Current Obesity Reports

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OBESITY TREATMENT (CM APOVIAN, SECTION EDITOR)

Intermittent Fasting: Is the Wait Worth the Weight?

Mary-Catherine Stockman 1 & Dylan Thomas 1 & Jacquelyn Burke 2 & Caroline M. Apovian 1

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Purpose of Review We review the underlying mechanisms and potential benefits of intermittent fasting (IF) from animal models
and recent clinical trials.
Recent Findings Numerous variations of IF exist, and study protocols vary greatly in their interpretations of this weight loss
trend. Most human IF studies result in minimal weight loss and marginal improvements in metabolic biomarkers, though
outcomes vary. Some animal models have found that IF reduces oxidative stress, improves cognition, and delays aging.
Additionally, IF has anti-inflammatory effects, promotes autophagy, and benefits the gut microbiome. The benefit-to-harm ratio
varies by model, IF protocol, age at initiation, and duration.
Summary We provide an integrated perspective on potential benefits of IF as well as key areas for future investigation. In clinical
trials, caloric restriction and IF result in similar degrees of weight loss and improvement in insulin sensitivity. Although these data
suggest that IF may be a promising weight loss method, IF trials have been of moderate sample size and limited duration. More
rigorous research is needed.

Keywords Intermittent fasting . Fasting . Obesity . Calorie restriction . Metabolism . Insulin resistance . Weight loss

Abbreviations CER Continuous energy restriction

IF Intermittent fasting RCT Randomized controlled trial
CR Calorie restriction GIR Glucose infusion rate
ICR Intermittent calorie restriction Si Insulin sensitivity
ER Energy restriction ROS Reactive oxygen species
TRF Time-restricted feeding ad lib Ad libitum
PF Prolonged fasting
ADER Alternate-day energy restriction
Introduction
This article is part of the Topical Collection on Obesity Treatment
With more than two in three adults suffering with overweight
* Mary-Catherine Stockman or obesity, Americans are searching for effective weight loss
Mary–[email protected] methods [1]. Fasting, called “the next big weight loss fad” [2],
has long been integral to many religious and ethnic cultures
Dylan Thomas
[email protected] [3•]. Intermittent fasting (IF) has many forms (Table 1); the
basic premise involves taking periodic breaks from eating.
Jacquelyn Burke
Common forms of IF include fasting for up to 24 h once or
[email protected]
twice a week with ad libitum (ad lib) food intake for the
Caroline M. Apovian remaining days, which is known as periodic prolonged fasting
[email protected]
(PF) or intermittent calorie restriction (ICR) [4••]; time-
1
Section of Endocrinology, Diabetes and Nutrition, Boston Medical
restricted feeding (TRF), such as eating for only 8 h then
Center, 720 Harrison Avenue, 8th Floor, Boston, MA 02118, USA fasting for the other 16 h of the day; and alternate-day fasting
2
College of Health and Rehabilitation Sciences, Boston University
(ADF) [5, 6]. Most ADF programs involve alternating feast
Sargent College, 635 Commonwealth Avenue, Boston, MA 02215, (ad lib intake) and fast days (≤ 25% of energy needs) with
USA some protocols allowing no caloric intake on fast days [4••].
 Curr Obes Rep

Table 1 Comparison of different types of intermittent fasting (T2D), as these comorbidities add complexity beyond the
Type of IF Description Metabolic states involved scope of this paper. We focused on pertinent publications from
the last 5 years that meet these criteria, but did not exclude
Alternate day Alternating feast (ad lib Fed, post-absorptive, older, high-impact papers.
fasting intake) and fast days fasting (short duration,
(≤ 25% of energy likely <36 h between
needs) meals)
Time-restricted Eating only during certain Fed, post-absorptive
Overview of Human Metabolism: the Fed-Fast
fasting time periods (i.e., 8 h), (maximum duration Cycle
then fasting for between meals is usually
remaining hours of the < 16 h) Glucose is the primary energy source for most tissues during
day
Periodic fasting Fasting for up to 24 h Fed, post-absorptive,
the day. Fatty acids (FA) represent an alternative fuel source
once or twice a week fasting (up to 48 h for the most metabolically active organs including the muscle,
with ad lib intake on between meals liver, and brain and rise overnight during fasting. In 1963,
the remaining days depending on whether Randle proposed a theory of energy metabolism during feed-
fast days are
consecutive)
ing and fasting known as the “glucose-fatty acid cycle” where-
by glucose and FA compete for oxidation [7]. Since 1963, this
cycle and its underlying mechanisms have been elucidated [8].
Thus, the degree of fasting varies in ADF based on the specific The fed-fast cycle has four stages: the fed state, the post-
protocol. absorptive or early fasting state, the fasting state, and the star-
IF continues to gain attention with new evidence from basic vation or long-term fast state (Fig. 1) [9].
science research and clinical trials. This paper reviews these
developments. First, we provide an overview of the key as-
pects of metabolism involved in fasting. Next, we review clin- The Fed-Fast Cycle, Circadian Rhythmicity
ical trial data of IF outcomes including changes in weight loss of FFA, and Intermittent Fasting
and body composition, insulin sensitivity (Si), cardiovascular
biomarkers, aging and cognition, psychosocial factors, and the The circadian clock regulates gene expression and broadly
gut microbiome. We review potential cellular mechanisms for affects various organs and the network of neurohormonal
these effects including modulation of oxidative stress, inflam- weight control signals [16]. Overnight fasting, or fasting dur-
mation, and autophagy. Finally, we assess the clinical impli- ing sleeping hours, is associated with a nocturnal rise in plas-
cations of these results and identify directions for future ma free fatty acids (FFA), ghrelin, growth hormone, and in-
research. creased hepatic gluconeogenesis [17]. Adipose tissue (AT)
orchestrates the cycling of triglycerides (TG) by controlling
the uptake, esterification, and release of FFA to meet the met-
abolic demands of the liver and muscle tissue. Hence, integra-
Methods tion of circadian rhythms and eating may be beneficial.

