Stote et al. (Stote et al., 2007) and
Carlson et al. (Carlson et al., 2007) fasting glucose increased, and glucose control decreased,
when subjects ate all of their energy needs as one meal within a 4-h window. The massive

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energy load in this one meal might have caused the negative effect on glucose concentrations
(Carlson et al., 2007; Stote et al., 2007). Conversely, Martens et al. (Martens et al., 2020)
reported no change in fasting glucose, but did find a significant decrease in glucose area
under the curve (iAUC) during 8-h TRE. Parr et al. (Parr et al., 2020) measured 24-h glucose
during a 5 day 8-h TRE intervention. Participants significantly lowered post-prandial glucose
peak and iAUC after breakfast, and decreased glucose iAUC during sleep (Parr et al., 2020).
In a study by McAllister et al. (McAllister et al., 2020) glucose concentrations did not
significantly change. Moro et al. (Moro et al., 2016) combined 8-h TRE with resistance
training and found that fasting glucose concentrations decreased after 8-weeks. Further, in a
study by Kahleova et al. (Kahleova et al., 2014) fasting glucose decreased more in the group
who consumed all of their energy needs for the day as only 2 meals, relative to the group who
consumed all of their energy needs as 6 meals. Taken together, the findings for the effects of
isocaloric TRE on fasting glucose are equivocal, with some studies showing improvements
and others showing little or no effect.

Ten studies have examined the effect of ad libitum TRE on glucose concentrations (Table 2)
(Arnason et al., 2017; Antoni, 2018; Gabel et al., 2018; Hutchison et al., 2019; Tinsley et al.,
2019; Chow, 2020; Cienfuegos et al., 2020; Karras et al., 2020a; Karras et al., 2020b;
Wilkinson et al., 2020). The majority of these trials report no change in fasting glucose with
4-h, 6-h, 8-h, or 10-h TRE (Gabel et al., 2018; Anton et al., 2019; Tinsley et al., 2019;
Cienfuegos et al., 2020; Karras et al., 2020a; Wilkinson et al., 2020). However, some trials
show minor improvements in fasting glucose. For instance, Hutchison et al. (Hutchison et al.,
2019) reported significantly lower fasting glucose concentrations when subjects ate within an
early 9-h TRE window (all food consumed before 5 pm), versus baseline. Fasting glucose
also improved in the TRE studies by Chow et al. (Chow, 2020), Antoni et al. (Antoni, 2018)
and Karras et al. (Karras et al., 2020b). Due to the paucity of data and the different trial
designs implemented, it is difficult to ascertain the effects of ad libitum TRE on fasting
glucose concentrations. Larger sample sizes and controlled timing of the eating window may
be necessary to understand the effect of TRE on blood glucose.

Fasting insulin
As blood glucose levels rise, beta-cells of the pancreas increase insulin production to shuttle
excess glucose into storage and maintain normal blood glucose concentrations. (Diseases,
2020). However, the need for beta-cells to produce consistently high insulin is a main risk

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factor for beta-cell death, insulin resistance, and type 2 diabetes. Eight studies have examined
the effect of isocaloric TRE on insulin concentrations (Stote et al., 2007; Kahleova et al.,
2014; Moro et al., 2016; Sutton et al., 2018; Jamshed et al., 2019; Martens et al., 2020;
McAllister et al., 2020; Parr et al., 2020). In the studies by Jamshed et al. (Jamshed et al.,
2019), Moro et al. (Moro et al., 2016), and Kahelova et al. (Kahleova et al., 2014) fasting
insulin decreased during isocaloric TRE. In a 5 day study by Parr et al. (Parr et al., 2020),
participants had a significantly lower peak insulin level after breakfast, which could be due to
the influence of circadian rhythmicity on morning glucose regulation. The trial by Sutton et
al. (Sutton et al., 2018) examined the effects of early 6-h TRE (all food consumed by 15:00
h) versus controls (all food consumed within a 12-h window) in men with pre-diabetes. Food
was provided to all participants and both diets were isocaloric and eucaloric. After 5-weeks,
body weight was maintained, and fasting insulin levels were reduced in the early 6-h TRE
group only (Sutton et al., 2018). Thus, TRE may improve fasting insulin levels independent
of weight loss, especially in those who have prediabetes.

