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Purpose of review: Obesity and obesity-related diseases, largely resulting from urbanization and behavioral changes, are now of global importance. Energy restriction, though, is associated with health improvements and increased longevity. We review some important mechanisms related to calorie limitation aimed at controlling of metabolic diseases, particularly diabetes. Recent findings: Calorie restriction triggers a complex series of intricate events, including activation of cellular stress response elements, improved autophagy, modification of apoptosis, and alteration in hormonal balance. Intermittent fasting is not only more acceptable to patients, but it also prevents some of the adverse effects of chronic calorie restriction, especially malnutrition. There are many somatic and potentially psychologic benefits of fasting or intermittent calorie restriction. However, some behavioral modifications related to abstinence of binge eating following a fasting period are crucial in maintaining the desired favorable outcomes.
The main depots of human adipose tissue (AT) types according to their relative amounts, functional specificities and the clinical significance are listed (a). Discrete functional-metabolic, endocrine and expanding characteristics of human AT depots, primarily that of subcutaneous- and the visceral depots, can influence metabolic health/risk. Thus, in contrast to subcutaneous depots, visceral depots are less sensitive to insulin, express higher levels of pro-inflammatory adipocytokines and grow mostly by adipocyte hypertrophy. Accordingly, subjects with more visceral AT can have a restricted (short term) capacity to buffer high calorie (nutritional) overload, and ultimately develop a higher risk insulin resistance and diabetes. Depots of AT in humans are predominantly white fat which is able to store lipids and have limited numbers of mitochondria. In contrast, brown and beige/bright adipocytes contain significantly more mitochondria that are rich in uncoupling protein-1 (UCP1), which regulates oxidative phosphorylation from ATP synthesis and energy dissipating as heat. Some depots of AT in newborn babies (interscapular), as well as in adults (deep neck, supraclavicular) are brown fat (a, right), and bright UCP1 containing adipocytes can be found within various AT depots, visceral and subcutaneous. Increases of the relative amounts of brown adipose tissue, brown/bright adipocytes in white AT, and the brown-like functional characteristics of white adipocytes—browning (b), may have greater relevance in obesity and diabetes type 2 treatment
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Health Benefits of Fasting and Caloric Restriction
Saeid Golbidi
&Andreas Daiber
&Bato Korac
&Huige Li
&M. Faadiel Essop
Ismail Laher
#Springer Science+Business Media, LLC 2017
Purpose of Review Obesity and obesity-related diseases,
largely resulting from urbanization and behavioral changes,
are now of global importance. Energy restriction, though, is
associated with health improvements and increased longevity.
We review some important mechanisms related to calorie lim-
itation aimed at controlling of metabolic diseases, particularly
Recent Findings Calorie restriction triggers a complex series
of intricate events, including activation of cellular stress re-
sponse elements, improved autophagy, modification of apo-
ptosis, and alteration in hormonal balance. Intermittent fasting
is not only more acceptable to patients, but it also prevents
some of the adverse effects of chronic calorie restriction, es-
pecially malnutrition.
Summary There are many somatic and potentially psycholog-
ic benefits of fasting or intermittent calorie restriction.
However, some behavioral modifications related to abstinence
of binge eating following a fasting period are crucial in main-
taining the desired favorable outcomes.
Keywords Calorie restriction .Diabetes .Adipose tissue .
Oxidative stress
It is abundantly clear that the obesity epidemic has affected
most countries in the Middle East more severely [1,2,3,4,
5]. It is disconcerting that increases in the rates of obesity and
type 2 diabetes continue unabated in spite of great efforts at
sounding the alarm of the health costssuggesting that the
many conferences, scientific articles, and public alerts have so
far had little impact in changing lifestyle choices. Another
approach is to harness the health and spiritual benefits of
obligatory and voluntary religious fasts, which are routinely
practiced in the Middle East, as an added means of producing
lasting lifestyle changes that will ultimately lead to improved
health outcomes. Fasting is an age-old practice that has been
prescribed in many religions and requires caloric restrictions
of various durations and formats [6,7]. Examples of religious
fasting regimens are shown in Table 1. We review the mech-
anisms by which periodic caloric restriction, through obliga-
Fasting by Muslims in the Middle East
Fasting during Ramadan displays some overlap with alternate-
day fasting as in both instances there are recurring periods of
fasting and feeding. However, alternate-day fasting involves
alternating 24-h periods of fasting and feasting while water
This article is part of the Topical Collection on Lifestyle Management to
Reduce Diabetes/Cardiovascular Risk
*Ismail Laher
Faculty of Medicine, Department of Pharmacology and Therapeutics,
The University of British Columbia, 2176 Health Sciences Mall,
Vancouver V6T 1Z3, Canada
Center of Cardiology, Cardiology 1, Medical Center of the Johannes
Gutenberg University, Mainz, Germany
Department of Physiology, Institute for Biological Research Sinisa
Stankovic, University of Belgrade, Belgrade, Serbia
Department of Pharmacology, Medical Center of the Johannes
Gutenberg University, Mainz, Germany
Department of Physiological Sciences, Stellenbosch University,
Stellenbosch, South Africa
Curr Diab Rep (2017) 17:123
intake is also allowed [6]. The data on the health benefits of
fasting remain inconclusive as some studies show lower,
higher, or no changes in nutrient intake during Ramadan [7].
Similar findings exist for BMI, blood metabolites profile (glu-
cose, lipids), and the onset of cardio-metabolic diseases [7].
Fasting times vary according to geographical location and
season. There are also cultural differences that likely impact
dietary intake and smoking patterns.
Unique cultural practices in the Middle East and North
Africa (MENA) region during Ramadan likely offset potential
benefits usually achieved by caloric restriction. A meta-
analysis reports that East Asian individuals displayed more
significant weight loss during Ramadan when compared to
West Asian populations [7]. Furthermore, others established
increased energy intake in Saudi Arabia when compared to
other countries [e.g., India] during Ramadan [8]. Thus, we
hypothesize that individuals within the MENA countries dis-
play unique cultural/behavioral patterns that pre-dispose them
to increased risk for the onset of cardio-metabolic diseases.
Although the major factor[s] driving this process remain un-
clear, we propose that altered circadian rhythms during
Ramadan may have a central role as the usual circadian
rhythm among fasting Muslims in this region is significantly
altered during Ramadan, with fasting individuals generally
remaining awake during the night while spending most of
the day sleeping [9,10].