We searched PubMed/MEDLINE and clinicaltrials.gov for

relevant clinical trials and animal studies in English with the The Effects of Intermittent Fasting
search terms: intermittent fasting, periodic, time-restricted,
adipose, alternate-day fasting, ADF, and obesity, from 1970 The following sections summarize the current literature on
to 2018. We reviewed references from key papers to identify various effects of IF.
additional articles. Reviews are cited to provide readers with
more details and references than is possible here.
In order to provide depth in this review, studies were most- Alterations in Weight and Body Composition
ly limited to those on ADF and modified ADF. While TRF is
another branch of IF, TRF-only studies were excluded from Nearly all IF studies have resulted in some degree of weight
this review due to their variability, particularly in regard to the loss, ranging from 2.5–9.9% [18, 19•], and associated fat mass
definition of TRF and whether breakfast- or dinner-skipping loss. Numerous studies have been conducted on IF (Table 2),
are considered types of TRF. Additionally, this review ex- but IF protocol, duration, and baseline characteristics of the
cludes papers on fasting-mimicking diets (FMD), as we con- sample population have varied greatly.
sider most FMD protocols to fall under the category of very The literature distinguishes between ADF and ICR regi-
low-calorie diets (VLCD). Lastly, we excluded studies that mens. Heilbronn et al. evaluated 22 days of ADF (0% intake
focused on comorbidities of obesity, such as type 2 diabetes on fast days, ad lib feast days) in 16 healthy subjects with
Curr Obes Rep

Fig. 1 The fed-fast cycle [9–14, 15•]. The four stages of the fed-fast through the fed, post-absorptive, and fasting states. Additionally, while
cycle. Only the fed and post-absorptive states are relevant to normal the figure is cyclic, it is possible to return to the food consumption point at
eating routines. Based on the IF regimen, an individual often goes any time

normal BMI [18]. ADF resulted in minor weight loss (2.5%), when evaluating weight loss methods. In the same study, hun-
fat loss (4%), and increased fat oxidation [18]. In contrast, ger did not change in either group, but satisfaction and fullness
Eshghinia and Mohammadzadeh evaluated 6 weeks of ADF increased in the ADF group only [5]. This is of particular
(very low-calorie diet (VLCD) on fast days, ad lib feast days) clinical significance, as diets are often not sustainable due to
in women with overweight or obesity [33]. ADF led to 7.1% dissatisfaction with dietary restrictions.
weight loss and visceral fat mass loss (5.7%). Another study An RCT comparing ADF, CR, and no-intervention con-
assessed the effects of 8 weeks of ADF with either a high- or trol found that mean weight loss was not significantly
low-fat diet in 32 women with obesity [34]. Weight, fat mass, different at 6 or 12 months between ADF and CR, but
and waist circumference decreased similarly in both groups. dropout rate was significantly higher in the ADF group
When comparing ADF to no-intervention control, ADF [23••]. Mean LDL cholesterol levels were significantly
resulted in 6.5% weight loss relative to the control group [5]. elevated (+ 11.5 mg/dL [95%CI, 1.9–21.1 mg/dL]) in the
However, dietary satisfaction is also important to consider ADF group at month 12 compared to the CR group. A
Table 2 This table highlights adult human RCTs studies that meet the following criteria: published between 2003 and 2018; IF evaluated as primary variable; IF regimen greater than 1 week. TRF and PF
studies were excluded due to the scope of this paper. The studies are ordered by highest N and longest duration

First author, Study population Study design Key results

Yeara,b
N completers (female/male), Groups and characteristics (N, IF regimen Duration
inclusion criteriac, dropout rate mAged, bBMIe)
(DR)

