ArticlePDF AvailableLiterature Review

Abstract

Endocannabinoids (eCBs) are internal lipid mediators recognized by the cannabinoid-1 and -2 receptors (CB1R and CB2R, respectively), which also mediate the different physiological effects of marijuana. The endocannabinoid 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/CB1R system in modulating the metabolism in several peripheral organs. We assess how eCBs, via activating the CB1R, 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 CB1R antagonists, which were pre-clinically tested in the management of energy homeostasis, and in ameliorating both obesity- and diabetes-induced metabolic complications.
Contents lists available at ScienceDirect
European Journal of Internal Medicine
journal homepage: www.elsevier.com/locate/ejim
Review Article
The therapeutic potential of targeting the peripheral endocannabinoid/CB
1
receptor system
Joseph Tam
, 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
ARTICLE INFO
Keywords:
Endocannabinoids
CB
1
receptor
Obesity
NAFLD
Chronic kidney disease
Bone remodeling
ABSTRACT
Endocannabinoids (eCBs) are internal lipid mediators recognized by the cannabinoid-1 and -2 receptors (CB
1
R
and CB
2
R, respectively), which also mediate the dierent physiological eects 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/
CB
1
R system in modulating the metabolism in several peripheral organs. We assess how eCBs, via activating the
CB
1
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 ecacy
of the recently developed peripherally restricted CB
1
R antagonists, which were pre-clinically tested in the
management of energy homeostasis, and in ameliorating both obesity- and diabetes-induced metabolic com-
plications.
1. The endocannabinoid system
The psychoactive and medicinal uses of Cannabis sativa (marijuana)
have been well known for millennia [1]. However, our understanding
of the underlying mechanisms of action in these physiological processes
emerged only during the 1960s, following the isolation, identication,
and synthesis of Δ
9
-tetrahydrocannabinol (THC), the psychoactive
component of marijuana [2]. 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
1
R and CB
2
R, respec-
tively) [35]. Cannabinoid-1 has been recently crystalized by two dif-
ferent groups [6,7]. Both receptors mainly signal via G
i
/G
o
proteins,
despite the fact that they can also activate G
s
,G
q/11
, as well as G pro-
tein-independent signaling pathways [8]. The cloning of CB receptors in
mammalian cells was followed soon afterward by identifying their in-
ternal ligands, arachidonoyl ethanolamide (AEA, anandamide) [9], 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-anity transport mechanism [12]. Their clearance depends on
cellular uptake and specic enzymatic degradation. Whereas AEA is
degraded mainly by membrane-associated fatty-acid amide hydrolase
(FAAH) [13], 2-AG is primarily degraded by monoglyceride lipase
(MAGL) [14]. 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
1
R system as a key modulator of energy homeostasis
and feeding
The well-documented role of cannabis as a bi-modulator of food
intake in rodents and humans [reviewed in [15]] provided early clues
as to the biological and metabolic functions of its internal counterparts.
A case in point is the munchies eect, which prompted a study that
provided evidence for the specic involvement of the eCB/CB
1
R system
in this phenomenon via regulating leptin signaling in the hypothalamus
[16]. CB
1
R is abundantly expressed on presynaptic nerve terminals [17]
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 [18], liver [19], skeletal muscle [20], kidney [21], bone [22],
and pancreas [23]. Therefore, it was not surprising to nd that its
blockade would inhibit food intake [2427]. In fact, these observations
provided the motivation for testing such compounds as a potential
treatment for obesity. Indeed, the rst-in-class CB
1
R antagonist rimo-
nabant (Acomplia®, Sano-Aventis) proved very eective 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 ([28]; [2934]).
https://doi.org/10.1016/j.ejim.2018.01.009
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: yossit@ekmd.huji.ac.il (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 ndings, along with a few additional energy
conservingphysiologic eects mediated by either cannabis consump-
tion and/or the activation of the eCB/CB
1
R system such as anxiolysis,
rewarding, motor suppression, sleep induction, and lipogenesis [re-
viewed in [35]], may suggest that the internal cannabinoid system is a
pivotal modulator of the thriftyphenotype, 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
blocking CB
1
R suggest that increased eCB tonemay be its unifying
pathologic feature that triggers the development of the metabolic syn-
drome [36].