Disturbances in circadian rhythms are linked with cardio-
metabolic diseases onset, as Ramadan fasting may affect the
timing of acute coronary event presentation [11] and moreover
that systemic cortisol levels are disrupted during Ramadan in a
Saudi Arabian cohort, with high levels during the evenings
compared to mornings [12]. Of note, such changes in cortisol
levels are typically associated with the metabolic syndrome,
e.g., hypercortisolemia is linked to insulin resistance due to
impaired insulin secretion and increased hepatic glucose out-
put [13,14]. Sleep deprivation also triggers a pro-
inflammatory milieu and micro/macro-vascular changes
linked to impaired vascular stimulation following a flow-
mediated dilation test. Altered adipokine levels also occur,
with increased circulating leptin and decreased adiponectin
in a Saudi Arabian cohort during Ramadan. Such an altered
adipokine signature is usually linked to insulin resistance. To
further compound the issue, there is excessive food intake
[gorging] during Ramadan nights in some of these countries
that will further fuel metabolic syndrome-like features such as
increased weight gain and insulin resistance [15]. In addition,
active/passive smoking is widespread in this region and fur-
ther fuels cardio-metabolic diseases [16,17]. For example,
Ramahi et al. [17] examined a Jordanian cohort and
established that indoor pollution (due to increased smoking
activity) increased to unsafe levels during Ramadan after
breaking of the fast. In light of these findings, we propose that
altered circadian rhythms during Ramadan trigger down-
stream effects that eventually contribute to the onset of
cardio-metabolic diseases (Fig. 1).
Intermittent Caloric Restriction [Fasting]
Calorie restriction (CR) is associated with health improve-
ment, increased longevity, and a reduction of morbidity and
mortality in animal studies [1922]. Calorie control also ben-
efits cardiovascular status, weight reduction, insulin sensitiv-
ity, diabetes control, cognitive function, and cancer prevention
among its many effects in humans [2326]. However, CR is
difficult to practice and increases the risk of malnutrition.
Intermittent fasting (IF) reduces the risk of malnutrition and
is easier to follow and is gaining popularity with health ex-
perts. We review some mechanistic insights for the health
benefits of IF.
Tissue Changes Following Energy Intake
Restriction: Putative Mechanisms
Stress-Activated Pathways
IF activates stress-induced pathways and increases transcrip-
tion of stress-induced proteins such as heat shock protein
Tabl e 1 Common fasts and their dietary restrictions in some religions
Religion Timing of fast Etiquette
Bahai 19 days (210 March) No food/drinks from sunrise to
Buddhist Usually on full-moon days and
other holidays
No solid food; some liquids
Catholics Ash Wednesday and Good
No meat (and no meat on
Fridays during Lent). Small
meals allowed
Fast periods include Lent,
ApostlesFast, Dormition
Fast, Nativity Fast. Also
includes every Wednesday
and Friday
No meat, dairy products, eggs.
Fish prohibited on some
fast days
Hindu New moon days, some
festivals such as Shivaratri,
Saraswati Puja, and Durga
Can involve 24 h of full
abstinence from al foods
and liquids; commonly
practiced with abstinence
from solid food
Islam 2830 days of Ramadan
(obligatory) and each
Monday and Thursday
No food /water from sunrise to
Jewish Yom Kippur, the Day of
Atonement, and 6 other
days of minor fasts
No food/drinks from sunset to
sunset (and from sunrise to
sunset for minor fasts
Mormon First Sunday of each month No food/water for two
consecutive meals
123 Page 2 of 11 Curr Diab Rep (2017) 17:123
(HSP) 70 [27]. Increased HSPs are a generic cellular response
to harsh conditions including oxidative stress [28], hypoxia
[29], protein degradation [30], and energy depletion [31].
HSPs attach to unfolded or misfolded proteins and restore
normal configurations [32] and have anti-inflammatory and
anti-apoptotic properties [33]. Decreased levels of HSPs occur
in skeletal muscles of diabetic patients, possibly related to
insulin resistance [3436]. This phenomenon may in part ex-
plain some of the metabolic benefits of IF, since elevations in
HSPs mitigate insulin resistance, glucose intolerance, and
diet- or obesity-induced hyperglycemia in animal studies [37].
Improved Autophagy
IF promotes cellular autophagy [38], a process by which
distorted molecules and impaired organelles are eliminat-
edthus providing cells with a limited supply of energy from
recycled materials. Cellular senescence is associated with re-
duced autophagy and accumulation of malfunctioning constit-
uents. CR attenuates the effects of aging on autophagy and
maintains cellular rejuvenation [39]. The role of sirtuin-1
(SIRT-1), a NAD
-dependent deacetylase, in the regulation
of autophagy has been shown in several cell lines (including
human cells). Caloric restriction stimulates sirtuin-1 activity
and enhances autophagy, while its pharmacological inhibition
is accompanied by decreased autophagy and accumulation of
biomarkers of aging [40].
Reduction of Advance Glycation End-Products [AGEs]
by Intermittent Fasting
Another putative mechanism for the beneficial effects of
fasting is reduced levels of AGEs that result from non-
enzymatic attachments of carbohydrate molecules to proteins,
lipids, or nucleic acids, mostly during normal metabolism but
also in the process of food cooking at high temperatures [41,
42]. Foods rich in AGEs include red meats, cheeses, and proc-
essed grains. There is increased production or reduced excre-
tion of AGEs in diabetes, where this can initiate several path-
ophysiologic processes [43]. Mice exposed to a diet low in
AGEs have extended mean and maximum life spans [44].
AGEs exert their functions through reaction with AGE recep-
tors, which are multiligand receptors that can also be activated
by other ligands with similar three-dimensional structures
[45]. Activation of AGE receptors on macrophages/
mesangial cells increases production of growth factors and
several pro-inflammatory cytokines, including nuclear factor
kappa B (NF-κB). Since AGE receptor signaling can override
cellular regulatory mechanisms, it perpetuates pro-
inflammatory cytokine production [46]. NF-κB and other pro-
inflammatory mediators in turn increase the expression of
AGE receptors [47] so that a short inflammatory circuit is
turned to a long-lasting process by a positive-feedback loop.
This provides a link between inflammation and oxidative
stress through a positive-feedback loop whereby ROS acti-
vates AGE/RAGE signaling [47] and RAGE stimulation in-
duces oxidative stress [48,49]. Serum AGEs levels can be
reduced by a low-calorie diet, which also reduces triglycer-
ides, waist circumference, and body mass index BMI [50,51].