Harvie 2013 [20] N = 115 ICR (n = 37, 45.6 ± 8.3, 29.6 ± 4.1) 25% energy needs4 restricted in all, 3-mon weight loss, • ↓ weight, body fat in ICR > CER
Women only ICR + PF (n = 38, 48.6 ± 7.3, energetic groups 1-mon weight groups
Age 20–69 31.0 ± 5.7) ICR without ad lib protein, fat: CR maintenance • ↑Si with both ICR
BMI 24.0–45.0 and/or body fat CER (n = 40, 47.9 ± 7.7, and carb restriction on 2 • Less FFM loss in ICR groups
>30% 32.2 ± 5.6) consecutive d/wk • Short term: ICR superior to CER re: Si
DR 11% in ICR group; 26% in ICR ICR + protein, fat (ICR + PF): same and ↓ body fat
+ PF and 33% in DER as ICR but with unlimited protein
and fat on restricted days
CER: daily 25% CR
Harvie 2011 [21] N = 107 ICR (n = 53, 40.1 ± 4.1, 30.7 ± 5.0) 25% energy restriction4 as ICR 6 mon • ICR and CER equally effective for
Women only CER (n = 54, 40.0 ± 3.9, (2 d/wk) or CER (7 d/wk) weight loss
Age 30–45 30.5 ± 5.2) • Comparable ↓leptin, free androgen
BMI 24.0–40.0 index, RP, total and LDL cholesterol,
DR 21% in ICR group; 13% in TG, BP + ↑sex hormone biding
CER group globulin
• Modest ↓ in Si, fasting insulin—
greater in ICR
Bhutani 2013 [22] N = 83 ADF + exercise (combo, n = 18, ADF: 25% energy needs2 fast day, 12 wk • ↓ weight in combo, ADF, exercise
80 F/3 M 45 ± 5, 35 ± 1) ad lib feast day groups
Age 25–65 ADF (n = 25, 42 ± 2 yo) Exercise: moderate intensity • ↓ LDL, fat mass, waist circumference;
BMI 30.0–39.9 Exercise (n = 24, 42 ± 2, 35 ± 1) exercise 3 d/wk ↑ HDL in combo only
DR: 9 dropped out of ADF, 8 out of Control (n = 16, 49 ± 2, 35 ± 1)
exercise. No dropouts in
exercise or control groups.
Trepanowski 2017a [23••] N = 79 ADF (n = 25, 46 ± 2, 34 ± 1) ADF: 25% energy needs1 on fast 4-wk baseline • ↓ weight (−6.8% in ADF and CR at
66 F/13 M CR (n = 29, 44 ± 2, 35 ± 1) days, 125% feast day with dietary run-in period 6 months, 6.0% in ADF and 5.3% in
Age 18–65 Control (n = 25, 44 ± 2, 34 ± 1) counseling for the first 12 wk →24-wk weight CR at 12 months)
BMI 25.0–39.9 CR: 75% needs1 daily + dietary loss intervention • ↑HDL in ADF at mon 6, not at mon 12
DR: 38% in ADF, 29% in CR, 26% counseling for the first 12 wk period → 24-wk • ↑LDL in ADF at month 12
in control only maintenance • NS differences between groups in BP,
Control: 100% needs daily; no period heart rate, TG, fasting glucose,
intervention fasting insulin, Si, CRP, or
homocysteine
Trepanowski 2017b [24] See Trepanowski, 2017a [23••] See Trepanowski, 2017a [23••] See Trepanowski, 2017a [23••] Only the first • ↑ FFM:total mass ratio in ADF and
28 weeks of CR (NS difference)
Trepanowski, • ↓leptin in ADF and CR (NS
2017a [23••] difference)
• No change in circulating adiponectin,
resistin, IL-6, or TNF=α in any group
Curr Obes Rep
Table 2 (continued)

First author, Study population Study design Key results

Yeara,b
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N completers (female/male), Groups and characteristics (N, IF regimen Duration

inclusion criteriac, dropout rate mAged, bBMIe)
(DR)

Teng 2013 [25] N = 56 ICR (n = 28, 59.6 ± 5.4, 26.8 ± 1.7) ICR: 300–500 kcal/d deficit with 3 mon • ↓weight, %fat, energy intake, fat
Men only Control (n = 28, 59.1 ± 6.2, 2 d/wk. Muslim Sunnah fasting. intake, BP, LDL, total cholesterol in
Age 50–70 26.7 ± 2.3 Fasting day included light meal ICR
BMI 23.0–29.9 before sunrise, no food and drink • ↓damage of DNA cells in ICR
DR: NR during the day (~ 13 h) and • ↑fat intake in control
complete meal after sunset • Maintained or ↑weight, BMI, %fat in
Control control group
Byrne 2017 [19•] N = 51 ICR (n = 26, 39.9 ± 9.2, 34.6 ± 4.2) During ER weeks, 67% energy 32 wk • ↓ weight, fat mass to greater degree in
Men only CER (n = 25, 39.3 ± 6.6, needs3 for weight maintenance Interspersed: ICR
Age 25–54 34.4 ± 3.3) 8 × 2-wk blocks • ↓ REE greater in ICR after adjusting
BMI 30.0–45.0 of CR and for changes in body composition
DR: NR 7 × 2-week
blocks of energy
balance
Varady 2011 [26] N = 49 ADF (n = 13, 47 ± 2, 32 ± 2) ADF: 75% energy needs2 on fast 12 wk • ↓ weight in ADF, CR, exercise groups
40 F/9 M CR (n = 12, 47 ± 3, 32 ± 2) days, ad lib feast days • ↓ LDL in ADF and CR only; ↑ HDL in
Age 35–65 Exercise (n = 12, 46 ± 3, 33 ± 1) CR: 75% energy needs2 daily exercise only
BMI 25.0–39.9 Control (n = 12, 46 ± 3, 32 ± 2) Exercise: moderate intensity 3 d/wk
DR: NR Control: usual
Keogh 2014 [27] N = 36 ICR (n = 19, 59.5 ± 8.7, 33.1 ± 3.8) ICR: 1-week ‘normal’ diet followed 8-wk weight loss • ↓ weight, waist and hip circumference
Women only CER (n = 17, 60.8 ± 12.5, by 1-wk CR (5500 kJ) intervention, (NS difference between groups)
Age ≥ 18 33.0 ± 7.5) CER: every day CR (5500 kJ) 12-wk weight • ↑ Healthy Eating Index at 12 mon in
BMI ≥ 27.0 loss CER only
Healthy or T2D managed by maintenance
diet alone
DR: 40% in first 8 wk, 20%
between 8 and 52 wk
Hussin 2013 [28] N = 31 FCR (n = 16, 59.7 ± 6.6, IF: 300–500 kcal/d reduction from 3 mon • ↓ anger, tension, confusion, weight,
Males only 26.7 ± 1.8) baseline6 + 2 d/wk of Muslim BMI, body fat in IF group
Age 50–70 Control (n = 15, 59.7 ± 6.2, Sunnah fasting; with counseling • NS changes in mean depression scores
BMI 23.0–29.9 26.8 ± 2.6) Control: ad lib, no counseling
DR: 0 subjects in ADF, 1 in control
Varady 2013 [29] N = 30 ADF (n = 15, 47 ± 3, 26 ± 1) ADF: 25% energy needs2 on fast 12 wk • ↓ weight, fat mass, TG, leptin in ADF
22F/8M Control (n = 15, 48 ± 2, 26 ± 1) day (meals provided), ad lib feast • ↑ adiponectin, LDL particle size in
Age 35–65 day ADF
BMI 20.0–29.9 Control: ad lib daily • Unchanged LDL, HDL,
DR: 6.2% (2 of 32) homocysteine, resistin
Teng 2011 [30] N = 25 FCR (n = 12, 59.3 ± 3.4, 3 mon • ↓ weight, BMI, body fat %, depression
Men only 27.0 ± 1.7a) in ICR
Table 2 (continued)

