Jacob Bell
New Member
SAVINA NODARI, ALESSANDRA MANERBA, MARCO METRA, LIVIO DEI CAS
Section of Cardiovascular Diseases, Department of Experimental and Applied Medicine, University of Brescia - Italy
ABSTRACT: The prevalence of obesity continues to increase and represents one of the principal
causes of cardiovascular morbidity and mortality. After the discovery of a specific receptor of the
psychoactive principle of marijuana, the cannabinoid receptors and their endogenous ligands,
several studies have demonstrated the role of this system in the control of food intake and energy
balance and its overactivity in obesity. Recent studies with the CB1 receptor antagonist rimonabant
have demonstrated favorable effects such as a reduction in body weight and waist circumference
and an improvement in metabolic factors (cholesterol, triglycerides, glycemia etc).
Therefore, the antagonism of the endocannabinoid (EC) system, if recent data can be confirmed,
could be a new treatment target for high risk overweight or obese patients. Obesity is a growing
problem that has epidemic proportions worldwide and is associated with an increased risk of
premature death (1-3). Individuals with a central deposition of fats have elevated cardiovascular
morbidity and mortality (including stroke, heart failure and myocardial infarction) and, because of
a growing prevalence not only in adults but also in adolescents, it was reclassified in AHA guidelines
as a "major modifiable risk factor" for coronary heart disease (4, 5). Although first choice
therapy in obesity is based on correcting lifestyle (diet and physical activity) in patients with abdominal
obesity and high cardiovascular risk and diabetes, often it is necessary to use drugs
which reduce the risks. The EC system represents a new target for weight control and the improvement
of lipid and glycemic metabolism (6, 7). (Heart International 2007; 3: 27-34)
KEY WORDS: Endocannabinoid system, Obesity, CB1 antagonists
THE ENDOCANNABINOID SYSTEM
The identification, in the mid-1960s, of the major psycochoactive
component of Cannabis sativa and marijuana
(Δ9-tetrahydrocannabinol, Δ9 THC) and the discovery
of its membrane receptors, paved the way to reveal
a whole endogenous signaling system known as
the endocannabinoid (EC) system (7).
Several studies have demonstrated the role of the EC
system in physiological functions, such as homeostasis
and stress response. EC have neuroprotective and analgesic
properties, controlling movement and some memory
processes (8, 9). Moreover, the EC system modulates
immune, endocrine and inflammatory response.
Finally, EC influence the pulmonary and cardiovascular
system, controlling blood pressure and heart rhythm
and having bronchodilatating properties (6-9).
Endocannabinoids
Anandamide (N-arachidonoyl-ethanolamine (AEA))
and 2-arachidonoyl-glycerol (2-AG) are the most studied
EC, but recently new synthetic and non-synthetic
molecules have been proposed as cannabinoid receptor
agonists (Fig. 1) (6, 7).
It is well established that AEA and 2-AG are not prestored
in secretory vesicles but are de novo biosynthesized
following an increase in the intracellular concen-
tration of calcium, within a framework of a metabolic reaction
involving phospholipid precursors (N-acylphosphatidyl-
ethanolamine and diacylglycerol) and
specific calcium-sensitive enzymes (phospholipasis D
and diacylglycerol lipasis). Therefore, the whole EC
production is triggered "on demand". EC are released
from the cell immediately after their biosynthesis and
then quickly removed from the extracellular space by a
rapid and selective cellular reuptake mechanism (not
yet clear). In particular, EC transport is not leaded by
transmembrane ionic gradients, but to passive diffusion
through a transporter not yet identified. Instead, EC
degradation consists of the hydrolysis of AEA to
ethanolamine and arachidonic acid by fatty acid amide
hydrolase (FAAH) and of 2-AG by monoacyl-glycerol lipases
(6, 7).
Cannabinoid receptors
To date, only two cannabinoid receptors have been
cloned: the CB1 and CB2 receptors (8, 9).
At first the CB1 receptor was thought to be expressed
just in the cortical brain region (neocortex, hippocampus,
amigdala), in the basal ganglia, in the mesolimbic system,
in the thalamus and hypothalamus and in the cerebellum:
neurons of these areas regulate the expression of orexigenic
and anorexigenic signals (10, 11).
Recent studies have demonstrated that CB1 receptors
are expressed in peripheral cells and tissues controlling
energy homeostasis, including gut, liver
adipocytes, skeletal muscle and pancreas.
