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European Journal of Internal Medicine
journal homepage: www.elsevier.com/locate/ejim
The therapeutic potential of targeting the peripheral endocannabinoid/CB
, Liad Hinden, Adi Drori, Shiran Udi, Shahar Azar, Saja Baraghithy
Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
Chronic kidney disease
Endocannabinoids (eCBs) are internal lipid mediators recognized by the cannabinoid-1 and -2 receptors (CB
R, respectively), which also mediate the diﬀerent physiological eﬀects of marijuana. The en-
docannabinoid system, consisting of eCBs, their receptors, and the enzymes involved in their biosynthesis and
degradation, is present in a vast number of peripheral organs. In this review we describe the role of the eCB/
R system in modulating the metabolism in several peripheral organs. We assess how eCBs, via activating the
R, contribute to obesity and regulate food intake. In addition, we describe their roles in modulating liver and
kidney functions, as well as bone remodeling and mass. Special importance is given to emphasizing the eﬃcacy
of the recently developed peripherally restricted CB
R antagonists, which were pre-clinically tested in the
management of energy homeostasis, and in ameliorating both obesity- and diabetes-induced metabolic com-
1. The endocannabinoid system
The psychoactive and medicinal uses of Cannabis sativa (marijuana)
have been well known for millennia . However, our understanding
of the underlying mechanisms of action in these physiological processes
emerged only during the 1960s, following the isolation, identiﬁcation,
and synthesis of Δ
-tetrahydrocannabinol (THC), the psychoactive
component of marijuana . It took almost three decades to isolate and
clone the THC binding sites in the brain and periphery, which were then
termed the cannabinoid-1 and -2 receptors (CB
R and CB
tively) [3–5]. Cannabinoid-1 has been recently crystalized by two dif-
ferent groups [6,7]. Both receptors mainly signal via G
despite the fact that they can also activate G
, as well as G pro-
tein-independent signaling pathways . The cloning of CB receptors in
mammalian cells was followed soon afterward by identifying their in-
ternal ligands, arachidonoyl ethanolamide (AEA, anandamide) , and
2-arachidonoyl glycerol (2-AG) [10,11]. Once eCBs are generated and
released, they remain attached to the cell membrane owing to their
lipophilicity, and therefore, they can be taken back up by cells through
a high-aﬃnity transport mechanism . Their clearance depends on
cellular uptake and speciﬁc enzymatic degradation. Whereas AEA is
degraded mainly by membrane-associated fatty-acid amide hydrolase
(FAAH) , 2-AG is primarily degraded by monoglyceride lipase
(MAGL) . The internal cannabinoids, their receptors, and the en-
zymes/proteins involved in their biosynthesis, transport, and
degradation jointly make up the ‘eCB system’.
2. The eCB/CB
R system as a key modulator of energy homeostasis
The well-documented role of cannabis as a bi-modulator of food
intake in rodents and humans [reviewed in ] provided early clues
as to the biological and metabolic functions of its internal counterparts.
A case in point is the ‘munchies eﬀect’, which prompted a study that
provided evidence for the speciﬁc involvement of the eCB/CB
in this phenomenon via regulating leptin signaling in the hypothalamus
R is abundantly expressed on presynaptic nerve terminals 
in central areas controlling food intake and energy expenditure and
reward-related responses. However, it is also present at much lower, yet
functionally relevant levels in many peripheral organs, such as adipose
tissue , liver , skeletal muscle , kidney , bone ,
and pancreas . Therefore, it was not surprising to ﬁnd that its
blockade would inhibit food intake [24–27]. In fact, these observations
provided the motivation for testing such compounds as a potential
treatment for obesity. Indeed, the ﬁrst-in-class CB
R antagonist rimo-
nabant (Acomplia®, Sanoﬁ-Aventis) proved very eﬀective not only in
reducing food intake and body weight, but also in improving the obe-
sity-induced insulin and leptin resistance, restoring glucose homeostasis
and dyslipidemias, as well as ameliorating hepatic fat accumulation in
obese/overweight people with the metabolic syndrome (; [29–34]).
Received 1 December 2017; Received in revised form 3 January 2018; Accepted 4 January 2018
Corresponding author at: Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, POB 12065, Jerusalem 9112001, Israel.
E-mail address: firstname.lastname@example.org (J. Tam).