First author, Study population Study design Key results

Yeara,b
N completers (female/male), Groups and characteristics (N, IF regimen Duration
inclusion criteriac, dropout rate mAged, bBMIe)
(DR)

Age 50–70 Control (n = 13, 58.3 ± 6.3, ICR: − 300 to − 500 kcal/day • ↑ energy component of QOL in ICR
BMI 23.0–29.9 26.5 ± 1.8) +2 days of fasting/wk for 3-mon
DR: 14% (4 of 28) period
Control: no intervention
Catenacci 2016 [31•] N = 25 ADF (n = 13, 36.9 ± 9.5, ADF: 0% energy needs5 on fast day, 8-wk intervention - ↓ weight in both groups, NS difference
19 F/6 M 35.8 ± 3.7) ad lib feast day 24-wk follow-up • ADF group regained more FFM and
Age 18–55 CR (n = 12, 42.7 ± 7.9, 39.5 ± 6) Control: 400 kcal/d deficit CR group regained more FM (NS)
BMI: ≥ 30.0
DR: 7 withdrew prior to
randomization; all 25 completed
intervention
Harder-Lauridsen 2017 N = 20 ADF (n = 10, 23 ± 3.6, NR) While on bed rest 8 days • NS differences in weight, body
[32] Males only Control (n = 10, 24 ± 1.8, NR) ADF: 25% energy needs2 on fast composition, biomarkers, or
Age ≥ 18 days (1 meal/d), 175% needs on glycemic control
BMI 18.5–2.05 feast days (4 meals/d) • ↓ systolic blood pressure in ADF
DR: 10% in ADF, 0 in control Control: 100% needs2 (3 meals/d) • ↓ FFM in both groups

Abbreviations: N (sample size of completers), F (females), M (males), mAge (mean age), bBMI (baseline BMI), IF (intermittent fasting), ADF (alternate-day fasting), mon (months), wk. (weeks), d (day), yo
(years old), combo (combination), LDL (low-density lipoprotein cholesterol), HDL (high-density lipoprotein cholesterol), NS (not statistically significant), FFM (fat free mass), BP (blood pressure), NR (not
reported)
a
Inclusion age in years and inclusion BMI in kilograms per square meter. Mean age (mAge) presented as mean ± SEM when available. Mean baseline BMI (bBMI) presented as mean ± SEM when
available
b
Energy needs calculated by 1 doubly labeled water technique, 2 Mifflin-St. Jeor equation, 3 measured REE (indirect calorimetry) × self-reported physical activity level, 4 calculated resting metabolic rate ×
activity factor, 5 [(372 + 23.9 × FFM) × 1.5], 6 Diet history questionnaire (DHQ)
Curr Obes Rep
Curr Obes Rep

