Narrative Review
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The impact of keto-adaptation on exercise performance and the role of
metabolic-regulating cytokines
Matthew Sherrier1 and Hongshuai Li2
1 Department of Physical Medicine and Rehabilitation, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; and 2 Musculoskeletal Growth and
Regeneration Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
ABSTRACT
The ketogenic diet (KD) is a normocaloric diet composed of high-
fat, low-carbohydrate, and adequate protein that induces fasting-
like effects and results in the production of ketone bodies. Initially
used widely for children with refractory epilepsy, the KD gained
popularity due to its beneficial effects on weight loss, diabetes,
and cancer. In recent years, there has been a resurgence in interest
surrounding the KD and exercise performance. This review provides
new insights into the adaptation period necessary for enhancement in
skeletal muscle fat and ketone oxidation after sustained nutritional
ketosis. In addition, this review highlights metabolically active
growth factors and cytokines, which may function as important
regulators of keto-adaptation in the setting of exercise and the KD.
Am J Clin Nutr 2019;00:1–12.
Keywords: ketogenic diet, low-carbohydrate high-fat diet, keto-
adaptation, exercise, skeletal muscle, FGF21, adiponectin, IL-6,
microbiome
Introduction
The ketogenic diet (KD) is a normocaloric diet composed of
high fat, low carbohydrate, and adequate protein that induces
fasting-like effects and results in the production of ketone
bodies (KBs) [β-hydroxybutyrate (βHB), acetoacetate (AcAc),
and acetone]. Initially used widely for children with refractory
epilepsy, the KD gained popularity due to its beneficial effects
on weight loss, diabetes, and cancer (1). However, a less well-
explored question is whether a KD may exert beneficial effects
on exercise and athletic performance. It has been hypothesized
that nutritional ketosis, through an increase in availability of
free fatty acids (FFAs) and an enhanced ability for skeletal
muscle (SM) to oxidize fat and KBs while simultaneously sparing
glycogen, could elicit enhancement in the metabolic demands
of athletic performance. This concept is in direct contrast to the
current dietary guideline recommendations of 6–10 g · kg−1 of
carbohydrates for athletes undergoing 1–3 h of exercise daily
(2). Theoretically, if an adaptation in metabolism from glucose
reliance to KBs occurs, adipose tissue could become the primary
fuel source for low- to moderate-intensity exercise.
Am J Clin Nutr 2019;00:1–12. Printed in USA. Copyright © American Society for Nutrition 2019. All rights reserved.
β-Oxidation of fatty acids (FAs) and KBs generates a far
greater supply of energy than carbohydrates. In total, 108 ATPs
are produced per 16 carbon FAs compared with 30–32 ATP
yield per glucose (3). With regard to KBs, 100 g of βHB
yields 10,500 g of ATP, and 100 g of AcAc generates 9400
g of ATP; however, 100 g of glucose can produce only 8700
g of ATP (3). Not only does oxidation of FAs and KBs yield
greater quantities of this bioenergetic molecule, but ATP is also
produced more efficiently, representing a preferential substrate to
glucose for cells in a low-oxygen environment or experiencing a
mitochondrial stressor, including exercise (4, 5). Therefore, an
enhanced efficiency in SM mitochondrial ATP production from
FA and KB oxidation would theoretically improve performance
in certain athletic endeavors. Despite the theorized benefit
and multiple rodent studies showing an increase in endurance
performance measures in response to a 5-wk (6), 8-wk (7),
and 12-wk (8) KD, investigations into the impact of a KD on
sports performance in humans have been inconclusive (9, 10).
However, variations in diet macronutrient composition, prestudy
athletic status of participants, self-reported diet controls, small
sample sizes, difference in training protocols, and inconsistent
measurement of KBs affect the meaningful interpretation of
results. Furthermore, many studies failed to acknowledge or
This work was mainly supported by a startup fund to HL from the
Department of Orthopaedic Surgery, University of Pittsburgh. This work was
partially supported by the Samuel and Emma Winters Foundation (funding
junior faculty members in the greater Pittsburgh area for biomedical research)
to HL.
Address correspondence to HL (e-mail: hol24@pitt.edu).
Abbreviations used: AcAc, acetoacetate; ACAT, acetoacetyl-CoA thiolase;
AMPK, AMP-activated protein kinase; BDH, 3-hydroxybutyrate dehydro-
genase; CPT, carnitine palmitoyl transferase; Epi, epinephrine; FA, fatty
acid; FFA, free fatty acid; FGF, fibroblast growth factor; GH, growth
hormone; HAD, β-hydroxyacyl CoA dehydrogenase; IMTG, intramuscular
triacylglycerol; KB, ketone body; KD, ketogenic diet; KO, knockout; LCHF,
low-carbohydrate, high-fat diet; NE, norepinephrine; PGC-1α, peroxisome
proliferator-activated receptor γ coactivator 1α; SIRT1, sirtuin 1; SM,
skeletal muscle; T4, thyroxine; βHB, β-hydroxybutyrate.
Received January 9, 2019. Accepted for publication June 19, 2019.
First published online 0, 2019; doi: https://doi.org/10.1093/ajcn/nqz145.
1
2 Sherrier and Li
did not pay enough attention to the adaptation status, which
may, in part, account for the variance in conclusions. Here we
review and discuss the key steps for keto-adaptation with an
intention of providing new insights into the understanding of this
topic, how adaptation to a KD may impart a beneficial effect on
aerobic exercise capacity, and potential biomarkers as indicators
of adequate keto-adaptation. As human data in this realm are
often limited, we draw on small animal models to provide
insight into the alterations of bioenergetic regulatory proteins
and gene expression in addition to the timeframe whereby these
adaptations occur. In addition, we introduce metabolically active
growth factors and cytokines, which may function as important
regulators of keto-adaptation in the setting of exercise and the
KD.