European Journal of Internal Medicine xxx (xxxx) xxx–xxx
0953-6205/ © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Tam, J., European Journal of Internal Medicine (2018), https://doi.org/10.1016/j.ejim.2018.01.009
The abovementioned ﬁndings, along with a few additional ‘energy
conserving’physiologic eﬀects mediated by either cannabis consump-
tion and/or the activation of the eCB/CB
R system such as anxiolysis,
rewarding, motor suppression, sleep induction, and lipogenesis [re-
viewed in ], may suggest that the internal cannabinoid system is a
pivotal modulator of the ‘thrifty’phenotype, which has helped humans
to survive evolution during frequent periods of starvation. However, in
our Western society of abundant food supplies, combined with a se-
dentary lifestyle, and an increased lifespan, this phenotype has become
the main cause of the epidemic spread of obesity and its metabolic
complications. In fact, the observations that reducing eCB action by
R suggest that increased eCB ‘tone’may be its unifying
pathologic feature that triggers the development of the metabolic syn-
3. Moving from globally acting to peripherally restricted CB
antagonism for the treatment of obesity
An open question remains, regarding the relative importance of
central versus peripheral CB
Rs involved in energy homeostasis and
metabolism. This question has considerable practical and clinical im-
plications in light of the growing documented evidence of anxiety,
depression, and/or suicidal ideation that was reported in a small but
signiﬁcant fraction of humans treated with rimonabant . These
reports led not only to the eventual withdrawal of rimonabant from the
market, but also to the discontinuation of developing all CB
by big pharmaceutical companies, which raised doubts about the
therapeutic potential of this class of molecules .
Generally, the baseline expression level of CB
Rs in periphery is
very low, but it is markedly elevated during obesity and diabetes.
Indeed, increased expression of CB
Rs was reported in adipose tissue
[18,39], liver [39–41], skeletal muscle , kidney , and pancreas
. Whereas the expression levels of receptors and the amount of their
internal ligands are usually inversely correlated, a few examples of an
obesity-related parallel increase in eCBs in the same tissues were
documented [40,42,44]. Moreover, several studies have shown that
circulating eCB levels are positively associated with biomarkers for the
metabolic syndrome [45–48] as well as in genetic causes of obesity,
such as Prader-Willi syndrome . These ﬁndings, together with ad-
ditional studies conducted in murine models for the metabolic syn-
drome showing that (i) activation of CB
R increases lipogenesis in
adipocytes and liver [19,50]; (ii) CB
R blockade attenuates obesity-
induced dysregulation of lipid metabolism in visceral adipose tissue
; and (iii) enhanced insulin receptor signaling results in β-cell
proliferation and mass , suggest that the apparent increase in
peripheral eCB ‘tone’in obesity plays an important physiological role.
This, in turn, may support strategies for antagonizing CB
R only in
peripheral tissues for the treatment of the metabolic syndrome. In fact,
evidence for the inability of rimonabant to reduce food intake in mice
with a selective deletion of CB
Rs in CAM kinase IIα-expressing neurons
, which are prominently expressed not only in forebrain and per-
ipheral sympathetic neurons , but also in peripheral sensory neu-
rons [51,52], implies a peripheral site of action for CB
R in mediating
Indeed, if peripherally present CB
Rs do contribute to the devel-
opment of the metabolic syndrome, then limiting the access of CB
blockers to the brain may improve their therapeutic index by reducing
their potential to cause centrally mediated neuropsychiatric adverse
eﬀects while retaining their metabolic actions in the periphery. This
notion was followed by a series of studies demonstrating the involve-
ment of the peripheral eCB/CB
R system in the development of cardi-
ometabolic abnormalities associated with the metabolic syndrome, as
well as the ability of peripherally restricted CB
R antagonists to im-
prove obesity- and diabetes-induced comorbidities.