preplanned secondary analysis compared changes in body glucose uptake and Si were unchanged during the clamp per-
composition and fat distribution measured by DEXA and formed 14-h post-fasting [38]. Thus, it is unknown when Si
MRI at week 24 [24]. There was no significant difference improves the most post-fasting and if this is a sustainable
between ADF and CR in the relative amounts of fat mass, change, particularly in healthy men. However, a more clini-
FFM, or visceral and subcutaneous fat loss. cally relevant question is whether IF can benefit subjects with
In a study comparing ICR and CER in men with obesity, impaired baseline Si.
greater weight loss was seen in the ICR group (12.6 vs. 7.2%) In a study comparing ADF and CER, there were no be-
[19•]. Fat mass loss was also greater in the ICR group (12.3 vs. tween group differences in lipids or Si [31•]. This differs from
6.6 kg), but changes in fat free mass (FFM) were similar [19•]. results of a larger randomized controlled trial (RCT), which
Teng et al. evaluated ICR compared to no-intervention control found that Si and fasting insulin improved more in the ICR
in men (BMI 18.5–29.9 kg/m2) [30]. The ICR group had group, compared to the CER group, despite similar effects on
decreased weight and fat mass, but weight and fat mass in- weight and other biomarkers [21]. A preplanned secondary
creased in the CER group. FFM was similar pre- and post- analysis of a 2017 RCT [23••] found that serum leptin de-
intervention in both groups. In contrast to these two studies, creased similarly in both CR and ADF groups, and HOMA-
Bhutani et al. found that only subjects in the ADF plus exer- IR decreased more in the ADF group (− 42%) than in the CR
cise group experienced decreased fat mass, not those in the group (− 18%) [24].
ADF or exercise groups alone [22]. To further add complexity Another RCT reinforced these findings [20]. Subjects were
to the mixed results, other studies comparing IF and CER have randomized to one of three CR protocols: CER; carbohydrate-
seen similar weight effects in both groups [21, 27•, 31•, 35•]. and energy-restricted ICR with ad lib protein and fat (IECR+
For example, Catenacci et al. observed 8.8% weight loss in the PF); or carbohydrate- and energy-restricted ICR without ad lib
ADF group and 6.2% in the CER group after 8 weeks, though protein and fat (IECR) [20]. Both IECR groups experienced
the between group difference was only marginally significant greater improvements in Si than the CER group at 3 months.
[31•]. Both groups also experienced a larger reduction in body fat
While weight and fat mass decreased in most studies, it is than the CER group, although total weight loss at 3 and
important to consider protocol adherence and dropout rates in 4 months was not significantly different.
IF interventions. Some studies have found that the ADF group Because IF in animal studies were associated with de-
ate more than prescribed on fasting days and less than pre- creased serum glucose and insulin, these beneficial effects
scribed on feast days [23••]. Based on these findings, two were anticipated in humans. However, human trials have
questions arise. First, does IF, or simply the intervention itself, shown only stable or decreased fasting insulin with no change
lead to weight loss? Secondly, does the ADF intervention in fasting glucose [20, 21, 33, 39–41], which is a difficult
become CER in the real-world setting due to difficulty follow- endpoint to translate to the clinical setting. Thus, while some
ing the protocol? Furthermore, dropout rates have been as animal studies [42] suggest an association between IF and Si,
high as 40%. Thus, despite the statistical significance of the results may not be extrapolated to humans.
weight loss results, the clinical significance and practicality
of sustaining an IF regimen are questionable.

Cardiovascular Effects
Effects on Glucose Metabolism and Insulin
Sensitivity Limited literature exists on the cardiovascular effects of IF in
humans. A 2010 study in rats found that IF compared to daily
Si may be assessed by several methods, including HOMA-IR CR improves glycemic control and protects the myocardium
and hyperinsulinemic euglycemic clamp [36]. Halberg et al. against ischemia-induced cellular damage and inflammation
evaluated Si by hyperinsulinemic euglycemic clamp in eight [43]. ADF in male C57BL/6 mice for 4 weeks was associated
healthy men (BMI 25.7 ± 0.4 kg/m2) pre- and post-ADF with with a decreased proportion of visceral fat, increased
20 h of fasting [37]. Insulin-mediated glucose uptake was adiponectin, decreased resistin, and improved lipid profiles
assessed by glucose infusion rate (GIR). The final clamp [44]. IF also resulted in increased adiponectin prior to and
was performed after a 36 h fast. Although subjects maintained after induced myocardial infarctions [43].
stable weight, Si improved, as indicated by significant in- A 2016 crossover study of 10 healthy participants (BMI
creases in GIR, adiponectin, and inhibition of insulin- 25–45 kg/m2) found significant alterations in postprandial
mediated lipolysis. Soeters et al. sought to replicate these re- glucose and lipid metabolism [45•]. The study, which evalu-
sults in a crossover study of eight healthy men who followed a ated total (100%) and partial (75%) CR compared to no CR,
standard diet or ADF with 20 h of fasting for 2 weeks [38]. suggests that CER could alter cardiometabolic risk, indepen-
Weight remained unchanged. Unlike the Halberg study, dent of weight change [45•].
 Curr Obes Rep