CB2 receptors are present in several immune cells
and blood cells where they participate in the regulation
of cytokine release and function (10). Nevertheless, CB2
receptors also develop functions in other cells such as
the cheratinocitis, the osteoclastis and the endocrine
pancreas.
Since CB2 agonists have no psychological effects on
central nervous system they have become the object of
numerous studies in the therapeutic use of cannabinoids,
particularly as regards the analgesic, anti-inflammatory
and antineoplastic effects.
Endocannabinoids act primarily at cannabinoid CB1
and/or CB2 receptors with different efficacy. Synthetic
cannabinoids have been created so as to act as highly
selective agonists or antagonists for CB1 or CB2 receptors.
Δ9-tetrahydrocannabinol and 2-AG approximately
have similar affinity for CB1 and CB2 receptors, while
the AEA has a marginal selectivity for CB1 receptors.
However, the effectiveness of the Δ9-THC and the AEA
is lower in CB2 receptor than in CB1 receptor (7).
Both receptors belong to the family of the receptors
coupled to the G protein (GPCRs). The intracellular signaling
events include:
1. inhibition of stimulus-induced adenylate cyclase and
subsequent impairment of cAMP/protein kinase Amediated
short and long-term effects;
2. stimulation of mitogen-activated protein kinase signaling;
3. in case of CB1 receptors, inhibition of voltage-gated
Ca2+ channels and stimulation of inwardly rectifying
G protein-coupled K+ channels;
4. in case of CB1, stimulation of phosphatidylinositol 3-
kinase and of intracellular Ca2+ mobilization (7).
ENDOCANNABINOID SYSTEM AND MODULATION OF
ENERGETIC BALANCE
The EC system participates in the modulation of the
so-called mechanisms of pleasure and the manipulation
of this system influences appetite. Elevated CB1 expression
in cerebral areas involved in the control of
pleasure indicates a strong involvement of this system
in different psychological functions, regulated by these
regions of the brain, including appetite (10).
Under these circumstances, the ingested food that
acts on the nervous fibers which connect the hindbrain
29
and the midbrain to the hypothalamus influences
dopamine, opioids, serotonine and noradrenaline modulating
appetite and satisfaction.
The most remarkable route of pleasure is represented
by the mesolimbic dopaminergic system. The study of
this system clearly shows the existence of an increase
of dopamine extracellular levels inside the accumbens
nucleus after the ingestion of tasty food. Psychoactive
drugs such as marijuana and ethanolol, but also pleasant
stimuli or tasty foods, are known to induce the release
of dopamine in specific cerebral regions. At this
level, the existence of a relationship has also been
shown between the EC system and the oppioid and
serotoninergic system (12).
It is now widely accepted that EC released from depolarized
post-synaptic neurons retrogradely activate
presynaptic CB1 receptors, thereby reducing both inhibitory
(GABA mediated) and excitatory (glutamate mediated)
neurotransmission. This property seems to participate
in EC regulation of the hypothalamic networks
and of the anorexigenic (arcuate nucleus expressing cocaine-
amphetamine regulated transcript — CART and
paraventricular nucleus expressing corticotrophin-releasing
hormone) and orexigenic signals (lateral hypoyhalamus
neurons containing melanin-concentratinghormone
and orexins) (13-15).
Signals coming from various peripheral organs such
as the liver, the gut and the adipose tissue direct hormonal
and biochemical signals to the hypothalamus to
notify the central nervous system about nutritional
state. An example of this peripheral control is leptin, a
hormone produced only by adipose tissue able to interact
with specific receptors located in the hypothalamus
to carry an anorexigenic signal. The EC system is modulated
by leptin too; it was demonstrated that acute
treatment with leptin reduces hypothalamic levels of
AEA and 2-AG in normal mice, but above all it was underlined
that, in mice made obese and hyperphagic by a
defect of the leptin signal, EC hypothalamic levels are
permanently and pathologically elevated (14, 15).
Finally, some experimental evidence indicated that
EC and CB1 receptors regulate energetic metabolism
through a peripheral action at the level of the adipose
tissue, liver and pancreas (16-18).
Cota et al (11) demonstrated for the first time that
wild-type rats exhibit significantly higher amounts of fat
mass than CB1 receptor deficient rats. In addition, CB1
receptors stimulate lipoprotein lipase; as a consequence
they activate lipogenesis, suggesting that EC contribute
to the accumulation of body fat not only stimulating food
intake, but also acting directly at the adipose tissue level.