Among the several compounds developed, AM6545 was the ﬁrst
that underwent a detailed pharmacological, metabolic, and behavioral
assessment in mouse models of obesity. It was shown to ameliorate
insulin resistance, hepatic steatosis, and dyslipidemia in both diet- and
genetically induced obesity . These ﬁndings were followed by a few
studies demonstrating the ability of AM6545 to reduce food intake, the
meal size, the rate of feeding, and body weight in obese animals
[54–56], as well as to attenuate obesity-induced dyslipidemia via ac-
tivating brown adipose tissue . Shortly after the metabolic char-
acterization of AM6545, another novel peripherally restricted blocker
(JD5037) was developed and pre-clinically tested in diﬀerent murine
models of obesity. Its ability to reduce body weight, food intake, im-
prove glycemic control, and attenuate fatty liver was comparable to
SLV319 (Ibipinabant®). The hypophagia and weight reducing ef-
fects of JD5037 were directly linked to its capacity to reverse the
obesity-induced increased leptin levels and consequent leptin resistance
by reducing leptin secretion from adipocytes as well as increasing its
clearance via the kidney . Interestingly, despite that JD5037 is
restricted to the periphery, we recently demonstrated that it restores
hypothalamic leptin sensitivity and elicits anorectic response via acti-
vating proopiomelanocortin (POMC) neurons in the hypothalamus,
which have been shown to modulate eCB-induced feeding , as well
as by disinhibiting melanocortin MC4R signaling . In this work, we
further demonstrated that unlike rimonabant, which signiﬁcantly re-
duced food intake and body weight in mice lacking MC4R, the anorexia
and weight-reducing eﬀects of the peripherally restricted CB
tagonist JD5037 were substantially attenuated in these mice or in wild-
type obese animals receiving the MC4R antagonist SHU-9119 . In
addition, JD5037 was found to be eﬀective in reducing hyperphagia
and weight in a well-established model of Prader–Willi syndrome, as
well as in improving all the metabolic parameters related to their obese
Additional evidence for peripheral regulation of energy metabolism
by the eCB system comes from a few studies utilizing genetic models
with speciﬁc deletions of CB
R. Interestingly, deletion of hepatic CB
was suﬃcient to protect obese mice from liver steatosis, dyslipidemia,
as well as insulin and leptin resistance . A recent study by Lutz et al.
characterized the metabolic phenotype of mice carrying a speciﬁc de-
letion of CB
R in adipocytes, and remarkably, found that these mice
were protected from diet-induced obesity and its consequent metabolic
alterations . Taken together, these pivotal studies highlight the
ability of the peripheral eCB/CB
R system to regulate feeding and en-
ergy balance via a crosstalk between peripheral organs and centrally
mediated hypothalamic signaling pathways. Next, we will brieﬂy dis-
cuss the available evidence and current knowledge regarding the role of
eCBs and CB
R signaling in modulating metabolic and physiological
activities in the liver, kidney, and bone.
4. Role of the eCB/CB
R system in the development of NAFLD
The possible involvement of eCBs via activating CB
R in the de-
velopment of non-alcoholic fatty liver diseases (NAFLD) has been the
focus of many recent studies. In fact, for many years the liver was
considered as a negative control to study the function of neuronal
Rs . Unlike normal conditions, in which CB
R is expressed in
fairly low levels in the liver [19,39,41,62], during liver pathologies its
expression is vastly upregulated [63–65]. Since eCBs are present in the
liver at levels that are comparable to those found in the brain [19,66],
it was reasonable to postulate a signiﬁcant role for the eCB/CB
system in regulating lipid metabolism in the liver.
Initially, Osei-Hyiaman and colleagues demonstrated the complete
resistance of CB
R null mice to develop obesity-induced fatty liver .
Later on, it was found that both globally acting and peripherally re-
R blockers can increase fatty acid oxidation as well as re-
duce hepatic inﬂammation and lipogenesis [19,40,53,58,67–71],
thus supporting the protective eﬀect of these compounds and their
potential pharmacological application in ameliorating NAFLD. Further
evidence for the eﬀectiveness of globally acting CB
R antagonists came
J. Tam et al. European Journal of Internal Medicine xxx (xxxx) xxx–xxx
from several studies in humans and rodents demonstrating the ability of
rimonabant to reduce the expression levels of hepatic lipogenic genes
and to reverse fatty liver disease [19,28,29,39,70,72,73]. Likewise,
peripherally restricted CB
R antagonists were also found to have similar
Consuming a high-fat diet or speciﬁc activation of CB
R reduces the
hepatic expression and activity of carnitine palmitoyl transferase–1
(CPT1), the rate-limiting enzyme in mitochondrial fatty acid oxidation.