Fasting is part of the Latter-Day Saints (LDS) religious post-intervention sera had increased SIRT1 levels and de-
practice. A meta-analysis of two observational studies on a creased TG. Additionally, post-intervention cells had de-
predominantly LDS population found that those who routine- creased proliferation, increased stress resistance, and upregu-
ly fasted were 35% less likely to develop coronary artery lation of longevity-inducing genes, all of which suggest that
disease (95% CI, 0.46–0.94) and 44% less likely to develop IF plays a role in aging and longevity [54]. However, a differ-
T2D (95% CI, 0.36–0.88) compared to those who followed ent 3-week ADF protocol (25% ER on fast days) was not
normal eating patterns [46]. Routine fasting was also associ- associated with changes in whole-blood SIRT1 RNA [40].
ated with a lower BMI. This population had a lower preva- Most studies assessing IF and aging are conducted on an-
lence of smoking, however, which may confound the associ- imals. Furthermore, evidence regarding biomarkers of aging
ation between fasting and clinical outcomes. Nonetheless, the and cognition is mixed, and the conclusions of these studies
findings suggest that IF could also alter cardiometabolic risk cannot yet be generalized to the larger population.
factors. Additionally, a randomized comparison of IF and
CER found comparable reductions in leptin, free androgen
index, C-reactive protein, total and LDL cholesterol, TG, Psychosocial Impact
and blood pressure as well as similar increases in sex hormone
binding globulin and insulin-like growth factor (IGF) binding Because long episodes of fasting may lead to large portions of
proteins 1 and 2 [21]. These findings reinforce the potential unhealthy foods at the end of the fast, it is questionable wheth-
cardioprotective effects of IF, though more studies need to be er weight loss benefits of IF can be maintained. Binge eating
conducted in humans. disorder (BED), which affects 2.8 million Americans, is espe-
cially prevalent among individuals with obesity and those
seeking weight loss [55]. BED is larger than normal food
Impact on Aging and Cognition consumption in a small time period, often accompanied by a
loss of control over eating [56]. Some studies suggest that IF
Animal models provide preliminary evidence that CR and IF may have implications on depression and BED.
may delay aging. Evidence includes improved biomarkers, Hoddy et al. found that 8 weeks of ADF in 59 subjects with
reduced oxidative stress, and preserved memory [47–49]. obesity decreased depression and binge eating (p < 0.01)
Oxidative stress is an imbalance between the production of [57••]. While the decrease in depression and binge eating
reactive oxygen species (ROS) and antioxidant defenses was statistically significant, it does not appear clinically sig-
[50]. Both CR and ADF diets reduce age-related deficits in nificant, as the absolute changes were minimal. Additionally,
cognitive and motor function in animal models. The combi- purgative behavior and fear of fatness remain unchanged, al-
nation of CR and IF has been found to promote longevity and though ADF increased restrictive eating and improved per-
increase resistance to age-related diseases in rodents and mon- ceived body image [57••]. It is important to consider whether
keys [48]. ADF in mice has been shown to reduce serum the decrease in depression and binge eating indicators is clin-
glucose and insulin and to increase neuronal resistance to in- ically significant enough to risk increased restrictive eating.
jury, even with isocaloric intake and stable weight [51]. Inbred Further, it is essential to define “restrictive eating” consistently
male mice following an ADF regimen have also shown among studies, as Bhutani et al. found that in subjects ran-
prolonged lifespan under certain conditions, but strong inter- domized to ADF or ADF plus exercise, restrained eating in-
actions exist between the genotype, age at initiation, and effect creased while uncontrolled eating decreased [22].
of ADF on body weight and aging [52]. While animal models Despite the acute psychosocial benefits that Hoddy et al.
have provided some promising results, the paucity of human and Bhutani et al. found, research studies should evaluate the
studies prohibit extrapolation of these effects to human long-term associations between IF, BED, and depression in
models. order to minimize risk of negative psychosocial effects. In
In a subset of subjects (n = 11), Heilbronn et al. found in- the interim, CER seems more appropriate for individuals at
creased muscle gene expression of SIRT1 post-ADF [39]. risk of any eating disorder, including BED.
SIRT1 is an enzyme that may be implicated in human longev-
ity [53]. Additionally, women had slightly impaired glucose
response though this did not change in men. Women had Interaction with the Gut Microbiome
unchanged insulin response, though there was a significant
reduction in men. Hence, there may be gender differences in The microbiome modulates adiposity and protects against the
the metabolic response to ADF. development of obesity-associated metabolic dysfunction.
The SIRT1 finding is consistent with another study in This recent discovery has sparked interest in modulators of
which human serum collected pre- and post-intervention was microbial balance. Preliminary animal models suggest that
used to culture hepatoma cells. Cells that were cultured in IF may be one of these modulators [58]. ADF in mice,
Curr Obes Rep