In a study of ten patients with rheumatoid arthritis, 54 days of
IF significantly decreased urinary excretion of pentosidine (an
AGE) along with a reduction in severity of the rheumatologic
markers [52].
Hormonal Changes
CR and IF increase adiponectin levels in humans and labora-
tory animals [53,54]. This adipose-secreted protein is inverse-
ly related to body weight, adiposity, and insulin-resistance
[55]. Adiponectin modulates insulin activity [56] and also
reduces insullin levels and beta cell dysfunction [57,58].
Lower levels of adiponectin occur in patients with diabetes
[59]. Long-lived humans and animals have increased levels
of adiponectin [6063]. For instance, Ames mice have
adiponectin levels that are three times higher than control mice
[64]. It is hypothesized that the propensity of adiponectin to
shift metabolism from glucose burning to fat burning reduces
oxidative stress and promotes longevity [38]. Dietary manip-
ulation of four strains of mice [obese-prone C57BL/6, genet-
ically obese ob/ob, obese-resistant A/J and peroxisome
proliferator-activated receptor-αgene knockout] strongly
Fig. 1 Disturbances in circadian rhythms related to sleep/awake cycles,
nutritional and smoking patterns may be a unifying factor that eventually
contributes to the onset of cardio-metabolic diseases. Such changes can
increase psycho-social stress and circulating cortisol levels, triggering
oxidative stress and inflammation (systemically and target organs).
Such events, with/without a genetic pre-disposition, can lead to a
tipping pointbeing reached that will result in pathological outcomes
as indicated [18]
Curr Diab Rep (2017) 17:123 Page 3 of 11 123
suggests that it is the amount of calories, rather than the fat
content, that is the major determinant of adiponectin secretion
[65]. Adiponectin also mediates the cardiovascular benefits of
IF as shown in animal studies [66]; however, its prognostic
value in human disease has been questioned as higher levels of
adiponectin are associated with less favorable outcomes in
congestive heart failure [54](Fig.2).
Tissue and Metabolic Changes
Adipose Tissue
The complex role of adipose tissue (AT), white and brown
(WAT and BAT, respectively) in overall energetic homeosta-
sis, in both physiological and pathological conditions is intri-
cately linked with lipid (fatty acid, FA) metabolism in AT- and
non-AT (muscle, heart), where the liver acts as an integrative
metabolic organ (Figs. 3and 4).
There are three sources of FA: food intake, storage from
white adipose tissue (WAT), and de novo synthesis (mainly in
liver and also in AT). Together with other lipids, FA from
different sources (in the form of triacylglycerols, TAG) are
packaged in lipoprotein particles: chylomicrons in the intes-
tine and VLDL (very-low-density lipoproteins) in the liver
and through lymphatic or blood vessels move to capillary of
extrahepatic tissues [67,68].
All aspects of AT biology are connected with the develop-
ment of metabolic disorders, including metabolic syndrome,
obesity, cardiovascular diseases, type II diabetes, cancer, and
neurodegenerative disorders. This involves the following spe-
cific alterations: morphological and cellular (hypertrophy/hy-
perplasia/atrophy), metabolic (ratio of lipolysis/lipogenesis
and degree of re-esterification and releasing of adipocyte
FA, level of FFA in circulation, and balance of re-
esterification of FA between AT and liver), and physiological
and endocrine (production of adipocytokines with depot-
specific signature).
IF affects WAT cellularity at the level of the size of
adipocytes. Studies in humans show that enlarged sub-
cutaneous abdominal adipocyte size, but not obesity it-
self, predicts type II diabetes [69]. Increases in fat cell
size (hypertrophic obesity) play a more important role
in metabolic diseases than increases in fat cell number
(hyperplastic obesity)[70]. The authors suggest that
larger adipocytes have higher capacity for TAG synthe-
sis and lipolysis. Consequently, higher FA release from
WAT and flux of FFA in circulations contribute to met-
abolic diseases [70]. Another study [71] reports that
inguinal (subcutaneous depot) and epididymal (visceral
depot) fat cells were smaller in IF. The large reduction
in adipocyte size of both WAT depots correlates with
their increased insulin sensitivity, likely due to increases
in insulin receptor number [72]. Studies in animals and
humans demonstrate that IF and CR positively modulate
the secretory signatures of adipocyte cytokines by de-
creasing secretion of pro-inflammatory mediators and
the development of a pro-inflammatory phenotype in
WAT [73,74••].
Experiments by Ding et al. [75] showed that fasting
for up to 24 h significantly reduced the body weight of
both male and female mice, with moderate reductions in
weight of subcutaneous visceral fat depots. Recent results
of Fabbiano et al. [76] show that long-term CR or IF
regimens stimulate browning of WAT. Indeed, induction
of browningin WAT or transplantation of BAT is con-
sidered by some to have a therapeutic potential [77].
Stimulation of browningin WAT by dietary means can
influence body weight and the potential success of anti-
obesity therapies. Hence, even though induction of
browningin WAT is logically contrary to the physiolog-
ical response to negative energy balance due to IF and
Hsp27 ↑
Cytokines ↓ AGE/RAGE ↓
Caloric restricon / intermient fasng
Decreased vascular dysfuncon, cardiovascular
risk and/or mortality
Lepn ↓
Ghrelin ↑
Insulin/IGF-1 ↓
AMPK ↑ ROS ↓ Nrf2 ↑
Fig. 2 Some of the mechanisms
involved in cardiovascular effects
of intermittent fasting
123 Page 4 of 11 Curr Diab Rep (2017) 17:123
CR, it should be kept in mind that different food constit-
uents and intermediary metabolites can induce browning
of WAT. For example, lactate and the ketone body β-
hydroxybutyrate [78] are strong browninginducers,
while the amino acid L-arginine improves all metabolic
aspects in WAT and BAT, and has the potential to induce
browning[79,80]. Similar effects are also produced by
exercise training where browningof WAT occurs in vis-
ceral and especially subcutaneous adipose depots [80].