Recent studies in vitro on adipose cell cultures underlined
that CB1 receptors blockage induces an arrest
of adipocytis proliferation, while chronic stimulation of
these receptors induces differentiation of preadipocytis
to adipocytis, shown by the early appearance of the differentiation
marker PPAR (peroxisome proliferator activated
receptor). These results confirm that EC actively
participate in adipogenesis and fat accumulation; however,
it was observed that AEA is able to act on PPAR receptors,
independently from CB1 receptors (7).
In the liver, CB1 receptors are expressed around the
centrolobular vein, where, stimulating the expression of
SREBP-1c (steroid regulatory element binding protein
1-c) and its target (acetilCoA-carboxylase 1 and fatty
acid synthase), they activate lipogenesis and fatty acid
synthesis (7).
More recently, it was observed that EC are able to
regulate insulin levels, peripheral glucose uptake; and
therefore, to increase glucose tolerance. EC through
CB1 activation, would seem to be able to modify the secretion
of Ca2+ and, therefore, of insulin (19). Nevertheless,
further studies will be necessary to define the role
of the EC system in the pancreas.
ENDOCANNABINOID OVERACTIVITY IN OBESITY
Obesity is probably a condition associated to the hyperactivity
of the EC system. This recent hypothesis is
supported by a series of studies developed on animal
models of obesity; nevertheless, it still needs to be
demonstrated in humans.
It was demonstrated that the CB1 receptor is overexpressed
in tissues which control energetic metabolism
such as the liver (18), skeletal muscles (9) and the adipose
organ (12, 16) when animals are made obese by a high fat
diet. In addition, the most important demonstration about
metabolism, is that the hyperactivation of the EC system
induces in adipocyte cultures a reduction in the levels of
adiponectin and an increase in visfatin, two adipokines
having opposing roles. Adiponectin, a hormone produced
only by adipose tissue, plays an important role in
the modulation of fat and glucose metabolism, because
it inhibits hepatic gluconeogenesis and controls free
fatty acid production, through the suppression of lipogenesis
and the activation of fatty acid oxidation (16)
(Fig. 2).
It is still premature to express a judgment on the clinical
meaning of circulating levels of EC in humans and
the mechanisms that would stimulate overactivity of the
EC system in obesity remain unclear. In obese women, with no others comorbidities, and
whose cause of obesity was correlated to alimentary
disorders or to the menopause, AEA and 2-AG levels
were significantly greater than in the control group (17)
(Fig. 3). In addition, in patients affected by diabetes
mellitus type 2, EC levels were significantly greater than
in non-diabetic controls (20).
According to a recent study (21), a possible mechanism
of EC system hyperactivation would be represented
by a reduced degradation of AEA; the authors identified
in a population of obese subjects a polymorphism,
at the level of the FAAH sequence, the enzyme appointed
to the degradation of AEA, which would behave as
reduced enzymatic activity (21).
ENDOCANNABINOID SYSTEM ANTAGONISTS IN THE
TREATMENT OF OBESITY
The increasing evidence of the role of the EC system
in the regulation of food intake and energetic balance
has stimulated the development of CB1 receptor blockers,
whose the most studied one in the treatment of
obesity is rimonabant (Fig. 4).
An extensive study of experimental phase III denominated
RIO (rimonabant in obesity), was conducted on
about 6600 obese or overweight patients (22). This experiment
was composed of four substudies (RIO-North
America, RIO-Europe, RIO-Lipids and RIO-Diabetes) directed
to identify the effectiveness of rimonabant on
bodyweight as a primary end-point and on various
metabolic alterations such as secondary end-point.
The pharmacological treatment, of 5 or 20 mg of rimonabant
vs. placebo, was associated with a reduction
in energy intake of 600 calories in respect of basal
metabolic rate and to an increase in physical activity
(Fig. 5). In RIO-North America (23) compared to RIO-Europe
(24), patients enrolled after the first year were re-
randomized to placebo or rimonabant, for monitoring
possible resumption of body weight at the end of the
drug treatment. RIO-Lipids (25) and RIO-Diabetes (26)
were programmed for investigating the improvements
due to the administration of rimonabant, in patients that
were associated with obesity or with overweight diabetes
and dyslipidemia, respectively.
In all studies, treatment with rimonabant 20 mg produced
results significantly greater than 5 mg and the results
were equivalent for primary and secondary endpoints.