Ten studies have examined the effects of ad libitum TRE on insulin levels (Table 2)
(Arnason et al., 2017; Antoni, 2018; Gabel et al., 2018; Hutchison et al., 2019; Tinsley et al.,
2019; Chow, 2020; Cienfuegos et al., 2020; Karras et al., 2020a; Karras et al., 2020b;
Wilkinson et al., 2020). Nine of the ad libitum studies did not report a significant change in
participants’ fasting insulin concentrations (Arnason et al., 2017; Antoni, 2018; Gabel et al.,
2018; Hutchison et al., 2019; Tinsley et al., 2019; Chow, 2020; Karras et al., 2020a; Karras
et al., 2020b; Wilkinson et al., 2020). However, in the study by Cienfuegos et al. (Cienfuegos
et al., 2020), fasting insulin was reduced with 4-h and 6-h TRE, versus controls, after 8-
weeks of treatment. Thus, the body of evidence to date suggests that ad libitum TRE appears
to have little effect on fasting insulin concentrations in individuals who do not have diabetes.

Insulin resistance
Consistently high concentrations of glucose and insulin decrease the ability of muscle, fat and
liver cells to utilize and store glucose, resulting in insulin resistance. Insulin resistance is the
main contributing factor to both metabolic disease and cardiovascular disease. Five studies
have examined the effect of isocaloric TRE on insulin resistance (Moro et al., 2016; Sutton et
al., 2018; Jamshed et al., 2019; Martens et al., 2020; Parr et al., 2020). Jamshed et al.
(Jamshed et al., 2019) demonstrated that 6-h early TRE decreased insulin resistance in the

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morning significantly more than the 12-h group. Moro et al. (Moro et al., 2016) also reported
improved insulin resistance with 8-h TRE. In the short term TRE study by Parr et al. (Parr et
al., 2020), participants improved beta-cell function (Parr et al., 2020), therefore improving
insulin sensitivity. Further, Sutton et al. (Sutton et al., 2018) demonstrated improved beta-cell
function in the early 6-h TRE group, independent of weight loss. Eight studies have examined
the effect of ad libitum TRE on insulin resistance (Arnason et al., 2017; Gabel et al., 2018;
Chow, 2020; Cienfuegos et al., 2020; Karras et al., 2020a; Karras et al., 2020b; Parr et al.,
2020; Wilkinson et al., 2020). Of these, only one reported significant changes (Cienfuegos et
al., 2020) in this parameter. More specifically, insulin resistance decreased by ~30% in both
the 4-h and 6-h TRE groups when compared to controls. Overall, it would appear as though
isocaloric TRE produces more consistent reductions in insulin resistance, when compared to
ad libitum TRE. However, most of the studies examining the effect of TRE glycemic control
are quite short (<12 weeks) and have very limited sample sizes. Further, the eating windows
in most of these trials were not standardized. Circadian rhythm influences glucose regulation,
and it is well known that insulin sensitivity decreases over the course of the day. Therefore, it
will be important to examine the effect of the timing of the eating window on these markers
of glucoregulation. Additionally, 24-hour glucose monitors and hyperinsulinemic euglycemic
clamps should be used in future studies of TRE to strengthen these findings.

Plasma lipids
One in three deaths in the United States are caused by cardiovascular disease (Promotion,
2019). Risk factors include high blood pressure, high concentrations of low-density
lipoprotein cholesterol (LDL) and triglycerides and low concentrations of high-density
lipoprotein (HDL) cholesterol. Accumulating evidence suggests that a 5% weight loss can
improve LDL cholesterol, triglycerides, and blood pressure (Alberti et al., 2006; Bogers et
al., 2007; Ades & Savage, 2014).