Diabetes Mellitus
A popular method of IF involves 1 day of eating followed by a
day of fasting, while others suggest 20 h of fasting followed
by 4 h of eating time or 16 h of fasting followed by 8 h of
eating [81]. Several clinical trials have compared IF vs CR;
however, to our knowledge, there is no clinical study compar-
ing the various IF protocols with each other. For instance,
Adrienne et al. compared IF and CR in type II diabetic patients
Fig. 3 General overview of lipid
metabolic pathways in the body
with the accent to white adipose
tissue (WAT) biology (for
explanation see text). BAT, brown
adipose tissue; TAG,
triacylglycerols; FA, fatty acids;
FFA, free fatty acids; VLDL,
very-low-density lipoproteins;
LPL, lipoprotein lipase; HSL,
hormone sensitive lipase
Curr Diab Rep (2017) 17:123 Page 5 of 11 123
Fig. 4 The main depots of human adipose tissue (AT) types according to
their relative amounts,functional specificities and the clinical significance
are listed (a). Discrete functional-metabolic, endocrine and expanding
characteristics of human AT depots, primarily that of subcutaneous- and
the visceral depots, can influence metabolic health/risk. Thus, in contrast
to subcutaneous depots, visceral depots are less sensitive to insulin,
express higher levels of pro-inflammatory adipocytokines and grow
mostly by adipocyte hypertrophy. Accordingly, subjects with more
visceral AT can have a restricted (short term) capacity to buffer high
calorie (nutritional) overload, and ultimately develop a higher risk
insulin resistance and diabetes. Depots of AT in humans are
predominantly white fat which is able to store lipids and have limited
numbers of mitochondria. In contrast, brown and beige/bright adipocytes
contain significantly more mitochondria that are rich in uncoupling
protein-1 (UCP1), which regulates oxidative phosphorylation from ATP
synthesis and energy dissipating as heat. Some depots of AT in newborn
babies (interscapular), as well as inadults (deep neck,supraclavicular) are
brown fat (a, right), and bright UCP1 containing adipocytes can be found
within various AT depots, visceral and subcutaneous. Increases of the
relative amounts of brown adipose tissue, brown/bright adipocytes in
white AT, and the brown-like functional characteristics of white
adipocytesbrowning (b), may have greater relevance in obesity and
diabetes type 2 treatment
123 Page 6 of 11 Curr Diab Rep (2017) 17:123
[82]. They found that even though CR is superior in terms of
weight reduction, CR and intermittent fasting had comparable
effects in visceral fat mass reduction, fasting insulin, and in-
sulin resistance. IF also improves metabolic parameters in
non-diabetic individuals [83]. Data related to adherence rates
were not reported in the study [83]. Intermittent fasting dimin-
ishes fat mass while preserving lean body mass, as opposed to
daily CR, which results in reduced fat and lean body mass
Dietary modification is a critical factor in the management
of diabetes. In a 20-year longitudinal study of Rhesus mon-
keys, CR lowered age-related diseases including diabetes,
where 5 of 38 control animals developed diabetes and another
11 being pre-diabetic, while animals experiencing CR showed
no impairment of glucose homeostasis [85]. IF leads to similar
outcomes in both diabetic and pre-diabetic individuals, as a 1-
kg reduction of body weight is associated with 16% reduction
in diabetes risk [86]. A number of studies confirm the effec-
tiveness of IF in reducing risk factors for diabetes or its com-
plications. For instance, intermittent fasting reduces visceral
fat, an important site for producing TNF-αin diabetic patients
[87]. Reductions of visceral fat after 6 to 24 weeks of IF have
been reported in several studies [74••,8891]. In almost all of
these investigations, reductions of visceral fat paralleled loss
of body weight. IF decreases fasting glucose and insulin levels
in non-obese [92], overweight/obese [90,91], and diabetic
individuals [93] with simultaneous improvements in insulin
Several mechanisms have been proposed to explain the
modifying effects of CR on glucose metabolism. First, re-
duced energy intake reduces pancreatic cell apoptosis, as
shown in diabetic rats where caloric restriction attenuates beta
cell apoptosis [94]. Improved insulin sensitivity increases the
expression of SIRT-1 [94]. It is likely that SIRT-1 adjusts
hepatic gluconeogenic/glycolytic pathways in response to
CR. SIRT-1 increases hepatic glucose output by affecting
PPARγco-activator alpha [PGC]-1α[95]. Overexpression
of SIRT-1 in mice increases metabolic rate and reduces
weight, blood cholesterol, adipokines, fasting blood sugar,
and insulin levels [96]. In other words, SIRT-1 activity pro-
motes the beneficial effects of CR. The life extending effects
of CR is lost in SIRT1 deficient mice [97]. Six months of CR
in overweight adolescents also increased expression of SIRT-1
and other genes whose protein products are essential for mi-
tochondrial function [98].
The aggravating effects of oxidative stress in the pathogen-
esis of diabetes and its complications [99] include impeding
the ability of endothelial cells to combat glucotoxicity associ-
ated with an array of the cardiovascular consequences of
diabetes [100]. Hyperglycemia triggers several pathways
that lead to the mitochondrial and non-mitochondrial pro-
duction of reactive oxygen species [ROS] that participates
in the pathogenesis of diabetes-induced vascular damage
[101]. Increased levels ROS inhibit the activity of
glyceraldehyde-3-phosphate dehydrogenase [GAPDH] and
lead to increased concentrations of glyceraldehyde-3-
phosphate [GA3P] and other upstream glycolytic interme-
diates. Levels of methylglyoxal, which are elevated by
GA3P, lead to [i] increased production of AGE and [ii]
activation of protein kinase C (PKC), which has a number
of effects including reduced activity of endothelial nitric
oxide synthase [eNOS], production of ROS by the phago-
cyte NADPH oxidase isoform, over-activity of the coagu-
lation system, increased expression of some growth fac-
tors, and stimulation of NF-κB all of which promote an
inflammatory state. Non-mitochondrial origins of ROS in-
clude NAD[P]H oxidase, xanthine oxidase, uncoupled
eNOS, lipoxygenase, cyclooxygenase, cytochrome P450
enzymes, and other hemoproteins [102].
CR boosts the activity of endogenous antioxidant systems.
In a study of 46 overweight [BMI 2529.9] individuals,
6 months of CR increased plasma glutathione peroxidase ac-
tivity and reduced plasma protein carbonyl levels, which were
associated with non-significant decreases in plasma 8-epi-
prostaglandin F2αlevels [103]. The antioxidant effects of
CR manifest several days after initiation of the diet, as shown
in a study of 40 overweight/obese women [BMI 32 ± 5.8]
where F2-isoprostane concentrations were reduced after 5 days
of a 25% CR diet [104].