The treatment with 20 mg rimonabant determined in
comparison to the placebo group a significant reduction
in body weight (8.7 vs. 2.8 kg in RIO-North America, 8.6
vs. 3.6 kg in RIO-Europe, 8.6 vs. 2.3 kg in RIO-Lipids,
6.1 vs. 1.9 kg in RIO-Diabetes) and of waist circumference
(8.5 vs. 4 cm in RIO-North America, 9 vs. 3 cm in
RIO-Europe, 9 vs. 4 cm in RIO-Lipids, 5.2 vs. 1.9 cm in
RIO-Diabetes) (Fig. 6). In the group treated with rimonabant
a significant improvement in the lipidic profile was
also observed, with an increase in high-density lipoprotein
(HDL) cholesterol, a reduction in triglycerides, and
an improvement in glycemia and insulinemia during oral
glucose tolerance test.
In RIO-Lipids, changes in leptin and adiponectin levels
were observed, demonstrating a significant decrease
of leptin and an increase of the circulating levels
of adiponectin in patients treated with rimonabant. Multivariate
analysis showed that rimonabant had independent
positive effects from weight loss on lipidic profile
and adiponectin levels. In RIO-Europe around 50% of
the variation in HDL cholesterol and in triglycerides was
independent from weight loss, while in the RIO-Lipids
the increase of 57% in adiponectin did not seem justifiable
on the basis of caloric reduction only, but rather related
to the peripheral action of rimonabant.
In RIO-Diabetes, the HbA1 levels were lower in both
rimonabant groups compared to the placebo group and
showed a persistent reduction in the rimonabant 20 mg
group. In addition, it was possible to show that the reduction
of HbA1 levels, that was two-fold higher than
the reduction due to weight loss, was independent from
the reduction in body weight, related to a peripheral action
of rimonabant.
Finally, in RIO-North America during the second year
of treatment in the group that continued with rimonabant,
a continuous and progressive reduction in body
weight was observed, while in the group randomized to
placebo a recovery of most of the weight lost during the
first year was associated with an increase in triglycerides
and a reduction in HDL cholesterol.
Rimonabant was generally well tolerated and the
most frequent side effects were gastrointestinal (nausea
and diarrhea) and humoral (anxiety and depression).
CONCLUSIONS
The prevalence of obesity is continuously increasing
and represents one of the principal causes of cardiovascular
morbidity and mortality. The recent discovery
of the role of the EC system in the control of energetic
metabolism and the presence of the overactivity of this
system in obesity, has enabled the development of new
drugs, antagonists of CB1 receptors such as rimonabant.
These drugs are able not only to determine a reduction
in body weight, but also to promote favorable
effects on lipidic and glycemic profiles, independently
from weight reduction.
Therefore, CB1 antagonists could represent a new
therapeutic option for the treatment of obesity and the
comorbidities related to it, when the currently available
data will be confirmed by further clinical studies.
REFERENCES
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obesity with cardiovascular disease. Nature 2006; 444;
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2. James PT, Rigby N, Leach R. International Obesity Task
Force. The obesity epidemic, metabolic syndrome and
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3. Adams KF, Schatzkin A, Harris TB, et al. Overweight, obesity,
and mortality in a large prospective cohort of persons
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4. Berenson GS, Srinivasan SR, Bao W, Newman WP 3rd,
Tracy RE, Wattigney WA. Association between multiple
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Med 1998; 338: 1650-6.
5. Eckel RH, Kahn R, Robertson RM, Rizza RA. Preventing
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6. De Petrocellis L, Cascio MG, Di Marzo V. The endocannabinoid
system: a general view and latest additions.
Br J Pharmacol 2004; 141: 765-74.
7. Matias I, Di Marzo V. Endocannabinoids and the control of
energy balance. Trends Endocrinol Metab 2007; 18:
27-37.
8. Piomelli D. The molecular logic of endocannabinoid signalling.
Nat Rev Neurosci 2003; 4: 873-84.
9. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The
emerging role of the endocannabinoid system in endocrine
regulation and energy balance. Endocr Rev 2006;
27: 73-100.
10. Howlett AC, Barth F, Bonner TI, et al. International Union
of Pharmacology. XXVII. Classification of cannabinoid receptors.
Pharmacol Rev 2002; 54: 161-202.
11. Cota D, Marsicano G, Tschoep M, et al. The endogenous
cannabinoid system affects energy balance via central
orexigenic drive and peripheral lipogenesis. J Clin Invest
2003; 112: 423-31.
12. Cota D, Marsicano G, Lutz B, et al. Endogenous cannabinoid
system as a modulator of food intake. Int J Obes Relat
Metab Disord 2003; 27: 289-301.
13. Flier JS. Obesity wars: molecular progress confronts an
expanding epidemic. Cell 2004; 116: 337-50.