LDL cholesterol: LDL cholesterol is the main carrier of cholesterol in the circulatory
system. If LDL levels remain high, the hardening and narrowing of the arteries can ensue,
increasing the chances of a heart attack or stroke. Eight studies (Carlson et al., 2007; Stote et
al., 2007; Kahleova et al., 2014; Moro et al., 2016; Sutton et al., 2018; Jamshed et al., 2019;
Martens et al., 2020; McAllister et al., 2020) have examined the effect of isocaloric TRE on
LDL cholesterol levels. Three of these studies (Carlson et al., 2007; Stote et al., 2007;

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Jamshed et al., 2019) found that LDL cholesterol increased after the intervention. Though it
should be noted that in the trials by Stote et al. (Stote et al., 2007) and Carlson et al. (Carlson
et al., 2007), subjects were required to consume all of their energy needs for the day in one
meal over the course of 8-weeks. Since LDL cholesterol increased with this eating pattern, it
is unadvisable to consume all energy in only one meal per day. McAllister et al. (McAllister
et al., 2020), Kahleova et al. (Kahleova et al., 2014), Moro et al. (Moro et al., 2016) and
Sutton et al. (Sutton et al., 2018) reported no significant change in LDL cholesterol after
TRE. These studies suggest that isocaloric TRE has little effect on LDL cholesterol levels,
unless all energy is consumed in one meal, which results in increased LDL cholesterol
concentrations.

Nine ad libitum TRE studies measured changes in LDL cholesterol levels (Tinsley et al.,
2017; Antoni, 2018; Gabel et al., 2018; Kesztyus et al., 2019; Chow, 2020; Cienfuegos et al.,
2020; Karras et al., 2020b; Wilkinson et al., 2020; Zeb et al., 2020). Seven of these studies
found no effect on LDL cholesterol (Tinsley et al., 2017; Gabel et al., 2018; Hutchison et al.,
2019; Kesztyus et al., 2019; Chow, 2020; Cienfuegos et al., 2020; Zeb et al., 2020). In
contrast, a few studies reported beneficial changes in this lipid parameter. For instance,
Wilkinson et al. (Wilkinson et al., 2020) demonstrated reduced LDL cholesterol after 12-
weeks of 10-h TRE. Karras et al. (Karras et al., 2020b) also reported a significant decrease in
LDL cholesterol in the TRE group compared to the Orthodox fasting group, 7 weeks after the
intervention had ended. Though some benefits have been reported, ad libitum TRE does not
produce consistent improvements in LDL cholesterol concentrations. It is possible however,
that favorable changes in this lipid parameter would only be evident once clinically
significant weight loss is attained (>5% from baseline). Since only minimal weight loss was
noted in these TRE trials (1-4%), this could explain why LDL cholesterol concentrations
generally remained unchanged.
HDL cholesterol: HDL cholesterol mediates the removal of atherogenic plaque from the
arteries and low levels of HDL cholesterol are associated with higher risk for cardiovascular
disease. Five studies of isocaloric or ad libitum TRE have reported an improvement in HDL
cholesterol levels (Stote et al., 2007; Moro et al., 2016; Jamshed et al., 2019; McAllister et
al., 2020; Zeb et al., 2020). Studies by Stote et al. (Stote et al., 2007) and Jamshed et al.
(Jamshed et al., 2019) reported an increase in HDL concentrations in the morning only. In a
study by McAllister et al. (McAllister et al., 2020) both the ad libitum and isocaloric TRE

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groups increased HDL cholesterol concentrations. The authors in this study (McAllister et al.,
2020) speculate that the increase in HDL cholesterol was partly the result of increases in
circulating adiponectin (McAllister et al., 2020). In a recent TRE study and follow-up from
Karras et al. (Karras et al., 2020a; Karras et al., 2020b), HDL cholesterol concentrations
decreased with weight loss during the TRE intervention and rebounded to baseline after 6
weeks of follow-up. Nine TRE studies (Kahleova et al., 2014; Tinsley et al., 2017; Antoni,
2018; Gabel et al., 2018; Sutton et al., 2018; Kesztyus et al., 2019; Chow, 2020; Cienfuegos
et al., 2020; Wilkinson et al., 2020) reported no change in HDL cholesterol with TRE. In
view of these contradictory findings, the effects of TRE on HDL cholesterol remain unclear.
Changes in HDL cholesterol in relation to hepatic gluconeogenesis, increased adiponectin,
and physical activity should be explored in future TRE studies.