Ketogenic Diet and Adaptation
Ketogenic diet
The KD is described as a diet that consists of high dietary
fat, adequate protein, and very low carbohydrates sufficient to
achieve a state of heightened KB production (11). Diverse types
of KDs have been described, and a large number of publications
equate a low-carbohydrate, high-fat diet (LCHF) to KDs, which
adds confusion to data interpretation. It should be pointed out
that currently, there are no international guidelines on how low
and how high the contents of carbohydrates and fat should be to
define a KD. By definition, a KD should lead the body to enter a
state of increased fat burning, leading to ketosis. For most people,
the upper limit of carbohydrate intake is ∼50 g · d−1 while protein
intake ranges from 1.2–2 g · kg−1 · d−1 to remain in nutritional
ketosis (12). Such a diet precipitates a high serum concentration
of nonesterified FAs, which the liver oxidizes into KBs. The
result is a mild ketonemia with serum βHB levels of 0.5–3.0
mmol · L−1 (9, 12). Circulating KBs are then used as oxidizable
carbon sources in the Krebs cycle and oxidative phosphorylation
to provide energy for extrahepatic tissues, in particular, the brain,
skeletal muscles, and cardiac muscles (13).
How the body uses and adapts to KBs as an energy source
When consuming a carbohydrate-inclusive diet, glucose is
the primary source of energy. When intake of carbohydrates
is reduced to <50 g · d−1 , the body is forced to undergo
certain metabolic changes to use fat as an alternative source
of energy. Generally, carbohydrate deprivation will lead to
depletion of glycogen stores. To compensate, the body will first
produce glucose endogenously via gluconeogenesis. When the
endogenous production of glucose is insufficient to keep up
with the needs of the body, ketogenesis begins to provide an
alternative source of energy in the form of KBs. As long as the
body is deprived of carbohydrates, metabolism remains in the
ketotic state. The chemical processes of gluconeogenesis and
ketogenesis have been previously reviewed (14), and the key steps
are summarized in Figure 1.
However, being in ketosis does not necessarily mean the body
is optimally using KBs for fuel. To efficiently produce and use
KBs as an energy source, the body needs specific adaptations to
accommodate the alteration in fuel preference from glucose to
KBs (15). This process has been termed keto-adaptation and is
thought to require dietary carbohydrate restriction for a prolonged
period of time to eventually reach metabolic adaptation, which
manifests as sustained ketosis, increased rates of fat oxidation,
and concomitantly a decreased rate of carbohydrate oxidation
in energy-demanding tissues such as SM (16–19). However, to
what extent that we can declare a successful or adequate keto-
adaptation status is still not clear. To be keto-adapted, the body
needs to reach homeostasis in multiple organs to use KBs as the
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primary fuel source. The adaptive metabolic changes have been
preliminarily discussed in several human studies at different time
points after consuming a KD. A time course study of a KD for
up to 15 d (18) demonstrated that the increased fat oxidation
reached a plateau at 5 d after KD, with no further changes over
the remaining 10 d. In the early work by Phinney et al. (17),
4 wk of KD in elite cyclists resulted in increased fat oxidation
rates but decreased resting muscle glycogen by half and the rate
of glycogen use during exercise by 4-fold. The longest time
duration study of metabolic adaptations from highly trained ultra-
endurance athletes was 20 mo (range, 9–36 mo) reported by Volek
et al. (19). In this study, keto-adapted athletes when compared
with athletes in the high-carbohydrate diet group showed greater
fat oxidation rates both at rest and during exercise (2-fold higher
of peak fat oxidation rate), lower rates of carbohydrate oxidation,
and a higher level of serum KBs and glycerol, which indicate
upregulated ketogenesis and lipolysis; one striking finding is
that there were no differences in preexercise muscle glycogen
concentrations or the rate of glycogen synthesis during recovery
compared with athletes in the high-carbohydrate diet group. The
different muscle glycogen levels after short-term and long-term
adaptions to a KD suggest that muscle glycogen may also need
a prolonged adaptive time to reach pre-KD baseline levels. In
addition to liver and SM, the kidneys are also involved in the
adaptation process. Initiation of a KD results in an elevation
in serum uric acid levels secondary to competitive excretion of
KBs, with a majority of studies indicating a return to baseline
after 4–6 wk of sustained nutritional ketosis (20, 21). In addition,
studies indicate that the sympathoadrenal system might also
play a role in adaptation to a KD (22–24). Activity of the
sympathoadrenal system is elevated at rest and after exercise
following a short-term (3-d) KD, which is important for the
initial preservation of work capacity while undergoing adaptation
(22–24). Taken together, keto-adaption is a prolonged process
involving adaptations from multiple organs to generate and use
KBs as an alternative energy source. It takes weeks for the body
to start using KBs as an alternative energy source and may require
months to reach an adequate and steady level. Furthermore, the
different glycogen responses from these studies and the adaptive
changes of the kidney suggested that biochemical processes
other than increased KB production and fat oxidation are also
involved and may also play an important role in keto-adaptation.
Apparently, more studies, especially longer time-course and
variability studies investigating the dynamic metabolic changes
during KD adaptation in human, are needed to fully understand
the keto-adaptation process.