3. Moving from globally acting to peripherally restricted CB
1
R
antagonism for the treatment of obesity
An open question remains, regarding the relative importance of
central versus peripheral CB
1
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
signicant fraction of humans treated with rimonabant [37]. These
reports led not only to the eventual withdrawal of rimonabant from the
market, but also to the discontinuation of developing all CB
1
R blockers
by big pharmaceutical companies, which raised doubts about the
therapeutic potential of this class of molecules [38].
Generally, the baseline expression level of CB
1
Rs in periphery is
very low, but it is markedly elevated during obesity and diabetes.
Indeed, increased expression of CB
1
Rs was reported in adipose tissue
[18,39], liver [3941], skeletal muscle [20], kidney [42], and pancreas
[43]. 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 [4548] as well as in genetic causes of obesity,
such as Prader-Willi syndrome [49]. These ndings, together with ad-
ditional studies conducted in murine models for the metabolic syn-
drome showing that (i) activation of CB
1
R increases lipogenesis in
adipocytes and liver [19,50]; (ii) CB
1
R blockade attenuates obesity-
induced dysregulation of lipid metabolism in visceral adipose tissue
[39]; and (iii) enhanced insulin receptor signaling results in β-cell
proliferation and mass [23], suggest that the apparent increase in
peripheral eCB tonein obesity plays an important physiological role.
This, in turn, may support strategies for antagonizing CB
1
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
1
Rs in CAM kinase IIα-expressing neurons
[41], which are prominently expressed not only in forebrain and per-
ipheral sympathetic neurons [41], but also in peripheral sensory neu-
rons [51,52], implies a peripheral site of action for CB
1
R in mediating
feeding behaviors.
Indeed, if peripherally present CB
1
Rs do contribute to the devel-
opment of the metabolic syndrome, then limiting the access of CB
1
R
blockers to the brain may improve their therapeutic index by reducing
their potential to cause centrally mediated neuropsychiatric adverse
eects 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
1
R system in the development of cardi-
ometabolic abnormalities associated with the metabolic syndrome, as
well as the ability of peripherally restricted CB
1
R antagonists to im-
prove obesity- and diabetes-induced comorbidities.
Among the several compounds developed, AM6545 was the rst
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 [53]. These ndings 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
[5456], as well as to attenuate obesity-induced dyslipidemia via ac-
tivating brown adipose tissue [57]. Shortly after the metabolic char-
acterization of AM6545, another novel peripherally restricted blocker
(JD5037) was developed and pre-clinically tested in dierent 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®)[58]. 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 [58]. 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 [59], as well
as by disinhibiting melanocortin MC4R signaling [60]. In this work, we
further demonstrated that unlike rimonabant, which signicantly re-
duced food intake and body weight in mice lacking MC4R, the anorexia
and weight-reducing eects of the peripherally restricted CB
1
R an-
tagonist JD5037 were substantially attenuated in these mice or in wild-
type obese animals receiving the MC4R antagonist SHU-9119 [60]. In
addition, JD5037 was found to be eective in reducing hyperphagia
and weight in a well-established model of PraderWilli syndrome, as
well as in improving all the metabolic parameters related to their obese
phenotype [49].
Additional evidence for peripheral regulation of energy metabolism
by the eCB system comes from a few studies utilizing genetic models
with specic deletions of CB
1
R. Interestingly, deletion of hepatic CB
1
R
was sucient to protect obese mice from liver steatosis, dyslipidemia,
as well as insulin and leptin resistance [40]. A recent study by Lutz et al.
characterized the metabolic phenotype of mice carrying a specic de-
letion of CB
1
R in adipocytes, and remarkably, found that these mice
were protected from diet-induced obesity and its consequent metabolic
alterations [61]. Taken together, these pivotal studies highlight the
ability of the peripheral eCB/CB
1
R system to regulate feeding and en-
ergy balance via a crosstalk between peripheral organs and centrally
mediated hypothalamic signaling pathways. Next, we will briey dis-
cuss the available evidence and current knowledge regarding the role of
eCBs and CB
1
R signaling in modulating metabolic and physiological
activities in the liver, kidney, and bone.
4. Role of the eCB/CB
1
R system in the development of NAFLD
The possible involvement of eCBs via activating CB
1
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
CB
1
Rs [62]. Unlike normal conditions, in which CB
1
R is expressed in
fairly low levels in the liver [19,39,41,62], during liver pathologies its
expression is vastly upregulated [6365]. 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 signicant role for the eCB/CB
1
R
system in regulating lipid metabolism in the liver.