However, this eﬀect was absent in globally or hepatocyte-speciﬁcCB
null, and was reversed by treatment with rimonabant or AM6545 [40,
53]. In a genome-wide expression proﬁling of mice lacking CB
treated with a CB
R blocker, it was further found that inactivating CB
during obesity increases the expression of hepatic genes associated with
fatty acid oxidation while suppressing the expression of hepatic lipo-
genic genes . Furthermore, blockade of CB
Rs reverses the obesity-
induced upregulation of hepatic fatty acid translocase/CD36, which
mediates the uptake of free fatty acids from the circulation to the liver
and may contribute to fat accumulation in the liver. This reversal was
found to be mediated indirectly by adiponectin .
Additional support for the hepatic role of eCBs in humans comes
from a few studies demonstrating the association of circulating eCBs
with the development of NAFLD. First, increased arterial and hepatic
venous concentrations of 2-AG, as well as the production of triglycer-
ides containing saturated fatty acids were found to be positively cor-
related with liver fat content . Second, upregulated blood levels of
2-AG and its precursor and breakdown molecule, arachidonic acid,
were found in both female and male patients with NAFLD regardless of
their BMI . The signiﬁcant correlation between 2-AG and the he-
patorenal index as well as serum alanine aminotransferase levels may
suggest that elevation of this molecule may reﬂect the degree of liver
injury associated with obesity . These ﬁndings are consistent with
additional studies in humans [45,46,48,49,78,79] suggesting a
possible role of circulating eCBs as potentially serving as biomarkers for
visceral obesity and its associated metabolic abnormalities.
5. The contribution of the eCB/CB
R system to obesity- and
diabetes-induced chronic kidney disease
Recently, greater attention was devoted to obesity-associated
kidney injury, which develops early in the progression of obesity
[80–82], and independently of the metabolic abnormalities associated
with it [83,84]. In fact, obesity-induced renal inﬂammation  and
oxidative stress  may eventually lead to kidney dysfunction, glo-
merulosclerosis, and tubulointerstitial ﬁbrosis [80,87–89]. Since the
kidney is a major source of eCBs, whose levels are elevated during
obesity [42,90], and the fact that CB
R is vastly expressed in many cells
within the kidney, the possible involvement of the eCB/CB
R system in
regulating obesity-associated kidney injury has been explored in several
recent studies. Of these, ﬁndings reporting amelioration of obesity-in-
duced chronic kidney disease by CB
R antagonists have shown that
rimonabant or AM251 can delay the development of proteinuria, glo-
merular and tubulointerstitial lesions, as well as reduce hypertrophy
and creatinine levels in genetically and high-fat diet-induced obese rats
Among the many cells in the kidney that express CB
R [reviewed in
], the renal proximal tubular cells (RPTCs) are critically important
in regulating normal kidney function because they are responsible for
active reabsorption of a large quantity (> 80%) of the ﬁltrate using a
mechanism requiring a large amount of energy. This is mainly due to
fatty acid oxidation, controlled by the cellular energy and redox sensor,
AMPK [94,95]. In a recent work done by our group, we showed that
obesity-induced renal abnormalities are mediated via CB
located on the RPTCs . Even though obese mice lacking CB
R in the
RPTCs had a metabolic phenotype identical to their obese wild-type
control animals, they remained completely protected from the dele-
terious eﬀects of obesity on the kidney, such as impaired renal lipid
metabolism, increased intracellular lipid accumulation, and kidney li-
potoxicity . At the molecular level, we found that CB
intracellular lipid accumulation in the RPTCs, and consequently, the
obesity-induced renal inﬂammation, ﬁbrosis, and injury by regulating
the AMPK signaling pathway . This further implies that manip-
R speciﬁcally in the RPTCs may have therapeutic potential
for treating obesity-induced nephropathy.
Strong evidence for the involvement of the eCB/CB
R system in the
development of chronic kidney disease associated with diabetes, also
termed diabetic nephropathy (DN), has recently emerged from murine
models for both type 1 and type 2 diabetes. In both cases, CB
pression in the kidney is predominantly upregulated in podocytes and
RPTCs [96–98], and its pharmacological inhibition by globally acting
R antagonists ameliorates diabetes-induced albuminuria, inhibits
ﬁbrosis and inﬂammation, and prevents podocyte dysfunction. Like-
wise, peripherally restricted CB
R antagonism was found to completely
prevent the development of DN . Moreover, in a recent study by
Barutta and colleagues, it was shown that combining peripherally re-
R antagonism and CB
R agonism treatment synergistically
ameliorates diabetes-induced albuminuria, inﬂammation, tubular in-
jury, and renal ﬁbrosis .