The biochemical mechanisms behind the shifts in fuel
utilization are believed to be due to the modifications of enzymes
essential in the process of KB production and utilization (18, 19),
such as upregulation of the key enzymes involved in oxidative
phosphorylation, the citric acid cycle, FA oxidation, and ketolysis
(25–27), along with downregulation of enzymes supporting
 Keto-adaptation on exercise performance 3

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FIGURE 1 Overview of the metabolism of ketone bodies (KBs) in liver and skeletal muscle. Ketogenesis is a process that takes place primarily in the
liver. During prolonged fasting or consumption of a ketogenic diet, lipids are released from adipose tissue and broken down into free fatty acids and glycerol.
Fatty acids enter hepatic mitochondria, are β-oxidized, and ultimately converted into KBs, most notably AcAc and βHB. KBs are transported systemically,
freely diffuse across cell membranes of extrahepatic tissues, and are transported into the mitochondrial matrix, where they are used as energy substrates in
the Krebs cycle and oxidative phosphorylation. Skeletal muscle expression of transporter protein and ketolytic enzymes upregulated by exercise is indicated
by the green cross. AcAc, acetoacetate; ACAT, acetoacetyl-CoA thiolase; BDH, 3-hydroxybutyrate dehydrogenase; CPT-1, carnitine palmitoyl transferase-1;
FFA, free fatty acid; HMGCL, 3-hydroxy-3-methylglutaryl-CoA lyase; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; HMGCS, 3-hydroxy-3-methylglutaryl-
synthetase; MCT-1, monocarboxylate transporter 1; SCOT, succinyl-CoA/3-ketoacid-CoA transferase; TCA, tricarboxylic acid cycle; βHB, β-hydroxybutyrate.

carbohydrate oxidation such as pyruvate dehydrogenase (28).
Those adaptive enzymatic changes were mainly derived from
short-term KD experiments, and the dynamic changes of those
key enzymes during prolonged keto-adaptation are still not
clear.
Does exercise help with keto-adaptation?
One of the classic responses to endurance training is a
greater capacity to oxidize fat and KBs (29). Adaptations
that account for increased fat oxidation in athletes include a
higher number of mitochondrial and ketolytic enzymes, a more
oxidative myofiber phenotype, and increased accumulation of
intramuscular triacylglycerol (IMTG) (30). Exercise has also
been demonstrated to enhance whole-body KB metabolism.
Studies suggest that aerobic exercise upregulates KB uptake
(31–33) and ketolysis (34, 35) rather than ketogenesis (34, 35).
Both human and animal data demonstrate that exercise increases
the absolute rate of KB uptake and oxidation by SM (36, 37).
An elevation in monocarboxylate transporter protein expression
has been observed in human and rodent SM in response to
exercise in an intensity and time duration-dependent manner,
which may account for the increased KB uptake by SM after
exercise (31–33). In addition, an increase in activity of the key
ketolytic enzymes β-hydroxybutyrate dehydrogenase (BDH),
acetoacetyl-CoA thiolase (ACAT), and succinyl-CoA/3-ketoacid
CoA transferase have also been demonstrated in the SM of
exercise-trained rodents (34, 35, 37–39). For ketogenesis, data are
limited but suggest that in exercise-trained rodents, the activity of
BDH, 3-hydroxy-3-methylglutaryl-CoA synthetase, and ACAT
are unchanged in the liver compared with untrained controls (34,
35, 38, 39).
Utilization of exercise to augment or accelerate keto-adaption
is an appealing approach with implications for athletes and
nonathletes alike. With regard to SM adaptation to exercise
and nutritional ketosis, there is likely a synergistic effect. Simi
and colleagues, in a rodent study investigating the individual
and combined effects of a KD and intensive treadmill training
program, found additive effects on maximal O2 uptake along
with SM β-hydroxyacyl CoA dehydrogenase (HAD) and citrate
synthase (8). A 6-wk study investigating the impact of voluntary
exercise and a high-fat diet (76% fat) found a significant
increase in SM HAD and carnitine acyltransferase in the high-
fat group compared with standard chow, suggesting improved β-
oxidation of fat in SM (40). In addition, mice that consumed a
KD and exercised for 12 wk demonstrated increased levels of
CD36, carnitine palmitoyl transferase (CPT) 1b, and HAD gene
expression compared with those consuming a KD in the absence
of exercise (41). Thus, the enhancement in cellular machinery
for KB and FA uptake and metabolism in SM seen with aerobic
4 Sherrier and Li
exercise and nutritional ketosis may accelerate keto-adaptation,
providing a unique advantage for endurance-trained athletes.
The importance of keto-adaptation on athletic performances
As aforementioned, a KD should theoretically be able to better
support the energy needs of exercise and athletic performances,
especially for endurance type of exercises (3). However, inves-
tigations into the impact of a KD on sports performance in
humans have been inconclusive (9, 10). Much confusion has
been generated by crossover studies designed to test performance
in the first few days of carbohydrate restriction, during which
time the subjects are clearly not sufficiently keto-adapted. Those
studies consistently and clearly demonstrated that short-term KD
(1–7 d) is detrimental to endurance capacity and the performance
of prolonged exercise (42, 43). The impairment in performance
is likely due to a combination of the predepletion of muscle
glycogen stores and the absence or inadequacy of any worthwhile
increase in the capacity for fat utilization during exercise to
compensate for the reduction in available carbohydrate fuel.
Mixed results were found in medium-termed KD (up to 60
d). Burke et al. (44) reported impaired performances in elite
endurance athletes after 3 wk of KD. However, most studies
failed to observe compromised endurance performances (17,
45–47). Some of the studies even showed favorable results
after consuming a KD (48, 49). To date, only 2 studies have
discussed the effects of a long-term KD adaptation period (over
60 d) on exercise performance. McSwiney et al. (50) reported
enhanced body composition, fat oxidation during exercise, and
increased performance in 12-wk keto-adapted endurance athletes
when compared with a high-carbohydrate diet group. Mohorko
et al. (51) found significant improvement in a fitness index,
number of repetitions in a chair stand test, and a 2-km walk
test in obese men and women consuming a KD for 12 wk.