Triglycerides: Triglycerides play a key role in energy storage and elevated triglycerides are
associated with increased risk of metabolic disease. Seven studies (Carlson et al., 2007; Stote
et al., 2007; Kahleova et al., 2014; Moro et al., 2016; Sutton et al., 2018; Jamshed et al.,
2019; McAllister et al., 2020) have examined the effect of isocaloric TRE on triglyceride
levels. Kahleova et al. (Kahleova et al., 2014) reported a reduction in triglycerides after 12-
weeks when all energy was consumed as either 2 meals/d or 6 meals/d. Conversely, in the
trial by Sutton et al. (Sutton et al., 2018) triglyceride concentrations increased during early 6-
h TRE. In this trial, participants fasted for 18-h overnight prior to the blood draw. Acute
fasting has been shown to elevate circulating triglycerides and free fatty acids through
augmented lipolysis. Thus, this spike in circulating triglyceride levels may be due to the acute
effects of fasting, rather than the chronic effects of early 6-h TRE. The effects of ad libitum
TRE on triglycerides have also been evaluated. Hutchison et al. (Hutchison et al., 2019),
Chow et al. (Chow, 2020), Zeb et al. (Zeb et al., 2020) and Karras et al. (Karras et al., 2020a)
demonstrate improvements fasting triglycerides with various TRE interventions (8-9-h TRE).
In contrast, six studies (Tinsley et al., 2017; Antoni, 2018; Gabel et al., 2018; Kesztyus et al.,
2019; Cienfuegos et al., 2020; Wilkinson et al., 2020) did not report any significant change in
this lipid parameter. Taken together, TRE may lower triglyceride concentrations, but these
effects are not consistent.

Blood pressure

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Blood pressure is another common factor for metabolic disease. When blood pressure is
consistently high, arterial walls can weaken leading to heart failure. A decrease of 5 mm Hg
systolic or diastolic blood pressure is clinically significant following a lifestyle intervention
(Wing et al., 2011). Under isocaloric conditions, participants (Sutton et al., 2018) reported a
significant decrease in systolic blood pressure and diastolic blood pressure after 5 weeks of 6-
h early TRE. Similarly, McAlister et al. (McAllister et al., 2020) reported a decrease in
systolic blood pressure in both the isocaloric and ad libitum groups, independent of energy
deficit. The trial by Arnason et al. (Arnason et al., 2017) did not demonstrate a change in
blood pressure with 4-6-h TRE, however this trial was only 2 weeks long and may have been
too short to see an effect. Systolic and diastolic blood pressure in the trials by Tinsley et al.
(Tinsley et al., 2019) and Stote et al. (Stote et al., 2007) also did not significantly change,
however participants were already lean, active, and normotensive. Three ad libitum TRE
trials (Anton et al., 2019; Chow, 2020; Cienfuegos et al., 2020) also did not report changes in
systolic or diastolic blood pressure. Gabel et al. (Gabel et al., 2018) and Wilkinson et al.
(Wilkinson et al., 2020) demonstrated reductions in systolic blood pressure after 12 weeks of
ad libitum TRE. Thus, both isocaloric and ad libitum TRE appear to be effective
interventions to lower blood pressure.

Conclusion

In summary, TRE produces several cardiometabolic benefits. Body weight is generally

reduced by 1-4% under ad libitum conditions due to a spontaneous energy deficit (20-30%
from baseline) induced by the shortened eating window. Weight loss occurs primarily due to
fat mass loss, but some minor reductions in lean mass have also been reported. Adherence to
these regimens is generally quite high, which bodes well for the feasibility of these diets
long-term. The effects of TRE on fasting glucose are equivocal, with some studies showing
improvements and others showing little or no effect. Fairly consistent reductions in fasting
insulin and insulin resistance have been reported for TRE, particularly in individuals with
prediabetes. As for plasma lipids, some studies report improvements in LDL cholesterol and

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triglyceride levels, though the majority of trials report no change. Blood pressure is regularly
decreased with TRE, and these improvements are noted with and without weight loss.

Figure 3:Future directions for TRE

The current evidence for TRE is promising but inconclusive. The trials reviewed here are
limited in that they involved small sample sizes, which lacked statistical power for some
primary and most secondary outcomes. In addition, these trials were short term (<12 weeks),
lacked control groups, and did not standardize the timing of the eating window. Nevertheless,
data from these pilot studies can be used to design larger, longer, well-powered human trials
of TRE (Figure 3). Future trials in this area should assess: 1) the efficacy and feasibility of
TRE versus daily energy restriction or other forms of intermittent fasting, 2) how the length
of the eating window (4-h, 6-h, 8-h, or 10-h) and timing of the eating window (early versus

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late) impacts weight loss and metabolic disease risk, and 3) whether these diets can be used to
maintain weight loss and sustain improvements in cardiometabolic health.