Initially, Osei-Hyiaman and colleagues demonstrated the complete
resistance of CB
1
R null mice to develop obesity-induced fatty liver [19].
Later on, it was found that both globally acting and peripherally re-
stricted CB
1
R blockers can increase fatty acid oxidation as well as re-
duce hepatic inammation and lipogenesis [19,40,53,58,6771],
thus supporting the protective eect of these compounds and their
potential pharmacological application in ameliorating NAFLD. Further
evidence for the eectiveness of globally acting CB
1
R antagonists came
J. Tam et al. European Journal of Internal Medicine xxx (xxxx) xxx–xxx
2
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
1
R antagonists were also found to have similar
capabilities [53,55,58,67,74].
Consuming a high-fat diet or specic activation of CB
1
R reduces the
hepatic expression and activity of carnitine palmitoyl transferase1
(CPT1), the rate-limiting enzyme in mitochondrial fatty acid oxidation.
However, this eect was absent in globally or hepatocyte-specicCB
1
R
null, and was reversed by treatment with rimonabant or AM6545 [40,
53]. In a genome-wide expression proling of mice lacking CB
1
Ror
treated with a CB
1
R blocker, it was further found that inactivating CB
1
R
during obesity increases the expression of hepatic genes associated with
fatty acid oxidation while suppressing the expression of hepatic lipo-
genic genes [75]. Furthermore, blockade of CB
1
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 [70].
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 [76]. 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 [77]. The signicant correlation between 2-AG and the he-
patorenal index as well as serum alanine aminotransferase levels may
suggest that elevation of this molecule may reect the degree of liver
injury associated with obesity [77]. These ndings 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
1
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
[8082], and independently of the metabolic abnormalities associated
with it [83,84]. In fact, obesity-induced renal inammation [85] and
oxidative stress [86] may eventually lead to kidney dysfunction, glo-
merulosclerosis, and tubulointerstitial brosis [80,8789]. Since the
kidney is a major source of eCBs, whose levels are elevated during
obesity [42,90], and the fact that CB
1
R is vastly expressed in many cells
within the kidney, the possible involvement of the eCB/CB
1
R system in
regulating obesity-associated kidney injury has been explored in several
recent studies. Of these, ndings reporting amelioration of obesity-in-
duced chronic kidney disease by CB
1
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
[91,92].
Among the many cells in the kidney that express CB
1
R [reviewed in
[93]], 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 ltrate 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
1
R specically
located on the RPTCs [42]. Even though obese mice lacking CB
1
R in the
RPTCs had a metabolic phenotype identical to their obese wild-type
control animals, they remained completely protected from the dele-
terious eects of obesity on the kidney, such as impaired renal lipid
metabolism, increased intracellular lipid accumulation, and kidney li-
potoxicity [42]. At the molecular level, we found that CB
1
R governs
intracellular lipid accumulation in the RPTCs, and consequently, the
obesity-induced renal inammation, brosis, and injury by regulating
the AMPK signaling pathway [42]. This further implies that manip-
ulating CB
1
R specically in the RPTCs may have therapeutic potential
for treating obesity-induced nephropathy.
Strong evidence for the involvement of the eCB/CB
1
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
1
R ex-
pression in the kidney is predominantly upregulated in podocytes and
RPTCs [9698], and its pharmacological inhibition by globally acting
CB
1
R antagonists ameliorates diabetes-induced albuminuria, inhibits
brosis and inammation, and prevents podocyte dysfunction. Like-
wise, peripherally restricted CB
1
R antagonism was found to completely
prevent the development of DN [99]. Moreover, in a recent study by
Barutta and colleagues, it was shown that combining peripherally re-
stricted CB
1
R antagonism and CB
2
R agonism treatment synergistically
ameliorates diabetes-induced albuminuria, inammation, tubular in-
jury, and renal brosis [100].