Besides crossover studies at various time points, in an early time
duration study by Phinney et al. (21), a 1-wk KD significantly
decreased endurance performance; however, 6-wk KD adaptation
resulted in an increase in endurance performance to 155% of
baseline and 192% of the 1-wk value. Taken together, although
the optimal duration of adaptation to KD is still unclear and
there is a scarcity of well-designed studies to test the effects
of long-term KD adaptation on exercise performances, growing
evidence demonstrates that keto-adaptation status is clearly an
influence factor that affects the efficacy of KD on exercise
performance.
Possible biomarkers indicating keto-adaptation
A clear quantification (or criterion) for successful keto-
adaptation is still lacking. Various time durations have been
empirically used in literatures to indicate keto-adaptation,
generally referenced as short term (1–7 d), medium term (up to
60 d), and long-term (>60 d) (50, 52). However, time duration
might be the least accurate criterion due to lack of scientific
justification and without consideration of common biological
variations such as sex, age, and activity level. There is currently
a dearth of solid and easy to measure biomarkers to evaluate
adequate keto-adaptation mainly due to lack of knowledge in
this field. Many biochemical parameters have been implied to
evaluate KD adaptation, such as levels of serum KBs, fat and
carbohydrate metabolites, and muscle glycogen. Here, we review
what is currently known regarding the adaptive changes of
all those parameters and discuss the pros and cons of those
parameters as biomarkers for evaluation of keto-adaptation.
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KBs.
Consistent hepatic generation of KBs is the key feature of a
KD. Normal levels of blood KBs in adults are reported between
100 and 250 μmol · L−1 (53). A KD can increase circulating KB
concentrations to 0.5–3 mmol · L−1 (25). This range is below the
typical 5- to 10-mmol · L−1 range that occurs during prolonged
fasting (54) and well below concentrations characteristic of
ketoacidosis seen in uncontrolled diabetes. Studies demonstrated
that serum KBs increase rapidly after initiation of a KD, reaching
1–2 mmol · L−1 after 2–4 d (16, 22) and remaining within
this range even after a prolonged period (>20 mo) (19). The
early increase of serum KBs indicates the initiation of keto-
adaptation, and its levels may indicate the effectiveness of the
keto induction of different KD formulations. Given the early
plateau effect that occurs, serum KBs may represent a biomarker
of early keto-adaptation but do not provide information regarding
efficient usage of these substrates. It is worth noting that urinary
ketone levels correlate poorly with serum levels; as such, blood
levels remain the gold standard for determining the true level of
ketonemia (5).
Carbohydrate metabolites.
Changes in the serum levels of glucose, glucagon, and insulin
can provide insights into substrate utilization on a whole-body
level. After 2 d on a KD, plasma glucose concentrations are
reduced to an equivalent level of that induced by fasting (from
∼90 mg · dL−1 to 63 mg · dL−1 ), indicating the depletion of
hepatic glycogen stores (4, 54, 55). With the exception of 1 study
demonstrating a return in serum glucose concentration to baseline
in 3 d (55), most studies indicate that short-term adaptation to
a KD is associated with relative hypoglycemia (21, 44). In a
study on prolonged nutritional ketosis in obese adults, serum
glucose was found to be decreased after 1 and 2 wk but retuned to
baseline after week 4, where it remained until the conclusion of
the study at week 12 (51). Furthermore, participants consuming
a KD for >3 mo all maintained blood glucose at rest and during
exercise (19, 56, 57); these results suggest improved efficiency of
gluconeogenesis from noncarbohydrate sources with prolonged
keto-adaptation.
The pancreatic hormones insulin and glucagon serve to
balance serum glucose availability and have antagonistic effects
on lipolysis at physiologic levels. Decreases in resting and 24-
hour insulin concentrations have been reported in response to 2–
4 d of KDs (16, 22, 23, 55), likely secondary to enhanced fat
oxidation and the reduction in insulin requirement for glucose
uptake. Resting insulin levels remain lower than baseline after 1,
6, and 12 wk on a KD (51, 58); this is in contrast to sharp increases
in insulin concentration in the postexercise periods at both weeks
1 and 6 (21).
Glucagon is known to maintain glucose availability, increase
lipolysis, and induce ketogenesis (59). After consumption of a
 Keto-adaptation on exercise performance
KD, resting glucagon is elevated after 1 wk and returns to baseline
by weeks 3 and 6 (21, 58). The effects of long-term adaptation to a
KD on serum glucagon levels are currently unknown, but a recent
abstract suggests that resting and exercised-induced glucagon
may be elevated in keto-adapted athletes (minimum 6 mo on
a KD) compared with high-carbohydrate fed controls (60). As
such, glucagon and insulin levels appear to reach homeostasis
in <6 wk, whereas it may take glucose levels in the serum
multiple months to reach their baseline during consumption
of a KD.
Fat metabolites.
Adipose tissue lipolysis produces increased serum levels of
FFAs and glycerol. The rate of lipolysis is known to increase with
dietary carbohydrate restriction (55); as such, these biomarkers
are often measured in studies of ketogenic or LCHF diets. Short-
term (7-d) adherence to an LCHF diet results in an increase
in plasma FFA concentration in the absence of an increase in
glycerol concentration, believed to be due to enhanced glycerol
uptake early in adaptation in an effort to enhance the rate
of gluconeogenesis and maintain consistent glycemia (4, 55).