14. Di Marzo V, Goparaju SK, Wang L, et al. Leptin-regulated
endocannabinoids are involved in maintaining food intake.
Nature 2001; 410: 822-5.
15. Jo YH, Chen YJJ, Chua SC Jr, Talmage DA, Role LW. Integration
of endocannabinoid and leptin signaling in an appetite-
related neural circuit. Neuron 2005; 48: 1055-66.
16. Bensaid M, Gary-Bobo M, Esclangon A, et al. The
cannabinoid CB1 receptor antagonist SR141716 increases
Acrp30 mRNA expression in adipose tissue of obese
fa/fa rats and in cultured adipocyte cells. Mol Pharmacol
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17. Engeli S, Bohnke J, Feldpausch M, et al. Activation of the
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2005; 54: 2838-43.
18. Osei-Hyiaman D, De Petrillo M, Pacher P, et al. Endocannabinoid
activation at hepatic CB1 receptors stimulates
fatty acid synthesis and contributes to diet-induced
obesity. J Clin Invest 2005; 115: 1298-305.
19. Juan-Pico P, Fuentes E, Javier Bermudez-Silva F, et al.
Cannabinoid receptors regulate Ca2+ signals and insulin
secretion in pancreatic beta-cell. Cell Calcium 2006; 39:
155-62.
20. Matias I, Gonthier MP, Orlando P, et al. Regulation, function,
and dysregulation of endocannabinoids in models of
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21. Sipe JC, Waalen J, Gerber A, Beutler E. Overweight and
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23. Pi-Sunyer FC, Aronne LJ, Rosenstock J: RIO-North
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24. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner
S: RIO-Europe Study Group. Effects of the cannabinoid-
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25. Despres JP, Golay A, Sjostrom L: Rimonabant in Obesity-
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26. Scheen A, Finer N, Hollander P, Jensen M, Van Gaal LF,
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type 2 diabetes: a randomised controlled study. Lancet
2006; 368: 1660-72.
Source: Endocannabinoids and cardiovascular prevention: real progress?
Section of Cardiovascular Diseases, Department of Experimental and Applied Medicine, University of Brescia - Italy
ABSTRACT: The prevalence of obesity continues to increase and represents one of the principal
causes of cardiovascular morbidity and mortality. After the discovery of a specific receptor of the
psychoactive principle of marijuana, the cannabinoid receptors and their endogenous ligands,
several studies have demonstrated the role of this system in the control of food intake and energy
balance and its overactivity in obesity. Recent studies with the CB1 receptor antagonist rimonabant
have demonstrated favorable effects such as a reduction in body weight and waist circumference
and an improvement in metabolic factors (cholesterol, triglycerides, glycemia etc).
Therefore, the antagonism of the endocannabinoid (EC) system, if recent data can be confirmed,
could be a new treatment target for high risk overweight or obese patients. Obesity is a growing
problem that has epidemic proportions worldwide and is associated with an increased risk of
premature death (1-3). Individuals with a central deposition of fats have elevated cardiovascular
morbidity and mortality (including stroke, heart failure and myocardial infarction) and, because of
a growing prevalence not only in adults but also in adolescents, it was reclassified in AHA guidelines
as a "major modifiable risk factor" for coronary heart disease (4, 5). Although first choice
therapy in obesity is based on correcting lifestyle (diet and physical activity) in patients with abdominal
obesity and high cardiovascular risk and diabetes, often it is necessary to use drugs
which reduce the risks. The EC system represents a new target for weight control and the improvement
of lipid and glycemic metabolism (6, 7). (Heart International 2007; 3: 27-34)
KEY WORDS: Endocannabinoid system, Obesity, CB1 antagonists
THE ENDOCANNABINOID SYSTEM
The identification, in the mid-1960s, of the major psycochoactive
component of Cannabis sativa and marijuana
(Δ9-tetrahydrocannabinol, Δ9 THC) and the discovery
of its membrane receptors, paved the way to reveal
a whole endogenous signaling system known as
the endocannabinoid (EC) system (7).
Several studies have demonstrated the role of the EC
system in physiological functions, such as homeostasis
and stress response. EC have neuroprotective and analgesic
properties, controlling movement and some memory
processes (8, 9). Moreover, the EC system modulates
immune, endocrine and inflammatory response.
Finally, EC influence the pulmonary and cardiovascular
system, controlling blood pressure and heart rhythm
and having bronchodilatating properties (6-9).