Many epidemiologic studies indicate an association
between reduced food intake and lower cardiovascular
diseases [105,106]. As mentioned before, CR reduces
oxidative stress in endothelial cells, a phenomenon that
is associated with increased expression of eNOS. SIRT-1
acetylates lysine residues to enhance eNOS activity
[107]. Greater bioavailability of eNOS-derived nitric ox-
ide (NO), associated with decreased ROS, reduces blood
pressure in both animal and human studies following
CR [108,109]. Apart from its vasodilating effects, NO
also reduces oxidative stress and has anti-inflammatory
properties [110]. Furthermore, the anti-proliferative ef-
fects of NO in vascular smooth muscle coupled with
its inhibitory action on platelet aggregation and inflam-
matory cell adhesion play a significant role in preven-
tion of atherosclerosis [105]. Several cytokines [e.g., IL-
6, IL-1β,IL-17A,TNF-α] are positively correlated with
cardiovascular outcome [111] and CR suppresses in-
flammatory pathways.
In light of the fact that the majority of parameters that are
changed by caloric restriction and IF [e.g., nuclear factor ery-
throid 2-related factor 2 (Nrf2) activation, decreased oxidative
stress, lower leptin levels, activation of AMP-activated protein
kinase (AMPK), higher adiponectin levels, suppressed AGE/
RAGE signaling and inflammation] is associated with de-
creased cardiovascular risk and mortality, it is not surprising
that CR/IF is highly beneficial for the aging heart and
Curr Diab Rep (2017) 17:123 Page 7 of 11 123
vasculature [112]. This evidence is supported by a systematic
review of three randomized controlled clinical trials of fasting
in humans reporting improvements in weight and other risk-
related outcomes as well as two observational clinical out-
come studies of fasting in humans showing an association
with a lower prevalence of coronary artery disease or new
onset of diabetes [113].
This brief overview summarizes some of the mecha-
nisms that are activated by intermittent fasting. The ben-
efits of fasting are described in some detail based on
findings from experimental animal studies, and epidemi-
ologic studies that confirm beneficial outcomes in hu-
man populations. Despite the many efforts to increase
awareness of the obesity/diabetes epidemic that appears
to be affecting the Middle East to a greater extent than
other regions, the prevalence of cardio-metabolic dis-
eases continues unabated [1,2,3,5]. A solution, at
least in part, may be found in religious edicts in the
Middle East where people of various religious persua-
sions fast regularly. In spite of the well-known health
benefits of intermittent caloric restriction, the prevalence
of obesity continues to escalate, with seemingly little
efforts for limiting overall energy intake. Fasting or pe-
riodic calorie restriction also prevents unwanted effects
of chronic energy restriction such as malnutrition.
Intermittent fasting, by acting as acute intermittent
stressor, activates stress-response pathways that lead to
improvement in well-being. Finding optimal methods of
fasting, in terms of the intensity of calorie restriction
and duration is proposed as a method to alleviate many
metabolic diseases. The requirement of many religions
in the Middle East to fast, either as obligatory fasts or
optional fasts, not only fulfills religious obligations but
has the added benefit of stemming the rising tide of
Compliance with Ethical Standards
Conflict of Interest Saeid Golbidi, Andreas Daiber, Bato Korac, Huige
Li, M. Faadiel Essop, and Ismail Laher declare that they have no conflict
of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
Papers of particular interest, published recently, have been
highlighted as:
Of importance
•• Of major importance
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... Dietary caloric restriction (CR), without severe nutritional deprivation, has been shown to exert an anti-inflammatory effect by modulating mitochondrial metabolism and autophagic flux, protecting the intestinal barrier, dampening inflammation, and inhibiting the transcription of critical genes such as NF-kB [406]. Increasing evidence suggests potential benefits from intermittent fasting and caloric restriction on markers of health and longevity [407,408]. During CR, there is a decline in glycolytic rates in favor of respiratory metabolism as the main energy source. ...
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Increasing evidence on the significance of nutrition in reproduction is emerging from both animal and human studies, suggesting a mutual association between nutrition and female fertility. Different “fertile” dietary patterns have been studied; however, in humans, conflicting results or weak correlations are often reported, probably because of the individual variations in genome, proteome, metabolome, and microbiome and the extent of exposure to different environmental conditions. In this scenario, “precision nutrition”, namely personalized dietary patterns based on deep phenotyping and on metabolomics, microbiome, and nutrigenetics of each case, might be more efficient for infertile patients than applying a generic nutritional approach. In this review, we report on new insights into the nutritional management of infertile patients, discussing the main nutrigenetic, nutrigenomic, and microbiomic aspects that should be investigated to achieve effective personalized nutritional interventions. Specifically, we will focus on the management of low-grade chronic inflammation, which is associated with several infertility-related diseases.
... By lowering blood glucose and cholesterol levels, decreasing the generation of late glycosylation final products and inflammatory cytokines, boosting the release of heat shock proteins and adiponectin, and speeding up cellular selfphagocytosis, IF can reduce the inflammatory response in DR (62,63). ...
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Intermittent fasting (IF) is gaining popularity as a therapeutic dietary strategy that regulates metabolism and can alter the development of metabolic disorders. An increasing amount of research has connected ocular diseases to IF and discovered that it has a direct and indirect effect on the eye’s physiological structure and pathological alterations. This article summarizes the progress of research on IF in regulating the physiological structures of the ocular vasculature, the anterior segment of the eye, the retina, and the choroid. We explored the therapeutic potential of IF for various common ocular diseases. In the future, a comprehensive study into the fundamental processes of IF will provide a direct and rigorous approach to eye disease prevention and therapy.
... In summary, our findings suggest that intermittent fasting can affect the composition and diversity of intestinal microbiota, and hence microbial metabolites, possibly resulting in different effects on human health. Other studies have also shown that intermittent fasting can have profound beneficial effects on animal and human health (49)(50)(51)(52)(53), although fastingbased interventions most commonly focus on young, healthy participants and do not consider age-or disease-related differences in metabolism and other factors. For example, severe protein restriction results in weight loss in older, but not younger, mice; conversely, low protein intake is associated with reduced mortality in people aged 65 years and younger, but not in individuals aged 66 years and older (54). ...