Phinney et al. (21) similarly found elevated serum FFAs at rest
and during exercise after 1 and 6 wk of a KD while resting
glycerol levels were unchanged from the baseline prior to dietary
intervention. This time course of elevations in FFAs corresponds
with the increased ability of the body to oxidize fat as fuel during
exercise, which has been shown to occur as early as 5 d after
consumption of a KD (18).
During submaximal exercise on an LCHF diet, glycerol
appears to peak around day 5, with subsequent decreases to
the predietary intervention baseline when measured during the
same exercise protocol at days 10 and 15 (18). However, in
cyclists consuming an LCHF diet for at least 8 mo, levels of
glycerol were significantly higher during exercise compared with
a control group (57). Although levels of gluconeogenesis were
equivalent, Webster et al. (57) suggest that glycerol constitutes a
greater proportion of gluconeogenic substrate in LCHF athletes
compared with athletes consuming a mixed diet given the
elevated rates of lipolysis in the former. Therefore, resting, mid-
exercise, and postexercise ratios of glycerol to FFA could be used
as a biomarker of the ability of SM to uptake and oxidize FAs and
the ability of the body to use glycerol preferentially as a substrate
for gluconeogenesis during exercise, indicating a certain level of
adaptation to a KD.
Major hormonal responses.
Early work on starvation and KDs in humans allows us to
determine the interplay of hormones and substrates important
in energy metabolism during keto-adaptation, namely, human
growth hormone (GH), testosterone, thyroid hormones, and
catecholamines. Understanding of the basal and exercise levels
of circulating hormones may influence the effectiveness of
training when consuming a KD. It is worth noting that the
serum concentrations of hormones do not necessarily reflect
underlying alterations in biosynthesis and secretion. In addition,
many studies use obese subjects, which provides confounding
5
variables of underlying metabolic and hormonal dysregulation in
addition to adaptive thermogenesis.
GH levels peak around day 3 of starvation before slowly
returning to the baseline by day 30 (54). Similarly, with short-
term (3-d) consumption of a KD, GH is increased (24), while
longer exposure to a KD (1 and 6 wk) does not have any
impact on resting GH concentration (21), although the expected
postexercise increase in GH is impaired with prolonged time
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on the KD (21). The effects of long-term sustained nutritional
ketosis on plasma GH levels in humans are currently unknown.
Following 3 d of an LCHF diet, serum testosterone levels
decrease (24). However, after 3 and 6 wk on a KD, free
testosterone levels have been found to be unchanged from
baseline concentrations compared with a control group (58).
Interestingly, a prolonged KD (11 wk) appears to significantly
increase total testosterone while not having an impact on free
testosterone compared with a control diet (61), making its
relevance on sports performance unclear. As such, the impact of
a KD on testosterone levels is currently not understood.
KDs have been shown to decrease serum triiodothyronine
concentrations in studies ranging from 4 d to 6 wk (16, 17, 21,
62). On the other hand, resting reverse triiodothyronine (rT3)
levels are increased after 1 wk but return to the baseline after
6 wk on a KD (21). Changes in thyroxine (T4) in response to
a short-term KD have produced mixed results. Multiple groups
have shown that exposure to a KD for 4 d to 6 wk is associated
with maintenance in serum T4 levels (16, 17, 21, 62), while 1
group reported a significant increase in T4 after 3 and 6 wk on a
KD (58). A recent study on the longitudinal changes in thyroid
hormone levels in children on a KD for treatment of drug-resistant
epilepsy found no changes in T4 or thyrotropin over the course
of 1 y (63).
With regard to catecholamines, the response of epinephrine
(Epi) and norepinephrine (NE) are time dependent. Epi increases
after 3 d on a KD (22, 24), while longer duration (2 and 8 wk)
on an LCHF diet does not induce any significant changes in
resting Epi concentration compared with baseline levels (64, 65).
NE, on the other hand, increases after 3 d on a KD and remains
elevated after 8 wk (22, 24, 65). Furthermore, a short-term (3-
d) KD increases sensitivity of the sympathetic nervous system
during exercise as determined by a decrease in NE threshold (24).
The long-term effects of a KD on resting and exercise-induced
catecholamine levels are currently unknown.
Muscle glycogen.