compared to isocaloric ad lib intake, induced white adipose tissue-specific effects on ROS balance in rats [72]. For exam-
tissue (WAT) beiging, weight loss, and changes in the gut mi- ple, biomarkers of oxidative damage were increased in the
crobiota, including an increase in the Firmicutes:Bacteroides liver and the brain but were reduced in the heart [72].
ratio [59]. This was associated with improvements in liver Hence, the effects of IF depend on the animal model, age at
steatosis and metabolic syndrome. However, in microbiota- initiation, and tissue sampled.
depleted mice, ADF did not improve obesity or liver steatosis, Autophagy is a catabolic process of nutrient recycling that
thus suggesting that the gut microbiota is necessary for ADF to is essential for defense against oxidative stress. Nutrient sens-
show these benefits. Furthermore, isocaloric ADF in mice mod- ing pathways induce autophagy [73]. IF has been shown to
ulates the gut microbiota, benefiting adiposity; this has been restore autophagic function, thereby preserving organelle
recently reviewed [60]. quality. This restorative function is impaired by insulin resis-
tance [74] and obesity-induced diabetes in mice fed a high fat
diet [75]. However, data on the mechanisms of IF in humans
Cellular Metabolism Underlying Effects of IF are limited. Twenty-three pre-menopausal women (BMI 25–
29.9 kg/m2) followed an ICR diet (2 days per week of 65%
In addition to its role as an energy carrier, beta- CR) for one menstrual cycle [76•]. After the intervention, 196
hydroxybutyrate (βOHB) binds to extracellular receptors metabolites increased (including βOHB and acylcarnitine)
and inhibits class I histone deacetylases, which may promote and 331 metabolites significantly decreased (including
resistance to oxidative stress [61, 62]. Thus, epigenetic mod- succinic acid, alanine, glutamic acid, and tyrosine). This group
ifications are likely driven by fasting-induced βOHB eleva- also compared the effects of their ICR protocol on the metab-
tions. Increases in βOHB alter gene expression in nutrient- olome in another group of pre-menopausal women and found
sensitive pathways that are implicated in longevity. βOHB many similar trends [77].
also has been shown to promote anti-inflammatory effects
by blocking activation of the NLRP3 inflammasome [63]
and activating a neuroprotective subset of macrophages in Inflammatory Effects
the mouse brain [64]. In addition to the association between
IF and neuronal resistance, animal studies have found that IF Oxidative stress is closely linked to inflammation. Ten sub-
can affect oxidative stress. jects with obesity and asthma followed an ADF protocol for
2 months [41]. Body weight decreased a mean 8% and peak
expiratory flow and asthma quality of life scores increased
Oxidative Stress [41]. This intervention was associated with significant reduc-
tions in inflammatory markers, including TNF-α and
CR reduces oxidative stress by limiting mitochondrial gener- ceramides, and markers of oxidative stress, including protein
ation of ROS and increasing endogenous antioxidant activity; carbonyls and 8-isoprostane.
this results in reduced oxidative damage to cellular proteins, In mice, IF increases vascular endothelial growth factor
lipids, and nucleic acids [65, 66]. However, IF has mixed (VEGF) in WAT, with associated alternative macrophage ac-
effects on oxidative stress in animal models [67]. In theory, tivation and WAT beiging [78••]. Gene expression of VEGF,
IF may induce hormesis, resulting in beneficial adaptive alternative macrophage activation, and beige adipocyte-
changes that include activation of AMP-activated protein ki- related proteins are also positively correlated in human AT.
nase, mitochondrial network and peroxisome remodeling, and This suggests that IF may regulate this same pathway.
increased production of antioxidant enzymes [47, 68, 69]. Fasting is associated with elevations in FFA and ketone bod-
In 8-month-old mice at high risk of lymphoma, ADF was ies, including βOHB, which may have opposing effects on
associated with a significant reduction in lymphoma (0 vs. inflammation. Elevated FFA during fasting may activate proin-
33% of controls), decreased spleen mitochondrial ROS gen- flammatory pathways [79] and reduce Si [80], while elevations
eration, and increased antioxidant superoxide dismutase activ- in βOHB may activate anti-inflammatory pathways and alter
ity [70]. However, Cerqueria reported increased oxidative fuel metabolism as reviewed above. Our group is currently
stress in 8-week-old Sprague-Dawley rats who underwent conducting a pilot clinical trial on the effects of dietary supple-
32 weeks of ADF [71]. The ADF group had worsened glucose mentation of medium chain triglycerides (MCT), which are
tolerance, lowered adiponectin, and increased insulin receptor metabolized into βOHB (NCT02783703). MCT supplementa-
nitration and release of ROS in intra-abdominal AT and mus- tion may activate anti-inflammatory pathways through βOHB
cle [71]. Hence unlike long-term CR, long-term ADF may be without the detriments of elevated FFAs.
associated with worsened Si and oxidative stress. Another FFA released from lipolysis in mast cells may play an im-
study further informed these mixed results. One month of portant role in eicosanoid release and control of immune acti-
ADF in 8-week-old Sprague-Dawley rats had complex, vation [81]. Saturated FFA induce an inflammatory response
 Curr Obes Rep

in macrophages while unsaturated FFA do not [82]. Hence, may also be potential contraindications to IF, including certain
FFA released from lipolysis play an important role in obesity- health conditions, medications, psychosocial barriers, and eat-
induced AT inflammation [83], immune regulation [84], and ing practices. Should IF become part of standard practice, a
stimulating hepatic VLDL production [85]. multidisciplinary approach should be used. Collaboration of
Sustained fasting is associated with acute hepatic steatosis registered dietitians, physicians, and other essential healthcare
and increased insulin resistance [86]. Normal weight subjects providers will ensure the safety of the patient and decrease the
who fasted for 72 and 120 h had increased intramuscular lipids possibility of adverse effects such as weight regain, depres-
(IMCL) [87, 88]. A 60-h fast in healthy males was associated sion, and BED.
with elevated IMCL, increased insulin resistance, and a nine-
fold elevation in FFA [87]. Prolonged elevations in FFA, com-
bined with metabolic syndrome and insulin resistance, con- Future Research
tribute to increasing hepatic IMCL and lipotoxicity, which
leads to nonalcoholic steatohepatitis [88]. However, ADF in Considering the American preference for highly palatable,
mice has been shown to induce metabolic changes that protect calorically dense foods, it is crucial for researchers and health
against steatosis [89]. Increases in ketogenesis during fasting practitioners to find unique strategies appropriate to this cul-
protects against steatohepatitis in mice [90]; thus, IF may have ture. Longer, statistically powered trials in humans are needed
these same protective effects in humans. to elucidate the current literature. First, the definitions of IF
The effects of IF on inflammation have been minimally regimens must be clearly defined. For instance, caloric intake
studied in humans. While cellular level mechanisms have on fast days should be consistent across ADF protocols. These
been evaluated in animal models, the application in human studies should account for the types of foods eaten on ad lib
models is scarce. Cellular analysis and animal models suggest days and how these choices influence weight loss and meta-
opposing influence of FFA and ketone bodies on inflamma- bolic markers.
tion. Despite understanding these cellular mechanisms, it is Future research should also determine whether outcomes
unclear whether IF has beneficial effects on oxidative stress differ by IF regimen. This would enable practitioners to better
and inflammation in human. recommend dietary changes. For instance, individuals seeking
weight loss may require a different IF regimen than those
pursuing cardioprotective benefits. There are several trials cur-
Clinical Implications rently underway that aim to determine the effects of IF on
numerous outcomes such as cancer, Alzheimer’s, diabetes,
While several rodent studies have demonstrated the statistical and longevity [93]. Given the positive outcomes thus far, IF
significance of IF on weight loss and metabolic biomarkers, it is may prove to be a promising approach to improving health
important to consider the clinical significance of these findings. once it is determined which individuals will best benefit and
For example, while LDL cholesterol levels at month 12 were be able to sustain it.
significantly in the ADF group, it is unlikely that an 11 mg/dL
difference would have implications on provider recommenda-
tions. Additionally, human studies suggest that IF regimens are Conclusions
difficult to sustain due to dietary restrictions [18, 51] and im-
plications on hunger and satisfaction [18, 71, 91]. Animal models and human trials suggest that IF may have
Research is not robust enough to suggest that healthcare beneficial effects on weight, body composition, cardiovascu-
professionals should be recommending IF to patients as stan- lar biomarkers, and aging. At the cellular level, IF may also
dard practice. It is unknown which individuals would most increase resistance against oxidative stress, decrease inflam-
benefit from IF and which form of IF is most effective. It is mation, and promote longevity. However, studies vary greatly
anticipated that IF would most benefit motivated individuals on their definition of IF, the prescribed protocol, and the du-
who are able to avoid overeating following fasting periods. ration of IF. Additionally, the studies have been conducted in
Further, individuals who are highly involved in social events diverse populations with mixed results.
may find it difficult to comply with IF regimens, and skipping Due to the increasing prevalence of overweight and obesi-
social events because they occur during planned fasting pe- ty, Americans are searching for effective weight loss methods.
riods is unlikely to be beneficial or sustainable. Additionally, The paucity of research on IF makes it difficult to prescribe IF
the decision to follow an IF regimen depends on the individ- as a reliable method for successful long-term weight loss and
ual’s goals and desired outcomes. For those interested in maintenance. However, IF appears to be a viable weight loss
weight loss methods, CER may be easier and as effective as method, though CER may be as effective. It is important to
IF [92]. Those interested in increasing their FFM may benefit consider desired outcomes when choosing whether an IF is an
more by combining IF with endurance exercise [22]. There appropriate diet. Given that CR is a proven method of weight
Curr Obes Rep