Though many questions remain unanswered, preliminary data are promising, and show that
TRE maybe a viable diet therapy for weight loss and metabolic disease risk reduction in
adults with obesity.
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Table 1: Effect of time restricted eating (TRE) on body weight and body composition

Reference Design Intervention Subjects Length %BW FM FFM

Δ

Isocaloric

4-6 h
TRE

Carlson, O. Crossover 1 meal (4-h) vs n= 21 male/female 8 weeks -2% ↓ NA

et al. 2007 3 meals/d normal weight

Stote et al. Crossover 1 meal (4-h) vs n= 21 male/female 8 weeks -2% ↓ NA

2007 3 meals/d normal weight

7-10 h
TRE

Tinsley, G. RCT TRE (4-h) + n= 18 male lean 8 weeks - - -

M. et al. exercise vs and active
2017 normal diet +
exercise

McAllister, Randomized TRE (8-h) ad n= 22 male normal 4 weeks ↓ ↓ ↑

M. J. et al. libitum vs weight
2020 isocaloric

Moro, T. et RCT TRE (8-h) vs n= 34 male lean 8 weeks - ↓ -

al. 2016 control and active

Kahleova, Crossover 2-meals/d vs 6- n= 54 12 weeks ↓ NA NA

H. et al. meals/d male/female
2014 T2DM
overweight/obese

Martens et Crossover TRE (8-h) vs n=22 normal 6 weeks - - -

al. 2020 normal diet weight older adults

Ad-
libitum
or
Energy
Deficit

4-6 h
TRE

Arnason, T. Longitudinal TRE (4-6 h) n= 10 male/female 2 weeks - 1% NA NA

G. et al. T2DM
overweight/obesity

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2017

Cienfuegos RCT TRE 4h vs n=49 male/female 8 weeks -3% ↓* TRE ↓ *6h

et al. 2020 TRE 6h vs obesity TRE
control

TRE 7-10
h

Hutchison, Crossover 9-h TRE early n=15 male 1 week – 1% - -

A. T. et al. vs late prediabetic
2019 overweight/obesity

Anton et al. Longitudinal TRE (8h) n=10 ≥65yo 28 days -2.6% NA NA

2020 male/female,
overweight/obesity

Karras et al. Longitudinal TRE (8h)vs TRE: n=23, 7 weeks ↓ - -

2020 Orthodox Orthodox: n=37
fasting
500-750 kcal
deficit

Karras et al. Longitudinal TRE (8h)vs TRE: n=23, 6 week ↓ ↓* TRE -

2020 Orthodox Orthodox: n=37 follow-up
fasting
500-750 kcal
deficit

Tinsley, G. RCT TRE (8h) vs n= 40 female 8 weeks + 1% ↓ ↑

M. et al. TRE (8h) + active
2019 HMB vs
Control
(200kcal
deficit)

Antoni et RCT 1h later – 5h n=16 male/female 10 weeks - ↓* NA

al. 2018 earlier BMI- 20-39
(window)
vs control

Gabel, K. et Historical TRE (8h) vs n= 23 male/female 12 weeks -3%* - -

al. 2018 RCT control obesity
(historical)

Kesztyus, Longitudinal TRE (8-9 h) n= 40 male/female 12 weeks -2% NA NA

D. et al. overweight/obesity
2019

Wilkinson, Longitudinal TRE (10h) n= 19 male/female 12 weeks - 3% ↓ NA

M. J. et al. met. syndrome
2020 overweight/obesity

Chow et al. RCT TRE vs control n=20 male/female 12 weeks -4%* ↓* ↓

2020 overweight/obesity

Gill and Observational 10-12h TRE n=8 male/female 16 weeks -4% NA NA

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Panda 2015 overweight

All changes reported are statistically significant within group (baseline to post treatment)

*significant time x group interaction, - no change, NA - did not measure

Table 2: Effect of time restricted eating (TRE) on metabolic disease risk factors