Studies have shown that exposure to a KD for 1–4 d is
associated with hypoglycemia (66–68) and an increased feeling
of fatigue, likely a result of decreased SM glycogen and
absence of enhancement in fat and KB utilization enzymes
(52). Phinney et al. (21) found resting muscle glycogen in
obese subjects decreased to 57% of baseline after 1 wk on a
hypocaloric KD (<10 g · d−1 of dietary carbohydrate), associated
with an impairment in exercise performance. However, after
6 wk, there was a partial recovery in glycogen to 68% of
baseline. Interestingly after 6 wk, the subjects demonstrated a
155% increase in treadmill time to exhaustion at 60% maximal
oxygen intake despite decreased muscle glycogen, indicating a
successful transition in systemic utilization of energy to lipids
and KBs rather than carbohydrates. Even with a significantly
6 Sherrier and Li
lower rate of muscle glycogen utilization during exercise, well-
trained professional cyclists consuming a KD for at least 8
mo demonstrated a significantly lower glycogen content in SM
compared with mixed-diet counterparts (57). In contrast, Vogt et
al. (46) reported that the muscle glycogen stores were maintained
after a 5-wk high-fat diet period. Volek et al. (19), in a cross-
sectional study on ultra-endurance athletes who had consumed
KDs for an average of 20 mo, found similar SM glycogen content
at rest (∼140 mol · g−1 wet tissue) and postexercise glycogen
synthesis rates compared with athletes on a high-carbohydrate,
low-fat diet. The mechanism underlying this finding is currently
not understood, as gluconeogenesis is unlikely to account for
the similar glycogen levels in athletes self-reporting ingestion
of <50 g carbohydrates daily. Considering that the Krebs cycle
requires a source of oxaloacetate to continue metabolizing FAs
and that the primary source of oxaloacetate during exercise is
generated from glycolysis, it is possible that glucose is not
terminally oxidized and therefore is not reflected on indirect
calorimetry (19). Another possibility is that the carbon source for
gluconeogenesis is derived from lactate produced during exercise
(19). Interestingly, this result has also been demonstrated in small
animal models. In rat studies, 6 wk of a KD (69) and 12 wk
of an LCHF diet (8) while undergoing an intensive exercise
regimen did not alter resting glycogen levels compared with
controls. A recent study in mice found that exercise training
in combination with a KD for 12 wk enhanced expression
of genes related to lipid oxidation without decreasing glucose
utilization genes or glycogen mass in SM (41). Results suggest
that regular exercise while in nutritional ketosis may affect the
suppression of glucose utilization in SM, at least in small animal
models. As a result, resting and postexercise glycogen content
in SM might signify successful adaptation and a readiness to
compete for athletes. In addition, the ability of SM glycogen to
be preserved following a prolonged KD implies that the longer an
athlete maintains nutritional ketosis, the better the outcome could
be on exercise performance. It should also be noted that KBs
represent an alternative, or preferential (4), fuel source to glucose
eliciting a glycogen-sparing effect during submaximal exercise
and allowing glycogen usage during intermittent efforts of
high intensity during athletic competition (70). Further research
is required to identify the cellular mechanism whereby this
occurs.
Uric acid.
Uric acid may serve as a biomarker of keto-adaptation in
the kidney. Serum uric acid increases upon initiation of a KD,
reaching peak plasma levels in 1–2 wk, secondary to competitive
excretion of organic acids, such as KBs (21, 71). Most studies
suggest that after 4–6 wk of nutritional ketosis, plasma levels of
uric acid return to the baseline (20, 21, 54). However, others have
shown that serum uric acid remains above baseline levels even
after 12 wk on a KD (51). This gradual adaptation in urinary
excretion of KBs may provide insights into the timeframe of
adaptation in tissues other than liver and SM.
Taken together, keto-adaptation is a prolonged multiorgan-
involved process, and we have just scratched the surface in
our understanding. More studies are needed to verify current
biomarkers in prolonged dynamic studies; and to identify new
criteria or biomarkers to indicate an adequate level of keto-
adaptation, especially the correlation of those biomarkers with
exercise performance to predict beneficial effects of competitive
athletes consuming a KD.
Cytokines Related to Ketogenic Diet and
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Keto-Adaptation
In addition to the well-known energy metabolism-regulating
hormones, such as insulin, glucagon, and catecholamines, recent
studies have highlighted the regulatory role of cytokines from
peripheral metabolic tissues, such as adipose tissue, liver, and
SM. Several new cytokines have also been discovered to play an
important role in regulating energy metabolism, which may also
influence the adaptation to a KD. Understanding the regulatory
cytokine network in keto-adaptation is important for modulation
or acceleration of the process for medical or exercise performance
purposes. Here, we will discuss the possible role of metabolic
fibroblast growth factors (FGFs), IL-6, and adiponectin, along
with a newly emerging player, the oral and intestinal microbiomes
in regulating the adaptation to a KD.
Metabolic FGFs
FGFs are signaling proteins with diverse cell functions, includ-
ing cell growth, differentiation, angiogenesis, wound healing, and
metabolic homeostasis, which act as autocrine, paracrine, and/or
endocrine hormones by binding to FGF receptors and initiating
activation of downstream signaling pathways (72, 73). Three
FGFs have been recently identified as important components
of metabolic homeostasis: FGF21, FGF15/19, and FGF1. FGF1
is an autocrine/paracrine growth factor that binds locally while
FGF15/19 and FGF21 have reduced affinity for heparin, allowing
them to act as endocrine hormones (72).
FGF21.
FGF21 functions as a powerful endocrine and paracrine
regulator of glucose and lipid metabolism during prolonged
fasting (74, 75). Although uncertainty remains regarding the
physiological role of FGF21 as an endocrine mediator of keto-
adaptation, a growing body of literature implicates FGF21 as
a late-acting fed- and fasted-state hormone, acting on the heels
of insulin and glucagon to regulate metabolism in response to
nutritional ketosis (74).
Studies have observed increased hepatic gene expression of
FGF21 and the increase of circulating FGF21 in response to a
KD (76–78). Hepatic overexpression of FGF21 induces elevated
FA oxidation and ketogenesis in the liver (79). Pharmacologic
doses of FGF21 have also been shown to induce the expression
of enzymes involved in KB and FA metabolism, such as BDH
(80) and CPT-1 (81, 82). Furthermore, the results of FGF21-
class molecule pharmacotherapy in mice, nonhuman primates,
and humans are similar to the effects seen with the KD,
including decreased body weight, blood glucose levels, insulin,
triglycerides, total cholesterol, and total FFAs (83). On the other
hand, the beneficial effects of a KD are largely diminished in
the absence of FGF21. FGF21 knockout (KO) mice fed a KD
exhibited weight gain rather than weight loss, hepatosteatosis,
impairments in ketogenesis and glucose control, and a decrease
 Keto-adaptation on exercise performance 7

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FIGURE 2 Fibroblast growth factor 21 (FGF21) is an important regulator of skeletal muscle ketone body oxidation improvements seen with a ketogenic
diet (KD) and exercise. FGF21 enhances activation of the AMPK-SIRT1-PGC-1α pathway in skeletal muscle, resulting in favorable adaptations to a KD and
exercise with regard to mitochondrial biogenesis, development of IMTGs, myofiber-type switching to an oxidative phenotype, and ketolytic gene expression.