In a recent study by Kunos et al., diabetic podocyte-specicCB
1
R
null mice displayed a reduction in albuminuria, podocytes injury, and
tubular dysfunction [101]. Similarly, downregulating podocyte CB
1
R
expression or its pharmacological blockade was found to ameliorate
hyperglycemia-induced endoplasmic reticulum stress [102]. Type 1
angiotensin II receptor (AT1R) has also been suggested to regulate
CB
1
R-induced DN, since using Losartan, an AT1R antagonist, was found
to attenuate DN via a reduction in podocyte CB
1
R expression in rats
[99]. These ndings are further supported by the ability of CB
1
R and
AT1R to form heterodimers, which amplify AT1R activity [103], 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
1
R in mesangial
cells [104,105] and to promote their apoptosis [104], inammation,
and brosis [105], eects that were reversed by globally acting CB
1
R
antagonists. Taken together, these ndings highlight the key role of
CB
1
R in mediating hyperglycemia-induced podocyte and mesangial
dysfunction.
Similarly to the increased susceptibility of RPTCs to fatty acid ux
[42], these cells are particularly sensitive to the deleterious eects of
chronic hyperglycemia in diabetic patients [106] because glucose en-
ters these cells independently of insulin. Indeed, a recent study de-
monstrated that both glucose and albumin increase the expression of
CB
1
R in cultured RPTCs and that its activation results in hypertrophy
[97]. Like CB
1
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, inammation, and
tubulointerstitial brosis [108112]. Recently, our lab reported a novel
cellular mechanism by which CB
1
R regulates GLUT2 expression and
dynamics in RPTCs [113]. These eects were linked to modulating the
Ca
2+
inux and the expression of PKC-β1 in RPTCs. Our ndings 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
1
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
1
R
antagonism, peripherally restricted blockade of this receptor is of great
value in the treatment of DN [113].
6. Role of the eCB/CB
1
R system in bone remodeling and mass
The eCB system plays a signicant role in determining bone-mass
accrual by regulating bone remodeling [114], 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
3
mechanical demands [115,116]. Several principal constituents of the
eCB system have been identied 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
1
R and CB
2
R[119,120]. Since this
review focuses on the eCB/CB
1
R system, we will briey describe the
role of CB
2
R in bone [also reviewed in [121]], and then thoroughly
discuss the current knowledge regarding CB
1
R.
Several studies utilizing specic agonists for CB
2
R support its pro-
anabolic skeletal capabilities [120,122,123]. Additionally, mice
lacking CB
2
R display a phenotype reminiscent of human post-
menopausal osteoporosis, with increased age-related bone loss and
bone turnover [120]. In fact, two genetic studies in humans docu-
mented polymorphisms in the coding region of CB
2
R, which were as-
sociated with low bone mass and osteoporosis [124,125]. In contrast,
no signicant association between osteoporosis and four single nu-
cleotide polymorphisms spanning nearly 20 kb around the CB
1
R coding
exon were found [126]. Although some conicting evidence about the
signaling pathways modulated by CB
2
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
1
R is much more
complex, however. CB
1
Rs are mostly expressed on sympathetic nerve
endings [119], but they also have been detected in low amounts in
osteoclasts, osteoblasts, bone marrow stromal cells, macrophages, and
fat cells [128,129]. CB
1
R has been shown to modulate the activity of
the central nervous system in regulating bone remodeling via antag-
onizing skeletal sympathetic eects. Briey, norepinephrine, released
from sympathetic bers, inhibits bone formation and stimulates bone
resorption [130,131]. In fact, acute stimulation of CB
1
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 [119]. On the other hand, direct activation of
osteoblastic CB
1
R, whose levels are upregulated with age, protects age-
related osteoporosis [129], most likely via promoting osteoblast pro-
liferation.
Utilizing dierent animal models to determine the role of CB
1
Rin
modulating bone mass revealed its complex involvement in this pro-
cess, and also highlighted its importance in selecting the rightmouse
model to use. For instance, deletion of CB
1
R in congenic C57BL/6J mice
results in a low bone mass phenotype [22]. However, CB
1
R null mice,
maintained on an outbred CD1 genetic background, have a high peak
bone mass [22], 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
1
R expressed in sympathetic
neurons, and to rule out the direct eects of CB
1
R deletion on bone
cells. This was achieved utilizing a novel mouse strain that lacks CB
1
R
in adrenergic/noradrenergic cells [132]. Our ndings indicate that
conditional deletion of CB
1
R signaling in sympathetic nerve terminals
leads to enhanced age-related bone mass, associated with an enhanced
bone formation rate and reduced osteoclastogenesis. This eect was not
associated with increased sympathetic tone but rather, the opposite,
suggesting that constitutive genetic inactivation of the sympathetic
CB
1
R receptor disrupts the negative feedback loop between eCBs and
norepinephrine signaling in bone [133].