In a recent study by Kunos et al., diabetic podocyte-speciﬁcCB
null mice displayed a reduction in albuminuria, podocytes injury, and
tubular dysfunction . Similarly, downregulating podocyte CB
expression or its pharmacological blockade was found to ameliorate
hyperglycemia-induced endoplasmic reticulum stress . Type 1
angiotensin II receptor (AT1R) has also been suggested to regulate
R-induced DN, since using Losartan, an AT1R antagonist, was found
to attenuate DN via a reduction in podocyte CB
R expression in rats
. These ﬁndings are further supported by the ability of CB
AT1R to form heterodimers, which amplify AT1R activity , and
thus may provide a possible mechanism for the development of DN
under normoglycemic conditions. In addition, hyperglycemic condi-
tions were also found to enhance the expression of CB
R in mesangial
cells [104,105] and to promote their apoptosis , inﬂammation,
and ﬁbrosis , eﬀects that were reversed by globally acting CB
antagonists. Taken together, these ﬁndings highlight the key role of
R in mediating hyperglycemia-induced podocyte and mesangial
Similarly to the increased susceptibility of RPTCs to fatty acid ﬂux
, these cells are particularly sensitive to the deleterious eﬀects of
chronic hyperglycemia in diabetic patients  because glucose en-
ters these cells independently of insulin. Indeed, a recent study de-
monstrated that both glucose and albumin increase the expression of
R in cultured RPTCs and that its activation results in hypertrophy
. Like CB
R, the facilitative glucose transporter 2 (GLUT2), loca-
lized in RPTCs, is recruited to the apical/brush border membrane
(BBM) during diabetes [107,108]. This, in turn, increases glucose re-
absorption, which eventually leads to RPTC injury, inﬂammation, and
tubulointerstitial ﬁbrosis [108–112]. Recently, our lab reported a novel
cellular mechanism by which CB
R regulates GLUT2 expression and
dynamics in RPTCs . These eﬀects were linked to modulating the
inﬂux and the expression of PKC-β1 in RPTCs. Our ﬁndings fur-
ther indicate that diabetes-induced upregulation in renal GLUT2 ex-
pression and dynamic translocation can be mitigated by peripheral
pharmacological blockade or genetic deletion of CB
R in RPTCs to re-
duce glucose reabsorption and prevent the development of DN. More-
over, we showed that in comparison with the globally acting CB
antagonism, peripherally restricted blockade of this receptor is of great
value in the treatment of DN .
6. Role of the eCB/CB
R system in bone remodeling and mass
The eCB system plays a signiﬁcant role in determining bone-mass
accrual by regulating bone remodeling , which maintains skeletal
integrity and enables its ability to adapt to the constant changes in
J. Tam et al. European Journal of Internal Medicine xxx (xxxx) xxx–xxx
mechanical demands [115,116]. Several principal constituents of the
eCB system have been identiﬁed in bone. These include the main eCBs,
AEA, and 2AG, which are synthesized by osteoblasts and osteoclasts
and reach skeletal concentrations similar to those found in the brain
[22,117]; their biosynthesis and degrading enzymes [115,118,119];
and the cannabinoid receptors, CB
R and CB
R[119,120]. Since this
review focuses on the eCB/CB
R system, we will brieﬂy describe the
role of CB
R in bone [also reviewed in ], and then thoroughly
discuss the current knowledge regarding CB
Several studies utilizing speciﬁc agonists for CB
R support its pro-
anabolic skeletal capabilities [120,122,123]. Additionally, mice
R display a phenotype reminiscent of human post-
menopausal osteoporosis, with increased age-related bone loss and
bone turnover . In fact, two genetic studies in humans docu-
mented polymorphisms in the coding region of CB
R, which were as-
sociated with low bone mass and osteoporosis [124,125]. In contrast,
no signiﬁcant association between osteoporosis and four single nu-
cleotide polymorphisms spanning nearly 20 kb around the CB
exon were found . Although some conﬂicting evidence about the
signaling pathways modulated by CB
R in bone cells and their pre-
cursors have been reported [120,127,128], there is clear evidence
demonstrating the merit of targeting this receptor for the pharma-
cotherapy of osteoporosis.