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The human gut microbiota has been proposed to serve as a multifunctional organ in host metabolism, contributing effects to nutrient acquisition, immune response, and digestive health. Fasting during Ramadan may alter the composition of gut microbiota through changes in dietary behavior, which ultimately affects the contents of various metabolites in the gut. Here, we used liquid chromatography–mass spectrometry-based metabolomics to investigate the composition of fecal metabolites in Chinese and Pakistani individuals before and after Ramadan fasting. Principal component analysis showed distinct separation of metabolite profiles among ethnic groups as well as between pre- and post-fasting samples. After Ramadan fasting, the Chinese and Pakistani groups showed significant differences in their respective contents of various fecal metabolites. In particular, L-histidine, lycofawcine, and cordycepin concentrations were higher after Ramadan fasting in the Chinese group, while brucine was enriched in the Pakistani group. The KEGG analysis suggested that metabolites related to purine metabolism, 2-oxocarboxylic acid metabolism, and lysine degradation were significantly enriched in the total subject population pre-fasting vs. post-fasting comparisons. Several bacterial taxa were significantly correlated with specific metabolites unique to each ethnic group, suggesting that changes in fecal metabolite profiles related to Ramadan fasting may be influenced by associated shifts in gut microbiota. The fasting-related differences in fecal metabolite profile, together with these group-specific correlations between taxa and metabolites, support our previous findings that ethnic differences in dietary composition also drive variation in gut microbial composition and diversity. This landscape view of interconnected dietary behaviors, microbiota, and metabolites contributes to the future development of personalized, diet-based therapeutic strategies for gut-related disorders.
... The molecular architecture of the mammalian master clock is characterized by the presence of a transcriptional-translational feedback loop. In particular, two transcription factors, CLOCK and BMAL1, stimulate the transcription of Per and Cry genes encoding ad libitum days of eating; (3) chronic energy restriction, characterized by a significant reduction of caloric intake (up to 40%) and no change in the frequency of meals; (4) significant carbohydrate restriction (<20-50 g/d) [22][23][24]. Only the third and the fourth dietary approaches have been shown to lead definitively to the production of KBs for prolonged periods of time [15]. ...
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Chrononutrition is an emerging branch of chronobiology focusing on the profound interactions between biological rhythms and metabolism. This framework suggests that, just like all biological processes, even nutrition follows a circadian pattern. Recent findings elucidated the metabolic roles of circadian clocks in the regulation of both hormone release and the daily feeding–fasting cycle. Apart from serving as energy fuel, ketone bodies play pivotal roles as signaling mediators and drivers of gene transcription, promoting food anticipation and loss of appetite. Herein we provide a comprehensive review of the literature on the effects of the ketogenic diets on biological processes that follow circadian rhythms, among them appetite, sleep, and endocrine function.
Objects Caloric restriction (CR) is known to extend lifespan and exert a protective effect on organs, and is thus a low-cost and easily implemented approach to the health maintenance. However, there have been no studies that have systematically evaluated the metabolic changes that occur in the main tissues affected by CR. This study aimed to explore the target tissues metabolomic profile in CR mice. Methods Male C57BL/6J mice were randomly allocated to the CR group (n = 7) and control group (n = 7). A non-targeted gas chromatography–mass spectrometry approach and multivariate analysis were used to identify metabolites in the main tissues (serum, heart, liver, kidney, cortex, hippocampus, lung, muscle, and white adipose) in model of CR. Results We identified 10 metabolites in the heart that showed differential abundance between the 2 groups, along with 9 in kidney, 6 in liver, 6 in lung, 6 in white adipose, 4 in hippocampus, 4 in serum, 3 in cortex, and 2 in muscle. The most significantly altered metabolites were amino acids (AAs) (glycine, aspartic acid, l -isoleucine, l -proline, l -aspartic acid, l -serine, l -hydroxyproline, l -alanine, l -valine, l -threonine, l -glutamic acid, and l -phenylalanine) and fatty acids (FAs) (palmitic acid, 1 -monopalmitin, glycerol monostearate, docosahexaenoic acid, 16-octadecenoic acid, oleic acid, stearic acid, and hexanoic acid). These metabolites were associated with 7 different functional pathways related to the metabolism of AAs, lipids, and energy. Conclusion Our results provide insight into the specific metabolic changes that are induced by CR and can serve as a reference for physiologic studies on how CR improves health and extends lifespan.
The human intestinal microbiota is composed of several types of microorganisms, including bacteria, archaea, fungi, unicellular eukaryotes and viruses. Among them, bacteria are the most diverse and abundant with a gene catalog 150 times larger than the genes present in the human genome, which represents a tremendous metabolic potential. These bacteria actively participate in the maintenance of intestinal homeostasis. Dysbiosis of the gut microbiota could be observed at course of many human pathologies, particularly inflammatory diseases intestinal chronic diseases (IBD), such as Crohn's disease (CD) or Ulcerative colitis (UC). These dysbiosis could contribute to the onset and progression of diseases. For example, gut microbiota transplantation experiments in murine model have allowed to show that a dysbiotic microbiota is sufficient to induce chronic inflammation in the colon and thus lead to the development of a metabolic syndrome or colitis. Different intervention strategies, including fecal transplantation, administration of probiotics or even special nutritional diets have been developed to act on the microbial communities of the digestive tract and to restore homeostasis of host tissues. The success of some interventions like Fecal transplantation represent a proof of concept in humans that acting on the composition of the intestinal microbiota is a strong lever to resolve certain physio pathological situations associated with gut microbiota dysbiosis. Diet is another important method for modulating the gut microbiota since it is the most important factor influencing its composition. In fact, the nutrients ingested can act directly on the composition of the microbiota by serving as substrates for microorganisms and indirectly by modulating intestinal homeostasis and components of the immune system associated, themselves contributing to regulate the composition microbiota. It is expected that ingestion of these beneficial microorga nisms can stimulate the immune system, promote intestinal homeostasis and to some extent contribute to the balance of the microbiota intestinal. The use of probiotic microorganisms is found to be very effective in some studies to treat different physiopathological situations (colitis, metabolic syndrome) in laboratory model organisms (rats, mice), however the use of these same probiotics in humans have given relatively disappointing clinical results, with poorly reproducible results across cohorts of patients. Except for the treatment of antibiotic-associated diarrhea. These discrepancies in results between pre-clinical models and clinical trials encourage better characterization of the molecular mechanisms used by probiotics to exert their beneficial effects and especially better understand the relationship of these probiotic microorganisms with the resident microbiota and diet.Among the different rising intervention strategies practiced nowadays in the purpose to shape the microbiota, a growing interest is given to other dietary interventions, like caloric restriction (CR) which has demonstrated several beneficial effects on various physiological systems, including the gastro-intestinal system, by modulating the innate and adaptative immune responses. In fact, emerging evidence suggests that the immune system function might be heavily influenced by the sensing of nutrient, reinforcing the idea that diet can deeply influence the inflammatory responses.