An interesting open question, whether the use of cannabis per se
has signicant eects on the skeleton, has been recently addressed in a
study that determined the involvement of the eCB system in regulating
skeletal elongation [134]. 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
1
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 decits.
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 specically in relation to targeting CB
1
R. Although we
have mostly reviewed the current knowledge on the role of the eCB/
CB
1
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
1
R
system contributes to the development of the metabolic syndrome,
whereas either globally or peripherally restricted CB
1
R antagonism
attenuates or prevents the development of the cardio-metabolic co-
morbidities associated with it. These ndings support the idea that
peripherally selective CB
1
R antagonists may be useful therapeutics
against the metabolic syndrome, and also oer a superior therapeutic
benet 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 nding a new blockbuster therapeutic against
the metabolic syndrome. Moreover, with growing acceptance of using
medical cannabis for dierent clinical indications, future research is
warranted to decipher the eect and impact of medical cannabis on the
development of the metabolic syndrome via activating the eCB/CB
1
R
system.
Acknowledgment
This research was supported by an Israel Science Foundation grant
(#617/14), and an ERC-2015-StG grant (#676841) to J.T.
References
[1] Abel EL. Cannabis: eects on hunger and thirst. Behav Biol 1975;15:25581.
[2] Gaoni Y, Mechoulam R. Isolation, structure and partial synthesis of an active
constituent of hashish. J Am Chem Soc 1964;86:16467.
[3] Devane WA, Dysarz 3rd FA, Johnson MR, Melvin LS, Howlett AC. Determination
and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol
1988;34:60513.
[4] Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a can-
nabinoid receptor and functional expression of the cloned cDNA. Nature
1990;346:5614.
[5] Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral
receptor for cannabinoids. Nature 1993;365:615.
[6] Hua T, Vemuri K, Pu M, Qu L, Han GW, Wu Y, et al. Crystal structure of the human
cannabinoid receptor CB1. Cell 2016;167(750762):e714.
[7] Shao Z, Yin J, Chapman K, Grzemska M, Clark L, Wang J, et al. High-resolution
crystal structure of the human CB1 cannabinoid receptor. Nature 2016;540:6026.
[8] Howlett AC. Cannabinoid receptor signaling. Handb Exp Pharmacol 2005:5379.
[9] Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Grin G, et al.
Isolation and structure of a brain constituent that binds to the cannabinoid re-
ceptor. Science 1992;258:19469.
[10] Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, et al.
Identication of an endogenous 2-monoglyceride, present in canine gut, that binds
to cannabinoid receptors. Biochem Pharmacol 1995;50:8390.
[11] Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, et al. 2-
Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in
brain. Biochem Biophys Res Commun 1995;215:8997.
[12] Fowler CJ. The pharmacology of the cannabinoid systema question of ecacy
and selectivity. Mol Neurobiol 2007;36:1525.
[13] McKinney MK, Cravatt BF. Structure and function of fatty acid amide hydrolase.
Annu Rev Biochem 2005;74:41132.
[14] Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, et al. Brain
monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl
Acad Sci U S A 2002;99:1081924.
[15] Simon V, Cota D. MECHANISMS IN ENDOCRINOLOGY: endocannabinoids and
metabolism: past, present and future. Eur J Endocrinol 2017;176:R30924.
[16] Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, et al. Leptin-regulated
endocannabinoids are involved in maintaining food intake. Nature
J. Tam et al. European Journal of Internal Medicine xxx (xxxx) xxx–xxx
4
2001;410:8225.
[17] Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic
signaling. Physiol Rev 2003;83:101766.
[18] Bensaid M, Gary-Bobo M, Esclangon A, Marand JP, Le Fur G, Oury-Donat F, et al.
The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA ex-
pression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol
Pharmacol 2003;63:90814.
[19] Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Batkai S, et al.
Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synth-
esis and contributes to diet-induced obesity. J Clin Invest 2005;115:1298305.
[20] 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;27:73100.
[21] Larrinaga G, Varona A, Perez I, Sanz B, Ugalde A, Candenas ML, et al. Expression of
cannabinoid receptors in human kidney. Histol Histopathol 2010;25:11338.