Modulating bone remodeling and mass by CB
R is much more
complex, however. CB
Rs are mostly expressed on sympathetic nerve
endings , but they also have been detected in low amounts in
osteoclasts, osteoblasts, bone marrow stromal cells, macrophages, and
fat cells [128,129]. CB
R has been shown to modulate the activity of
the central nervous system in regulating bone remodeling via antag-
onizing skeletal sympathetic eﬀects. Brieﬂy, norepinephrine, released
from sympathetic ﬁbers, inhibits bone formation and stimulates bone
resorption [130,131]. In fact, acute stimulation of CB
R by 2-AG,
produced in the bone microenvironment, inhibits norepinephrine re-
lease, thus mitigating the inhibition of bone formation by the sympa-
thetic nervous system . On the other hand, direct activation of
R, whose levels are upregulated with age, protects age-
related osteoporosis , most likely via promoting osteoblast pro-
Utilizing diﬀerent animal models to determine the role of CB
modulating bone mass revealed its complex involvement in this pro-
cess, and also highlighted its importance in selecting the “right”mouse
model to use. For instance, deletion of CB
R in congenic C57BL/6J mice
results in a low bone mass phenotype . However, CB
R null mice,
maintained on an outbred CD1 genetic background, have a high peak
bone mass , yet they subsequently develop age-related low bone
mass owing to a defect in bone formation and to increased adipogenesis
within the skeletal microenvironment [128,129]. In a recent study, we
attempted to isolate the involvement of CB
R expressed in sympathetic
neurons, and to rule out the direct eﬀects of CB
R deletion on bone
cells. This was achieved utilizing a novel mouse strain that lacks CB
in adrenergic/noradrenergic cells . Our ﬁndings indicate that
conditional deletion of CB
R signaling in sympathetic nerve terminals
leads to enhanced age-related bone mass, associated with an enhanced
bone formation rate and reduced osteoclastogenesis. This eﬀect was not
associated with increased sympathetic tone but rather, the opposite,
suggesting that constitutive genetic inactivation of the sympathetic
R receptor disrupts the negative feedback loop between eCBs and
norepinephrine signaling in bone .
An interesting open question, whether the use of cannabis “per se”
has signiﬁcant eﬀects on the skeleton, has been recently addressed in a
study that determined the involvement of the eCB system in regulating
skeletal elongation . Both cannabinoid receptors are expressed in
hypertrophic chondrocytes of the epiphyseal growth cartilage. Studies
on humans reported that THC exposure during pregnancy reduces the
fetal growth rate, resulting in a reduced birth weight, a shorter stature,
and a reduced head size at birth [135,136]. Summing up, modulating
the skeletal eCB/CB
R system may serve as a therapeutic approach for
the treatment of a wide range of skeletal disorders, from treatment and
prevention of age-related osteoporosis to correction of growth deﬁcits.
7. Concluding remarks
The peripheral eCB system is involved in regulating energy meta-
bolism, food intake, and adiposity. It also modulates liver and kidney
function under normal and pathophysiological conditions, such as
obesity and diabetes, and it controls bone remodeling, skeletal mass,
and elongation. Therefore, it has important therapeutic and prognostic
implications speciﬁcally in relation to targeting CB
R. Although we
have mostly reviewed the current knowledge on the role of the eCB/
R system, one should also note the important aspects of this system
in modulating other peripheral organs, such as skeletal muscle, pan-
creas, and the gastrointestinal tract. Increased activity of the eCB/CB
system contributes to the development of the metabolic syndrome,
whereas either globally or peripherally restricted CB
attenuates or prevents the development of the cardio-metabolic co-
morbidities associated with it. These ﬁndings support the idea that
peripherally selective CB
R antagonists may be useful therapeutics
against the metabolic syndrome, and also oﬀer a superior therapeutic
beneﬁt for this condition. It remains to be seen whether this novel
pharmacological approach will be fully translated into use for humans,
and rekindle the spark for ﬁnding a new blockbuster therapeutic against
the metabolic syndrome. Moreover, with growing acceptance of using
medical cannabis for diﬀerent clinical indications, future research is
warranted to decipher the eﬀect and impact of medical cannabis on the
development of the metabolic syndrome via activating the eCB/CB
This research was supported by an Israel Science Foundation grant
(#617/14), and an ERC-2015-StG grant (#676841) to J.T.
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