Endocannabinoids
Anandamide (N-arachidonoyl-ethanolamine (AEA))
and 2-arachidonoyl-glycerol (2-AG) are the most studied
EC, but recently new synthetic and non-synthetic
molecules have been proposed as cannabinoid receptor
agonists (Fig. 1) (6, 7).
It is well established that AEA and 2-AG are not prestored
in secretory vesicles but are de novo biosynthesized
following an increase in the intracellular concen-
tration of calcium, within a framework of a metabolic reaction
involving phospholipid precursors (N-acylphosphatidyl-
ethanolamine and diacylglycerol) and
specific calcium-sensitive enzymes (phospholipasis D
and diacylglycerol lipasis). Therefore, the whole EC
production is triggered "on demand". EC are released
from the cell immediately after their biosynthesis and
then quickly removed from the extracellular space by a
rapid and selective cellular reuptake mechanism (not
yet clear). In particular, EC transport is not leaded by
transmembrane ionic gradients, but to passive diffusion
through a transporter not yet identified. Instead, EC
degradation consists of the hydrolysis of AEA to
ethanolamine and arachidonic acid by fatty acid amide
hydrolase (FAAH) and of 2-AG by monoacyl-glycerol lipases
(6, 7).
Cannabinoid receptors
To date, only two cannabinoid receptors have been
cloned: the CB1 and CB2 receptors (8, 9).
At first the CB1 receptor was thought to be expressed
just in the cortical brain region (neocortex, hippocampus,
amigdala), in the basal ganglia, in the mesolimbic system,
in the thalamus and hypothalamus and in the cerebellum:
neurons of these areas regulate the expression of orexigenic
and anorexigenic signals (10, 11).
Recent studies have demonstrated that CB1 receptors
are expressed in peripheral cells and tissues controlling
energy homeostasis, including gut, liver
adipocytes, skeletal muscle and pancreas.
CB2 receptors are present in several immune cells
and blood cells where they participate in the regulation
of cytokine release and function (10). Nevertheless, CB2
receptors also develop functions in other cells such as
the cheratinocitis, the osteoclastis and the endocrine
pancreas.
Since CB2 agonists have no psychological effects on
central nervous system they have become the object of
numerous studies in the therapeutic use of cannabinoids,
particularly as regards the analgesic, anti-inflammatory
and antineoplastic effects.
Endocannabinoids act primarily at cannabinoid CB1
and/or CB2 receptors with different efficacy. Synthetic
cannabinoids have been created so as to act as highly
selective agonists or antagonists for CB1 or CB2 receptors.
Δ9-tetrahydrocannabinol and 2-AG approximately
have similar affinity for CB1 and CB2 receptors, while
the AEA has a marginal selectivity for CB1 receptors.
However, the effectiveness of the Δ9-THC and the AEA
is lower in CB2 receptor than in CB1 receptor (7).
Both receptors belong to the family of the receptors
coupled to the G protein (GPCRs). The intracellular signaling
events include:
1. inhibition of stimulus-induced adenylate cyclase and
subsequent impairment of cAMP/protein kinase Amediated
short and long-term effects;
2. stimulation of mitogen-activated protein kinase signaling;
3. in case of CB1 receptors, inhibition of voltage-gated
Ca2+ channels and stimulation of inwardly rectifying
G protein-coupled K+ channels;
4. in case of CB1, stimulation of phosphatidylinositol 3-
kinase and of intracellular Ca2+ mobilization (7).
ENDOCANNABINOID SYSTEM AND MODULATION OF
ENERGETIC BALANCE
The EC system participates in the modulation of the
so-called mechanisms of pleasure and the manipulation
of this system influences appetite. Elevated CB1 expression
in cerebral areas involved in the control of
pleasure indicates a strong involvement of this system
in different psychological functions, regulated by these
regions of the brain, including appetite (10).
Under these circumstances, the ingested food that
acts on the nervous fibers which connect the hindbrain
29
and the midbrain to the hypothalamus influences
dopamine, opioids, serotonine and noradrenaline modulating
appetite and satisfaction.
The most remarkable route of pleasure is represented
by the mesolimbic dopaminergic system. The study of
this system clearly shows the existence of an increase
of dopamine extracellular levels inside the accumbens
nucleus after the ingestion of tasty food. Psychoactive
drugs such as marijuana and ethanolol, but also pleasant
stimuli or tasty foods, are known to induce the release
of dopamine in specific cerebral regions. At this
level, the existence of a relationship has also been
shown between the EC system and the oppioid and
serotoninergic system (12).