Cytochrome P450 2E1 (CYP2E1) plays an essential role in the susceptibility to acute acrylonitrile (AN)-induced toxicity. Here, we investigated the toxicity and mechanism of AN in fasting mice and potential underlying mechanisms. Convulsions, loss of righting reflex, and death 4 h after AN treatment were observed and recorded for each group of mice. Relative to ad lib-fed mice, 48 h fasting significantly increased the acute toxicity of AN, as noted by a more rapid onset of convulsions and death. In addition, fasting significantly enhanced CYP2E1-mediated oxidative metabolism of AN, resulting in increased formation of CN- (one of the end-metabolites of AN). Moreover, fasting decreased hepatic GSH content, abrogating the detoxification of GSH. However, trans-1,2-dichloroethylene (DCE), a CYP2E1 inhibitor, altered the level of hepatic CYP2E1 activity in response to fasting, reduced the acute toxic symptoms of AN and the content of CN- in AN-treated mice. These data establish that fasting predisposes to AN toxicity, attributable to induced CYP2E1and reduced hepatic GSH.
Acute kidney injury is a frequent complication in the clinical setting and associated with significant morbidity and mortality. Preconditioning with short-term caloric restriction is highly protective against kidney injury in rodent ischemia reperfusion injury models. However, the underlying mechanisms are unknown hampering clinical translation. Here, we examined the molecular basis of caloric restriction-mediated protection to elucidate the principles of kidney stress resistance. Analysis of an RNAseq dataset after caloric restriction identified Cyp4a12a, a cytochrome exclusively expressed in male mice, to be strongly downregulated after caloric restriction. Kidney ischemia reperfusion injury robustly induced acute kidney injury in male mice and this damage could be markedly attenuated by pretreatment with caloric restriction. In females, damage was significantly less pronounced and preconditioning with caloric restriction had only little effect. Tissue concentrations of the metabolic product of Cyp4a12a, 20-hydroxyeicosatetraenoic acid (20-HETE), were found to be significantly reduced by caloric restriction. Conversely, intraperitoneal supplementation of 20-HETE in preconditioned males partly abrogated the protective potential of caloric restriction. Interestingly, this effect was accompanied by a partial reversal of caloric restriction-induced changes in protein but not RNA expression pointing towards inflammation, endoplasmic reticulum stress and lipid metabolism. Thus, our findings provide an insight into the mechanisms underlying kidney protection by caloric restriction. Hence, understanding the mediators of preconditioning is an important pre-requisite for moving towards translation to the clinical setting.
Diabetes mellitus (DM) is one of the most prevalent chronic diseases worldwide. High morbidity and mortality caused by DM are closely linked to its complications in multiple organs/tissues, including cardiovascular complications, diabetic nephropathy, and diabetic neuropathy. Resveratrol is a plant-derived polyphenolic compound with pleiotropic protective effects, ranging from antioxidant and anti-inflammatory to hypoglycemic effects. Recent studies strongly suggest that the consumption of resveratrol offers protection against diabetes and its cardiovascular complications. The protective effects of resveratrol involve the regulation of multiple signaling pathways, including inhibition of oxidative stress and inflammation, enhancement of insulin sensitivity, induction of autophagy, regulation of lipid metabolism, promotion of GLUT4 expression, and translocation, and activation of SIRT1/AMPK signaling axis. The cardiovascular protective effects of resveratrol have been recently reviewed in the literature, but the role of resveratrol in preventing diabetes mellitus and its cardiovascular complications has not been systematically reviewed. Therefore, in this review, we summarize the pharmacological effects and mechanisms of action of resveratrol based on in vitro and in vivo studies, highlighting the therapeutic potential of resveratrol in the prevention and treatment of diabetes and its cardiovascular complications.
Type 2 diabetes (T2D) and its target organ injuries cause distressing impacts on personal health and put an enormous burden on the healthcare system, and increasing attention has been paid to T2D-associated cognitive dysfunction (TDACD). TDACD is characterized by cognitive dysfunction, delayed executive ability, and impeded information-processing speed. Brain imaging data suggest that extensive brain regions are affected in patients with T2D. Based on current findings, a wide spectrum of non-specific neurodegenerative mechanisms that partially overlap with the mechanisms of neurodegenerative diseases is hypothesized to be associated with TDACD. However, it remains unclear whether TDACD is a consequence of T2D or a complication that co-occurs with T2D. Theoretically, anti-diabetes methods are promising neuromodulatory approaches to reduce brain injury in patients with T2D. In this review, we summarize potential mechanisms underlying TDACD and promising neurotropic effects of anti-diabetes methods and some neuroprotective natural compounds. Constructing screening or diagnostic tools and developing targeted treatment and preventive strategies would be expected to reduce the burden of TDACD.
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Visceral adiposity is strongly associated with metabolic disease risk, whereas subcutaneous adiposity is comparatively benign. However, their relative physiological importance in energy homeostasis remains unclear. Here, we show that after 24-h fasting, the subcutaneous adipose tissue of mice acquires key properties of visceral fat. During this fast-induced 'visceralization', upregulation of miR-149-3p directly targets PR domain containing 16 (PRDM16), a key coregulatory protein required for the 'browning' of white fat. In cultured inguinal preadipocytes, overexpression of miR-149-3p promotes a visceral-like switch during cell differentiation. Mice deficient in miR-149-3p display an increase in whole-body energy expenditure, with enhanced thermogenesis of inguinal fat. However, a visceral-like adipose phenotype is observed in inguinal depots overexpressing miR-149-3p. These results indicate that in addition to the capacity of 'browning' to defend against hypothermia during cold exposure, the subcutaneous adipose depot is also capable of 'whitening' to preserve energy during fasting, presumably to maintain energy balance, via miR-149-3p-mediated regulation of PRDM16.