AMPK, AMP-activated protein kinase; IMTG, intramuscular triacylglycerol; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1α; SIRT1,
sirtuin 1.

in enzymes involved in lipolysis (78, 84). However, those results
have not been consistently replicated, and some studies have
shown that FGF21 KO mice fasted for 24 h show no difference
in ketonemia, plasma FFA, or circulating glucose levels (84–87).
Other studies found that FGF21 KO mice fed a KD for 8 wk had
equivalent plasma levels of βHB compared with wild-type mice
(88, 89). All those data challenge the importance of FGF21 in KB
metabolism or at least indicate that FGF21 is not indispensable
for the initiation of ketogenesis. Similarly, studies in humans have
shown that ketogenesis induced by a KD can occur independent
of serum FGF21 levels (77). Fazeli et al. (90) demonstrated
that in humans fasted for 10 d, ketone induction preceded an
increase in circulating FGF21. Interestingly, the upregulation in
ketolytic and FA oxidation enzymes in SM begins to occur around
the same timeframe as the increase of serum FGF21 (90, 91),
suggesting that FGF21 does not drive initial ketogenesis during
starvation but rather may maintain ketogenesis and facilitate KB
and FA utilization during prolonged fasting or adaptation to KD.
Further study is needed to assess the expression of FGF21 after
initial keto-adaption and to investigate the role of FGF21 in the
utilization of KBs.
Studies have shown that KDs and exercise share some similar
signaling mechanisms, specifically the AMP-activated protein
kinase (AMPK)–peroxisome proliferator-activated receptor γ
coactivator 1α (PGC-1α) signaling pathway (32, 85, 92–97),
which plays a predominant role in mediating KD and exercise-
induced physiological changes, such as enhanced mitochondrial
biogenesis, oxidative myofiber switching, and IMTG (25, 52,
92, 97–100). In adipocytes, a clear FGF21–AMPK–sirtuin 1
(SIRT1)–PGC-1α pathway has been delineated (82). Interest-
ingly, a similar FGF21-SIRT1-AMPK-PGC-1α pathway was
recently identified in SM and shown to promote myoblast
differentiation and transformation of anaerobic myofibers to an
oxidative phenotype (101). As a result, and in light of the fact
that both KDs and exercise can induce the expression of FGF21
(76–78, 102, 103), FGF21 may play an integral role in the context
of KD adaptation and exercise, which in turn may affect athletic
performance under KD (Figure 2).
FGF15/19 and FGF1.
Production of FGF15/19 (with FGF15 being the mouse
ortholog of human FGF19) in the liver is induced by postprandial
release of bile acids (104), fat-soluble vitamins A and D, and
cholesterol (105, 106) and primarily functions as a negative
feedback mechanism to decrease bile acid synthesis (107). In
addition to controlling the enterohepatic circulation of bile acid,
FGF15/19 also regulates systemic lipid and glucose metabolism
via its action in different metabolic organs, including the liver,
adipose tissue, and central nervous system (73, 108). FGF19
has similar but independent effects on hepatocytes to that of
insulin, stimulating protein and glycogen synthesis and inhibiting
gluconeogenesis (109, 110), while also inhibiting hepatic fatty
acid synthesis (111). In addition, FGF19 binds to and activates
FGFR1 in the hypothalamic arcuate nucleus to improve glycemic
homeostasis and reduce food intake in models of genetic and
acquired insulin resistance (104, 112, 113). There is currently
an absence of literature investigating the effects of a KD on
FGF15/19 expression and signaling or the function of FGF15/19
in regulating keto-adaptation.
FGF1 is one of the best characterized members of the
FGF superfamily, expressed in multiple tissues, including liver,
kidney, lung, brain, and white adipose tissue (72). FGF1 has
been implicated in a range of physiological processes, including
different stages of development and morphogenesis, angiogene-
sis, inflammation, wound healing, and adipogenesis (73). Beyond
those actions, FGF1 has also demonstrated metabolic activities.
FGF1 is highly upregulated in adipose tissue in response to
a high-fat diet, and mice lacking FGF1 develop an aggressive
diabetic phenotype coupled to aberrant adipose expansion when
challenged with a high-fat diet (114). Pharmacologic adminis-
tration of FGF1 has been shown to reliably improve glucose
8 Sherrier and Li
homeostasis in diabetic mouse models and increase whole-body
insulin sensitization via insulin-dependent SM glucose uptake
and suppression of glucose production in the liver (73, 115).
As such, FGF1 is considered an important regulatory factor in
metabolic homeostasis. Currently, the physiologic role of FGF1
in the context of a KD remains unknown.