It is now widely accepted that EC released from depolarized
post-synaptic neurons retrogradely activate
presynaptic CB1 receptors, thereby reducing both inhibitory
(GABA mediated) and excitatory (glutamate mediated)
neurotransmission. This property seems to participate
in EC regulation of the hypothalamic networks
and of the anorexigenic (arcuate nucleus expressing cocaine-
amphetamine regulated transcript — CART and
paraventricular nucleus expressing corticotrophin-releasing
hormone) and orexigenic signals (lateral hypoyhalamus
neurons containing melanin-concentratinghormone
and orexins) (13-15).
Signals coming from various peripheral organs such
as the liver, the gut and the adipose tissue direct hormonal
and biochemical signals to the hypothalamus to
notify the central nervous system about nutritional
state. An example of this peripheral control is leptin, a
hormone produced only by adipose tissue able to interact
with specific receptors located in the hypothalamus
to carry an anorexigenic signal. The EC system is modulated
by leptin too; it was demonstrated that acute
treatment with leptin reduces hypothalamic levels of
AEA and 2-AG in normal mice, but above all it was underlined
that, in mice made obese and hyperphagic by a
defect of the leptin signal, EC hypothalamic levels are
permanently and pathologically elevated (14, 15).
Finally, some experimental evidence indicated that
EC and CB1 receptors regulate energetic metabolism
through a peripheral action at the level of the adipose
tissue, liver and pancreas (16-18).
Cota et al (11) demonstrated for the first time that
wild-type rats exhibit significantly higher amounts of fat
mass than CB1 receptor deficient rats. In addition, CB1
receptors stimulate lipoprotein lipase; as a consequence
they activate lipogenesis, suggesting that EC contribute
to the accumulation of body fat not only stimulating food
intake, but also acting directly at the adipose tissue level.
Recent studies in vitro on adipose cell cultures underlined
that CB1 receptors blockage induces an arrest
of adipocytis proliferation, while chronic stimulation of
these receptors induces differentiation of preadipocytis
to adipocytis, shown by the early appearance of the differentiation
marker PPAR (peroxisome proliferator activated
receptor). These results confirm that EC actively
participate in adipogenesis and fat accumulation; however,
it was observed that AEA is able to act on PPAR receptors,
independently from CB1 receptors (7).
In the liver, CB1 receptors are expressed around the
centrolobular vein, where, stimulating the expression of
SREBP-1c (steroid regulatory element binding protein
1-c) and its target (acetilCoA-carboxylase 1 and fatty
acid synthase), they activate lipogenesis and fatty acid
synthesis (7).
More recently, it was observed that EC are able to
regulate insulin levels, peripheral glucose uptake; and
therefore, to increase glucose tolerance. EC through
CB1 activation, would seem to be able to modify the secretion
of Ca2+ and, therefore, of insulin (19). Nevertheless,
further studies will be necessary to define the role
of the EC system in the pancreas.
ENDOCANNABINOID OVERACTIVITY IN OBESITY
Obesity is probably a condition associated to the hyperactivity
of the EC system. This recent hypothesis is
supported by a series of studies developed on animal
models of obesity; nevertheless, it still needs to be
demonstrated in humans.
It was demonstrated that the CB1 receptor is overexpressed
in tissues which control energetic metabolism
such as the liver (18), skeletal muscles (9) and the adipose
organ (12, 16) when animals are made obese by a high fat
diet. In addition, the most important demonstration about
metabolism, is that the hyperactivation of the EC system
induces in adipocyte cultures a reduction in the levels of
adiponectin and an increase in visfatin, two adipokines
having opposing roles. Adiponectin, a hormone produced
only by adipose tissue, plays an important role in
the modulation of fat and glucose metabolism, because
it inhibits hepatic gluconeogenesis and controls free
fatty acid production, through the suppression of lipogenesis
and the activation of fatty acid oxidation (16)
(Fig. 2).
It is still premature to express a judgment on the clinical
meaning of circulating levels of EC in humans and
the mechanisms that would stimulate overactivity of the
EC system in obesity remain unclear. In obese women, with no others comorbidities, and
whose cause of obesity was correlated to alimentary
disorders or to the menopause, AEA and 2-AG levels
were significantly greater than in the control group (17)
(Fig. 3). In addition, in patients affected by diabetes
mellitus type 2, EC levels were significantly greater than
in non-diabetic controls (20).
According to a recent study (21), a possible mechanism
of EC system hyperactivation would be represented
by a reduced degradation of AEA; the authors identified
in a population of obese subjects a polymorphism,
at the level of the FAAH sequence, the enzyme appointed
to the degradation of AEA, which would behave as
reduced enzymatic activity (21).