loss, more research is needed to assess whether IF is a sustain- 7. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose
fatty-acid cycle. Its role in insulin sensitivity and the metabolic
able treatment for obesity as well as if the benefits of IF are
disturbances of diabetes mellitus. Lancet. Elsevier. 1963;281:785–
maintained long-term. 9. https://doi.org/10.1016/S0140-6736(63)91500-9.
8. Hue L, Taegtmeyer H. The Randle cycle revisited: a new head for
Funding Sources This work was supported in part by the National an old hat. Am. J. Physiol. Metab. Am Physiological Soc.
Institutes of Health [UL1TR001430, P30DK046200, T32DK007201]. 2009;297:E578–91. https://doi.org/10.1152/ajpendo.00093.2009.
9. Gropper S, Smith J. Integration and regulation of metabolism and
the impact of exercise and sport. In: Feldman E, Cronin S, Myers
Compliance with Ethical Standards M, editors. Advanced nutrition and human metabolism.
Wadsworth, Cengage Learning. 2013. p. 256–9.
Conflict of Interest Mary-Catherine Stockman declares that she has no 10. Unger RHH. Roth MGG. A new biology of diabetes revealed by
conflict of interest. leptin. Cell Metab. Elsevier. 2015;21:15–20. https://doi.org/10.
Dylan Thomas declares that he has no conflict of interest. 1016/j.cmet.2014.10.011.
Jacquelyn Burke declares that she has no conflict of interest. 11. Azzout B, Bois-Joyeux B, Chanez M, Peret J. Development of
Caroline M. Apovian has received research funding through grants gluconeogenesis from various precursors in isolated rat hepatocytes
from Sanofi-Aventis, Orexigen, Aspire Bariatrics, GI Dynamics, MYOS, during starvation or after feeding a high protein, carbohydrate-free
Takeda, Gelesis, Vela Foundation, Dr. Robert C. and Veronica Atkins diet. J Nutr. 1987;117:164–9. Available from: http://jn.nutrition.org/
Foundation, Coherence Lab, Energesis, Patient-Centered Outcomes content/117/1/164.short.
Research Institute (PCORI), the National Institutes of Health (NIH), Eli 12. Cahill GF. Fuel metabolism in starvation. Annu Rev Nutr. 2006;26:
Lilly, and MetaPrteomics LLC; has received compensation from 1–22. https://doi.org/10.1146/annurev.nutr.26.061505.111258.
Nutrisystem, Zafgen, Sanofi-Aventis, Orexigen, Novo Nordisk, GI 13. Wasserman DH. Four grams of glucose. Am. J. Physiol. Metab..
Dynamics, Takeda, Scientific Intake, Gelesis, Merck, Johnson & American Physiological Society. 2009;296:E11–21. https://doi.org/
Johnson, Amylin, EnteroMedics, Arena Pharmaceuticals, Rhythm 10.1152/ajpendo.90563.2008.
Pharmaceuticals, and Xeno Biosciences for service on advisory boards; 14. Stannard SR, Thompson MW, Fairbairn K, Huard B, Sachinwalla
and owns stock in Science-Smart LLC. T, Thompson CH, et al. Fasting for 72 h increases intramyocellular
lipid content in nondiabetic, physically fit men. Am. J. Physiol.
Human and Animal Rights and Informed Consent This article does not Metab.. American Physiological Society. 2002;283:E1185–91.
contain any studies with human or animal subjects performed by any of https://doi.org/10.1152/ajpendo.00108.2002.
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