IL-6
IL-6 is a pleiotropic cytokine with context-dependent pro-
and anti-inflammatory properties that can affect homeostasis
in a variety of tissues (116). Almost all stromal cells and
cells of the immune system produce IL-6 in the context of
infection, autoimmunity, or cancer. IL-6 was the first cytokine
(myokine) identified to be secreted from SM in response to
muscle contraction and plays an important role in regulating
systemic metabolism (117). Elevated levels of IL-6 are seen in
the setting of low SM glycogen levels induced by exercise and
are related to upregulation of hepatic glucose production, higher
lipolytic rate, and increased FA oxidation capacity via activation
of the AMPK pathway (118–121). Recent mouse studies have
shown that a KD further upregulates the expression of IL-6
from SM undergoing exhaustive, glycogen-depleting exercise
(7, 122). Similar observations were also found in humans. The
24-h consumption of a low-carbohydrate diet (3 g · kg−1 )
following glycogen-depleting exercise has been shown to elevate
IL-6 levels compared with a high-carbohydrate diet (10 g ·
kg−1 ) (123). A 3-wk study on elite race walkers consuming
a KD, a standard carbohydrate-rich diet, or a periodized-
carbohydrate diet resulted in a greater postexercise IL-6 response
in KD-fed athletes compared with athletes consuming the more
carbohydrate-inclusive diets (124). An elevation in postexercise
IL-6 was also seen in the KD cohort following 3 d of a high-
carbohydrate diet (125). Given the adaptation in fuel selection
toward FA and KB during a KD, exercise-induced IL-6 likely
contributes to enhanced FA utilization and may represent a
mechanism of accelerated keto-adaptation induced by exercise.
Currently, the dynamic levels of IL-6 in prolonged nutritional
ketosis are unknown. Given the pleiotropic nature of IL-6
regulation, multiple organ systems are likely affected by the
upregulation of this cytokine during long-term adherence to a
KD.
Adiponectin
Adiponectin is an abundant adipocyte-secreted factor with a
wide range of biological activities. It has been shown to improve
insulin sensitivity in major insulin target tissues, modulate
inflammatory responses, and play a crucial role in the regulation
of energy metabolism via upregulation of AMPK in the liver
and SM (25, 126). Although the regulation of adiponectin
expression is still not clear, ketogenic and LCHF diets have been
associated with increases in adiponectin in obese individuals (25,
51); βHB has been shown to induce adiponectin secretion in
adipocytes through the GPR109A receptor (127). It seems that
the level of nutritional ketosis may be an important determinant
in the extent to which KDs influence AMPK activity through
adiponectin. Furthermore, it is worth mentioning that adipose
tissue is the target of many metabolically active factors mentioned
above, many of which have been demonstrated to induce the
secretion of adiponectin from adipocytes, including FGF21 (128)
and FGF15/19 (129, 130). Whether adiponectin mediates the
metabolic function of those cytokines during keto-adaptation
remains unknown.
Microbiome
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Recently, the gut microbiota has emerged as a key regulator
of health and disease (131). Dietary factors are among the most
influential modulators of microbiota composition and function
(131).
Few studies have investigated the characteristics and com-
position of intestinal microbiota during nutritional ketosis.
Investigations into the KD on the microbiome of healthy
mice (132), mouse models of autism spectrum disorder (133),
and refractory epilepsy (132, 134) demonstrate decreases in
bacterial abundance and diversity. Similar findings were also
noted in patients with refractory epilepsy treated with a KD.
The reduction in microbiome diversity and differences in both
taxonomic and functional composition have been demonstrated
in children with refractory epilepsy consuming a KD (135–
137). However, patients with autoimmune multiple sclerosis
consuming a KD were found to have a significant increase in
bacterial richness after 6 mo following an initial decrease at 2 wk
(138). These results suggest that the changes in gut microbiota
composition may also be dynamic and associated with the process
of keto-adaptation. Although conducted in small cohorts with
specific metabolic conditions, and using different formulations
of ketogenic diets, such data clearly demonstrate the impact of a
KD on the gut microbiota.
The intestinal microbiota of elite athletes has been shown
to differ from control subjects and is thought to be primary
due to variation in dietary macronutrient composition (139,
140). In elite race walkers consuming a KD for 3 wk, there
was a relatively greater abundance of intestinal Bacteroides
and Dorea and a reduction of Faecalibacterium compared with
high-carbohydrate and periodized-carbohydrate groups (141). In
these same athletes, the oral microbiome had a decrease in the
relative amount of Haemophilus, Neisseria, and Prevotella spp.
and an increase in the relative amount of Streptococcus spp.;
these changes have been speculated to provide an environment
of impaired enterosalivary nitrate-nitrite-NO axis, which would
negatively affect exercise performance (142). As our collective
understanding of the diversity and functional changes of the
microbiome advances, its correlation with keto-adaptation may
be further unraveled.
Summary and Conclusions
Current investigations into the impact of a KD on exercise
and sports performance often neglect to account for a necessary
period of adaptation to the diet. Keto-adaptation is a whole-
body process whereby FAs and KBs are preferentially used
over glucose in metabolically active tissues. Keto-adaptation
is facilitated by aerobic exercise through an upregulation in
gene expression and enzymes involved in FA oxidation and
ketolysis and a more oxidative myofiber phenotype, providing
a unique advantage for endurance-trained athletes. The time
duration needed for adequate keto-adaptation has not been
 Keto-adaptation on exercise performance
well defined and is multifactorial and individualized; the time
course of dynamic changes in serum KBs, fat and carbohydrate
metabolites, muscle glycogen, and serum uric acid provides
potential biomarkers of keto-adaptation status. Furthermore,
FGF21, a hormonal regulator of glucose and lipid metabolism,
appears to play an important role in the AMPK-SIRT1-PGC-
1α pathway responsible for the adaptation of SM to a KD and
exercise. FGF15/19, FGF1, adiponectin, IL-6, and the micro-
biome represent emerging factors regulating whole-body keto-
adaptation. Future studies into the impact of nutritional ketosis on
exercise performance must account for and consistently quantify
keto-adaptation.
The authors’ contributions were as follows—HL: designed research
(project conception, development of overall research plan, and oversight),
had primary responsibility for final content, reference analysis, manuscript
preparation. MS: reference analysis, manuscript preparation. MS and HL
declare that they have no potential conflicts of interest to disclose.
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