[22] Tam J, Ofek O, Fride E, Ledent C, Gabet Y, Muller R, et al. Involvement of neuronal
cannabinoid receptor CB1 in regulation of bone mass and bone remodeling. Mol
Pharmacol 2006;70:78692.
[23] Nakata M, Yada T. Cannabinoids inhibit insulin secretion and cytosolic Ca2+
oscillation in islet beta-cells via CB1 receptors. Regul Pept 2008;145:4953.
[24] Colombo G, Agabio R, Diaz G, Lobina C, Reali R, Gessa GL. Appetite suppression
and weight loss after the cannabinoid antagonist SR 141716. Life Sci
1998;63:PL1137.
[25] Freedland CS, Poston JS, Porrino LJ. Eects of SR141716A, a central cannabinoid
receptor antagonist, on food-maintained responding. Pharmacol Biochem Behav
2000;67:26570.
[26] Simiand J, Keane M, Keane PE, Soubrie P. SR 141716, a CB1 cannabinoid receptor
antagonist, selectively reduces sweet food intake in marmoset. Behav Pharmacol
1998;9:17981.
[27] Williams CM, Kirkham TC. Anandamide induces overeating: mediation by central
cannabinoid (CB1) receptors. Psychopharmacology (Berl) 1999;143:3157.
[28] Despres JP, Golay A, Sjostrom L, Rimonabant in Obesity-Lipids Study, G. Eects of
rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N
Engl J Med 2005;353:212134.
[29] Despres JP, Ross R, Boka G, Almeras N, Lemieux I, Investigators AD-L. Eect of
rimonabant on the high-triglyceride/low-HDL-cholesterol dyslipidemia, in-
traabdominal adiposity, and liver fat: the ADAGIO-lipids trial. Arterioscler Thromb
Vasc Biol 2009;29:41623.
[30] Hollander PA, Amod A, Litwak LE, Chaudhari U. Eect of rimonabant on glycemic
control in insulin-treated type 2 diabetes: the ARPEGGIO trial. Diabetes Care
2010;33:6057.
[31] Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. Eect of rimona-
bant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors
in overweight or obese patients: RIO-North America: a randomized controlled trial.
JAMA 2006;295:76175.
[32] Rosenstock J, Hollander P, Chevalier S, Iranmanesh A. SERENADE: the study
evaluating rimonabant ecacy in drug-naive diabetic patients: eects of mono-
therapy with rimonabant, the rst selective CB1 receptor antagonist, on glycemic
control, body weight, and lipid prole in drug-naive type 2 diabetes. Diabetes Care
2008;31:216976.
[33] Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF. Ecacy and tolerability
of rimonabant in overweight or obese patients with type 2 diabetes: a randomised
controlled study. Lancet 2006;368:166072.
[34] Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Eects of the can-
nabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular
risk factors in overweight patients: 1-year experience from the RIO-Europe study.
Lancet 2005;365:138997.
[35] Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of
pharmacotherapy. Pharmacol Rev 2006;58:389462.
[36] Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance.
Nat Neurosci 2005;8:5859.
[37] Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Ecacy and safety
of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet
2007;370:170613.
[38] Jones D. End of the line for cannabinoid receptor 1 as an anti-obesity target? Nat
Rev Drug Discov 2008;7:9612.
[39] Jourdan T, Djaouti L, Demizieux L, Gresti J, Verges B, Degrace P. CB1 antagonism
exerts specic molecular eects on visceral and subcutaneous fat and reverses liver
steatosis in diet-induced obese mice. Diabetes 2010;59:92634.
[40] Osei-Hyiaman D, Liu J, Zhou L, Godlewski G, Harvey-White J, Jeong WI, et al.
Hepatic CB1 receptor is required for development of diet-induced steatosis, dys-
lipidemia, and insulin and leptin resistance in mice. J Clin Invest
2008;118:31609.
[41] Quarta C, Bellocchio L, Mancini G, Mazza R, Cervino C, Braulke LJ, et al. CB(1)
signaling in forebrain and sympathetic neurons is a key determinant of en-
docannabinoid actions on energy balance. Cell Metab 2010;11:27385.
[42] Udi S, Hinden L, Earley B, Drori A, Reuveni N, Hadar R, et al. Proximal tubular
cannabinoid-1 receptor regulates obesity-induced CKD. J Am Soc Nephrol
2017;28:351832.