ENDOCANNABINOID SYSTEM ANTAGONISTS IN THE
TREATMENT OF OBESITY
The increasing evidence of the role of the EC system
in the regulation of food intake and energetic balance
has stimulated the development of CB1 receptor blockers,
whose the most studied one in the treatment of
obesity is rimonabant (Fig. 4).
An extensive study of experimental phase III denominated
RIO (rimonabant in obesity), was conducted on
about 6600 obese or overweight patients (22). This experiment
was composed of four substudies (RIO-North
America, RIO-Europe, RIO-Lipids and RIO-Diabetes) directed
to identify the effectiveness of rimonabant on
bodyweight as a primary end-point and on various
metabolic alterations such as secondary end-point.
The pharmacological treatment, of 5 or 20 mg of rimonabant
vs. placebo, was associated with a reduction
in energy intake of 600 calories in respect of basal
metabolic rate and to an increase in physical activity
(Fig. 5). In RIO-North America (23) compared to RIO-Europe
(24), patients enrolled after the first year were re-
randomized to placebo or rimonabant, for monitoring
possible resumption of body weight at the end of the
drug treatment. RIO-Lipids (25) and RIO-Diabetes (26)
were programmed for investigating the improvements
due to the administration of rimonabant, in patients that
were associated with obesity or with overweight diabetes
and dyslipidemia, respectively.
In all studies, treatment with rimonabant 20 mg produced
results significantly greater than 5 mg and the results
were equivalent for primary and secondary endpoints.
The treatment with 20 mg rimonabant determined in
comparison to the placebo group a significant reduction
in body weight (8.7 vs. 2.8 kg in RIO-North America, 8.6
vs. 3.6 kg in RIO-Europe, 8.6 vs. 2.3 kg in RIO-Lipids,
6.1 vs. 1.9 kg in RIO-Diabetes) and of waist circumference
(8.5 vs. 4 cm in RIO-North America, 9 vs. 3 cm in
RIO-Europe, 9 vs. 4 cm in RIO-Lipids, 5.2 vs. 1.9 cm in
RIO-Diabetes) (Fig. 6). In the group treated with rimonabant
a significant improvement in the lipidic profile was
also observed, with an increase in high-density lipoprotein
(HDL) cholesterol, a reduction in triglycerides, and
an improvement in glycemia and insulinemia during oral
glucose tolerance test.
In RIO-Lipids, changes in leptin and adiponectin levels
were observed, demonstrating a significant decrease
of leptin and an increase of the circulating levels
of adiponectin in patients treated with rimonabant. Multivariate
analysis showed that rimonabant had independent
positive effects from weight loss on lipidic profile
and adiponectin levels. In RIO-Europe around 50% of
the variation in HDL cholesterol and in triglycerides was
independent from weight loss, while in the RIO-Lipids
the increase of 57% in adiponectin did not seem justifiable
on the basis of caloric reduction only, but rather related
to the peripheral action of rimonabant.
In RIO-Diabetes, the HbA1 levels were lower in both
rimonabant groups compared to the placebo group and
showed a persistent reduction in the rimonabant 20 mg
group. In addition, it was possible to show that the reduction
of HbA1 levels, that was two-fold higher than
the reduction due to weight loss, was independent from
the reduction in body weight, related to a peripheral action
of rimonabant.
Finally, in RIO-North America during the second year
of treatment in the group that continued with rimonabant,
a continuous and progressive reduction in body
weight was observed, while in the group randomized to
placebo a recovery of most of the weight lost during the
first year was associated with an increase in triglycerides
and a reduction in HDL cholesterol.
Rimonabant was generally well tolerated and the
most frequent side effects were gastrointestinal (nausea
and diarrhea) and humoral (anxiety and depression).
CONCLUSIONS
The prevalence of obesity is continuously increasing
and represents one of the principal causes of cardiovascular
morbidity and mortality. The recent discovery
of the role of the EC system in the control of energetic
metabolism and the presence of the overactivity of this
system in obesity, has enabled the development of new
drugs, antagonists of CB1 receptors such as rimonabant.
These drugs are able not only to determine a reduction
in body weight, but also to promote favorable
effects on lipidic and glycemic profiles, independently
from weight reduction.
Therefore, CB1 antagonists could represent a new
therapeutic option for the treatment of obesity and the
comorbidities related to it, when the currently available
data will be confirmed by further clinical studies.
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Source: Endocannabinoids and cardiovascular prevention: real progress?