Referen Design Interventi Subjects Leng Gluco Insul IR LD HD T

ce on th se in L L G

Isocalor
ic

4-6 h
TRE

Jamshed, Crossover TRE (6h) vs n= 11 4 days ↓ (AM) ↓ ↓(A ↑ ↑ -

H. et al. control male/female (AM) M) (AM) (AM
2019 (12h) overweight )

Carlson, Crossover 1 meal (4-h) n= 21 8 ↑ (AM) NA NA ↑ NA -

O. et al. vs 3 male/female weeks
2007 meals/d normal weight

Stote et Crossover 1 meal (4-h) n= 21 8 ↓ - NA ↑ ↑ -

al. 2007 vs 3 male/female weeks control
meals/d normal weight

Sutton et Crossover 6-h eTRE n=8 male 5 NA ↓ ↓ - - ↑

al. 2018 vs control prediabetic weeks

7-10 h
TRE

Parr et al. Randomiz TRE (8h) vs n=11 male, 5 days ↓* TRE ↓* ↑ NA NA N

2020 ed 15h overweight/ob sleep peak β-cell A
Crossover esity fxn

McAllist Randomiz TRE (8h) n= 22 male 4 - - NA - ↑ -

er, M. J. ed ad libitum normal weight weeks
et al. vs
isocaloric
2020

Moro, T. RCT TRE (8h) vs n= 34 male 8 ↓ ↓ ↓ - ↑ -

et al. control lean active weeks
2016

Kahleova Crossover 2-meals/d n= 54 12 ↓ ↓ NA - - ↓

, H. et al. vs 6- male/female

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2014 meals/d T2DM weeks
overweight/ob
esity

Martens Crossover TRE (8) vs n=22 normal 6 ↓ - - ↑ NA N

et al. normal diet weight older weeks A
2020 adults

Ad-
libitum
or
Energy
Deficit

4-6 h
TRE

Arnason, Longitudi TRE (4-6 h) n= 10 2 ↓ - - NA NA N

T. G. et nal male/female weeks A
al. 2017 T2DM
overweight/ob
esity

Cienfueg RCT TRE 4h vs n=49 8 - ↓* ↓*TR - - -

os et al. TRE 6h vs male/female weeks TRE E
2020 control obesity

7-10 h
TRE

Hutchiso Crossover 9-h TRE n=15 male 1 ↓ AUC - NA NA NA ↓

n, A. T. early vs late prediabetic week
et al. overweight/ob
2019 esity

Tinsley, RCT TRE (8h) vs n= 40 female 8 - - NA - - -

G. M. et TRE (8h) + active weeks
al. 2019 HMB vs
Control

Zeb et al. RCT 8h TRE: n=56, 25 NA NA NA - ↑ ↓

2020 Ramadan control: n=24 days
fasting Young men

Anton et Longitudi TRE (8h) n=10 >65yo 28 - NA NA NA NA N

al. 2019 nal male/female, days A
overweight/ob
esity

Karras et Longitudi TRE (8h)vs TRE: n=23, 7 - - - NA ↑* ↓*

al. 2020 nal Orthodox Orthodox: weeks
fasting n=37

Karras et Longitudi TRE (8h)vs TRE: n=23, 6 ↓* TRE - - ↓*TR NA N

al. 2020 nal Orthodox Orthodox: week E A
follow

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 fasting n=37 up

Antoni et RCT 1h later – n=16 10 ↓* - NA - - -

al. 2018 5h earlier male/female weeks
(window) BMI- 20-39
vs control

Gabel, K. RCT TRE (8h) vs n= 23 12 - - - - - -

et al. control male/female weeks
2018 (historical) obesity

Kesztyus, Longitudi TRE (8-9 h) n= 40 12 ↓HbA1 NA NA - - -

D. et al. nal male/female weeks c
2019 overweight/ob
esity

Wilkinso Longitudi TRE (10h) n= 19 12 - - - ↓* Ø Ø

n, M. J. nal male/female weeks
et al. Met.
2020 Syndrome
overweight/ob
esity

Chow et RCT TRE vs n=20 12 ↓ - - - - ↓

al. 2020 control male/female weeks
overweight/ob
esity

All changes reported are statistically significant within group (baseline to post treatment)

*significant time x group interaction, - no change, NA - did not measure

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