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The prevalence of type-2 diabetes mellitus (T2DM) has increased dramatically during the last 2 decades, a fact driven by the increased prevalence of obesity, the primary risk factor for T2DM. The figures for diabetes in the Arab world are particularly startling as the number of people with diabetes is projected to increase by 96.2% by 2035. Genetic risk factors may play a crucial role in this uncontrolled raise in the prevalence of T2DM in the Middle Eastern region. However, factors such as obesity, rapid urbanization and lack of exercise are other key determinants of this rapid increase in the rate of T2DM in the Arab world. The unavailability of an effective program to defeat T2DM has serious consequences on the increasing rise of this disease, where available data indicates an unusually high prevalence of T2DM in Arabian children less than 18 years old. Living with T2DM is problematic as well, since T2DM has become the 5(th) leading cause of disability, which was ranked 10(th) as recently as 1990. Giving the current status of T2DM in the Arab world, a collaborative international effort is needed for fighting further spread of this disease.
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The Arab world is experiencing an epidemic of obesity and type 2 diabetes mellitus. This review summarizes the major pathological factors linking obesity to diabetes, focussing on current epidemiological data related to obese diabetic patients in the Arab world, the etiology of the disease and the genetic determinants of diabetes and obesity. There are alarming data related to the rising prevalence of obesity and type 2 diabetes mellitus in children of Arab ethnicity. Replication studies identify several genetic variants in Arabs with obesitylinked diabetes. For example, variants of the ADIPOQ gene (the rs266729 single-nucleotide polymorphism) are associated with obesity and diabetes in various Arab countries. Gaps exist in our information about diabetes and obesity in Arab populations in relation to ethnic-specific cut-off points for diagnosis and treatment of diabetes. Further genome-wide association studies in obese and diabetic Arab populations could add to our understanding of the pathophysiology, prevention and reversal of this disease.
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Regular physical activity and exercise training have long been known to cause adaptations to white adipose tissue (WAT), including decreases in cell size and lipid content and increases in mitochondrial proteins. In this article, we discuss recent studies that have investigated the effects of exercise training on mitochondrial function, the "beiging" of WAT, regulation of adipokines, metabolic effects of trained adipose tissue on systemic metabolism, and depot-specific responses to exercise training. The major WAT depots in the body are found in the visceral cavity (vWAT) and subcutaneously (scWAT). In rodent models, exercise training increases mitochondrial biogenesis and activity in both these adipose tissue depots. Exercise training also increases expression of the brown adipocyte marker uncoupling protein 1 (UCP1) in both adipose tissue depots, although these effects are much more pronounced in scWAT. Consistent with the increase in UCP1, exercise training increases the presence of brown-like adipocytes in scWAT, also known as browning or beiging. Training results in changes in the gene expression of thousands of scWAT genes and an altered adipokine profile in both scWAT and vWAT. Transplantation of trained scWAT in sedentary recipient mice results in striking improvements in skeletal muscle glucose uptake and whole-body metabolic homeostasis. Human and rodent exercise studies have indicated that exercise training can alter circulating adipokine concentration as well as adipokine expression in adipose tissue. Thus, the profound changes to WAT in response to exercise training may be part of the mechanism by which exercise improves whole-body metabolic health. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
Periodical fasting, under a religious aspect, has been adopted by humans for centuries as a crucial pathway of induction of spiritual catharsis. Caloric restriction, with or without eviction of certain type of food, is a key component of most religious dietary patterns. Fasting varies significantly among different populations according to cultural habits and local climate condition. Religious fasting in terms of patterns (continuous vs. intermittent) and duration can vary from 1 to 200 days, thus their positive and negative impact on human health can be considerable.
Caloric restriction (CR) extends lifespan from yeast to mammals, delays onset of age-associated diseases, and improves metabolic health. We show that CR stimulates development of functional beige fat within the subcutaneous and visceral adipose tissue, contributing to decreased white fat and adipocyte size in lean C57BL/6 and BALB/c mice kept at room temperature or at thermoneutrality and in obese leptin-deficient mice. These metabolic changes are mediated by increased eosinophil infiltration, type 2 cytokine signaling, and M2 macrophage polarization in fat of CR animals. Suppression of the type 2 signaling, using Il4ra−/−, Stat6−/−, or mice transplanted with Stat6−/− bone marrow-derived hematopoietic cells, prevents the CR-induced browning and abrogates the subcutaneous fat loss and the metabolic improvements induced by CR. These results provide insights into the overall energy homeostasis during CR, and they suggest beige fat development as a common feature in conditions of negative energy balance.
Objective: To evaluate an impact of low calorie diet therapy (LCDT) on cerebral hemodynamics, cognitive functions and quality-of-life of patients with arterial hypertension and chronic cerebral ischemia. Material and methods: The main group consisted of 22 patients, 16 women and 6 men (mean age 54.4±2.4 years), assigned to the diet. The comparison group included 20 patients, 12 women and 8 men (mean age 55.6±1,0 years), who received standard antihypertensive treatment. The results of Doppler ultrasound of cerebral arteries, cognitive functions and quality-of-life were assessed after 6 months of treatment. Results and conclusion: A positive effect of LCDT on the cerebral hemodynamics, cognitive functions and quality-of-life indices maintained for 6 months. The efficacy of LCDT was comparable to that of standard treatment in the comparison group.
Intermittent fasting, alternate-day fasting, and other forms of periodic caloric desistance are gaining popularity in the lay press and among animal research scientists. Whether clinical evidence exists for or is strong enough to support the use of such dietary regimens as health interventions is unclear. This review sought to identify rigorous, clinically relevant research studies that provide high-quality evidence that therapeutic fasting regimens are clinically beneficial to humans. A systematic review of the published literature through January 2015 was performed by using sensitive search strategies to identify randomized controlled clinical trials that evaluated the effects of fasting on either clinically relevant surrogate outcomes (e.g., weight, cholesterol) or actual clinical event endpoints [e.g., diabetes, coronary artery disease (CAD)] and any other studies that evaluated the effects of fasting on clinical event outcomes. Three randomized controlled clinical trials of fasting in humans were identified, and the results were published in 5 articles, all of which evaluated the effects of fasting on surrogate outcomes. Improvements in weight and other risk-related outcomes were found in the 3 trials. Two observational clinical outcomes studies in humans were found in which fasting was associated with a lower prevalence of CAD or diabetes diagnosis. No randomized controlled trials of fasting for clinical outcomes were identified. Clinical research studies of fasting with robust designs and high levels of clinical evidence are sparse in the literature. Whereas the few randomized controlled trials and observational clinical outcomes studies support the existence of a health benefit from fasting, substantial further research in humans is needed before the use of fasting as a health intervention can be recommended. © 2015 American Society for Nutrition.