Cheng, Sulin

Pekkala, Satu

Wiklund, Petri

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Available online at www.sciencedirect.comJournal of Sport and Health Science 2 (2013) 60e61
www.jshs.org.cnResearch Highlight
Exercise, the endocannabinoid system and metabolic health
Petri Wiklund a, Satu Pekkala a, Sulin Cheng a,b,*
aDepartment of Health Sciences, University of Jyva¨skyla¨, FI-40014 Jyva¨skyla¨, Finland
b School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China
Received 18 January 2013; accepted 21 January 20131. The endocannabinoid system in obesity and metabolic
disorders
As obesity and associated metabolic disorders, such as type
2 diabetes and dyslipidemia, are becoming one of the most
serious health problems worldwide, development of effective
therapies is a high priority. In the search for treatments, the
recently discovered endocannabinoid system (ECS) has begun
to garner attention, and a wealth of research is now focusing
on this unique neuromodulatory system named after the plant
that led to its discovery.1
The ECS consists of G protein-coupled cannabinoid
receptors (CB1 and CB2), their endogenous lipid-derived
ligands (endocannabinoids, N-arachidonoylethanolamine,
named anandamide (AEA) and 2-arachidonoylglycerol (2-AG))
and the enzymes for ligand synthesis and degradation. Endo-
cannabinoids, the organic derivative of cannabis, produced
naturally in the body, are well known to modulate many
cognitive and emotional processes, through which they influ-
ence multiple behavioral responses.2 However, a number of
studies published in recent years indicate that endocannabinoids
are also key modulators of energy balance through central and
peripheral mechanisms.1 In the central nervous system, the
activation of CB1 receptors by endocannabinoids increases food
intake, whereas in the peripheral organs, such as gastrointestinal
tract, liver, adipose tissue, and skeletal muscle, endocannabi-
noids are involved in the regulation of nutrient absorption and
glucose and lipid metabolism.3 Considering the important* Corresponding author. School of Kinesiology, Shanghai University of Sport,
Shanghai 200438, China.
E-mail address: sulin.cheng@jyu.fi (S. Cheng)
Peer review under responsibility of Shanghai University of Sport
Production and hosting by Elsevier
2095-2546 Copyright  2013, Shanghai University of Sport. Production and hosti
http://dx.doi.org/10.1016/j.jshs.2013.01.003regulatory role of the ECS in energy metabolism, it is not
surprising to observe its dysregulation in obesity.
Recent data suggest that ECS overactivity is associated
with increased lipogenesis, insulin resistance, and dyslipide-
mia.4 Hence, the ECS has become a promising pharmaco-
logical target in combating obesity and the associated
metabolic disorders.5 Although some clinical trials with
specific CB1 receptor antagonists/inverse agonists have been
successful in terms of reduction of body weight and amelio-
ration of obesity-related metabolic abnormalities, the adverse
central and peripheral side effects of these compounds have
seriously limited their therapeutic potential.6 However, recent
findings show that combined calorie restriction and aerobic
exercise can modulate endocannabinoid-related gene expres-
sion in adipose tissue of obese women during weight loss,
suggesting that ECS may link exercise with metabolic adap-
tations and energy regulation.7
2. Plausible metabolic implications of exercise-induced
ECS activation
Apart from the above cited study, the metabolic effects of
ECS following exercise in humans have not been studied.
Several lines of evidence indicate that the ECS may participate
in the adaptive responses to exercise. A recent review by
Heyman et al.8 provides a comprehensive summary of the
topic, and several possible mechanisms can be suggested.
First, plasma AEA increases significantly following acute
strenuous aerobic exercise in humans, while circulating levels
of 2-AG appear not to be influenced by exercise.9e10 Since
AEA has vasodilatory11 and bronchodilatory12 effects,
increase in circulating AEA may aid exercise performance by
facilitating blood flow and breathing during exercise. AEA has
also been shown to improve insulin sensitivity, glucose uptake
and mitochondrial biogenesis in human skeletal muscle
cells,13 and inhibit fatty acid and cholesterol synthesis in
hepatocytes.14 These findings indicate that while CB1ng by Elsevier B.V. Open access under CC BY-NC-ND license.
Exercise and endocannabinoid system 61signaling negatively modulates insulin signaling and substrate
oxidation in metabolically active tissues,15 AEA has opposite
effects, which appear to be mediated independently of the
cannabinoid receptors.
Second, exercise-induced elevation of plasma AEA is
intensity-dependent. According to a recent study, only
moderate exercise intensities (w70%e85% age-adjusted
maximum heart rate) significantly increase circulating levels
of AEA.16 This observation is consistent with findings that
several cardio-metabolic risk factors are also most favorably
affected by moderate-intensity exercise compared to low-
intensity exercise.17
Third, chronic aerobic exercise has been shown to atten-
uate CB1 mRNA over-expression in visceral and subcuta-
neous adipose tissues of obese rats fed with a high-fat diet.18
Our unpublished data corroborate these findings by showing
that chronic aerobic exercise decreases CB1 protein expres-
sion in skeletal muscle of mice fed with a high fat diet. Given
the crucial role of skeletal muscle in whole body energy
expenditure and substrate oxidation, especially during exer-
cise, this observation may turn out to be of great importance
for the treatment of obesity and the associated metabolic
disorders.
Finally, it has been demonstrated that glucocorticoids
increase AEA in limbic structures,19 indicating that endo-
cannabinoid signaling is evoked by stress-induced activation
of the hypothalamic-pituitary-adrenal axis,20 which in turn, is
inhibited by endocannabinoid signaling via non-genomic fast-
feed mechanism.21 The concurrent increase in AEA and
cortisol observed during intense exercise10 suggests that the
increase in plasma AEA during exercise may be ascribed to
the exercise-induced alterations in circulating cortisol. Thus, it
seems that the ECS activation may be essential for the
recovery from a transient stressful condition, such as intense
physical exercise.3. Future challenges
Accumulating evidence shows that the ECS is associated
with physical activity, obesity and related metabolic disorders.
However, to date, no data on the responses of the ECS to
exercise in patients with metabolic diseases have been pub-
lished. Whether acute or chronic exercise can attenuate ECS
over-activity in humans remains to be confirmed. Both
mechanistic and randomized controlled studies are needed to
confirm whether the ECS is involved in the beneficial effects
of exercise on metabolism and energy balance. Understanding
the connection between exercise, ECS and metabolism
deserves further investigation as exercise may represent
a complementary approach to modulate ECS and treat and
prevent obesity and metabolic disorders.Acknowledgments
This study was supported by the Academy of Finland and
Shanghai overseas visiting professor scholarship program.References
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Exercise, the endocannabinoid system and metabolic health 

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Exercise, the endocannabinoid system and metabolic health

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