[43] Jourdan T, Godlewski G, Cinar R, Bertola A, Szanda G, Liu J, et al. Activation of
the Nlrp3 inammasome in inltrating macrophages by endocannabinoids med-
iates beta cell loss in type 2 diabetes. Nat Med 2013;19:113240.
[44] Bordicchia M, Battistoni I, Mancinelli L, Giannini E, ReG, Minardi D, et al.
Cannabinoid CB1 receptor expression in relation to visceral adipose depots, en-
docannabinoid levels, microvascular damage, and the presence of the Cnr1
A3813G variant in humans. Metabolism 2010;59:73441.
[45] Abdulnour J, Yasari S, Rabasa-Lhoret R, Faraj M, Petrosino S, Piscitelli F, et al.
Circulating endocannabinoids in insulin sensitive vs. insulin resistant obese post-
menopausal women. A MONET group study. Obesity (Silver Spring)
2014;22:2116.
[46] Bluher M, Engeli S, Kloting N, Berndt J, Fasshauer M, Batkai S, et al. Dysregulation
of the peripheral and adipose tissue endocannabinoid system in human abdominal
obesity. Diabetes 2006;55:305360.
[47] Di Marzo V, Verrijken A, Hakkarainen A, Petrosino S, Mertens I, Lundbom N, et al.
Role of insulin as a negative regulator of plasma endocannabinoid levels in obese
and nonobese subjects. Eur J Endocrinol 2009;161:71522.
[48] Engeli S, Bohnke J, Feldpausch M, Gorzelniak K, Janke J, Batkai S, et al. Activation
of the peripheral endocannabinoid system in human obesity. Diabetes
2005;54:283843.
[49] Knani I, Earley BJ, Udi S, Nemirovski A, Hadar R, Gammal A, et al. Targeting the
endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syn-
drome. Mol Metab 2016;5:118799.
[50] Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M, et al. The
endogenous cannabinoid system aects energy balance via central orexigenic
drive and peripheral lipogenesis. J Clin Invest 2003;112:42331.
[51] Carlton SM. Localization of CaMKIIalpha in rat primary sensory neurons: increase
in inammation. Brain Res 2002;947:2529.
[52] Price TJ, Jeske NA, Flores CM, Hargreaves KM. Pharmacological interactions be-
tween calcium/calmodulin-dependent kinase II alpha and TRPV1 receptors in rat
trigeminal sensory neurons. Neurosci Lett 2005;389:948.
[53] Tam J, Vemuri VK, Liu J, Batkai S, Mukhopadhyay B, Godlewski G, et al.
Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in
mouse models of obesity. J Clin Invest 2010;120:295366.
[54] Argueta DA, DiPatrizio NV. Peripheral endocannabinoid signaling controls hy-
perphagia in western diet-induced obesity. Physiol Behav 2017;171:329.
[55] Bowles NP, Karatsoreos IN, Li X, Vemuri VK, Wood JA, Li Z, et al. A peripheral
endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic
syndrome. Proc Natl Acad Sci U S A 2015;112:28590.
[56] Cluny NL, Vemuri VK, Chambers AP, Limebeer CL, Bedard H, Wood JT, et al. A
novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces
food intake and body weight, but does not cause malaise, in rodents. Br J
Pharmacol 2010;161:62942.
[57] Boon MR, Kooijman S, van Dam AD, Pelgrom LR, Berbee JF, Visseren CA, et al.
Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and
diminishes dyslipidemia and obesity. FASEB J 2014;28:536175.
[58] Tam J, Cinar R, Liu J, Godlewski G, Wesley D, Jourdan T, et al. Peripheral can-
nabinoid-1 receptor inverse agonism reduces obesity by reversing leptin re-
sistance. Cell Metab 2012;16:16779.
[59] Koch M, Varela L, Kim JG, Kim JD, Hernandez-Nuno F, Simonds SE, et al.
Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature
2015;519:4550.
[60] Tam J, Szanda G, Drori A, Liu Z, Cinar R, Kashiwaya Y, et al. Peripheral canna-
binoid-1 receptor blockade restores hypothalamic leptin signaling. Mol Metab
2017;6:111325.
[61] Ruiz de Azua I, Mancini G, Srivastava RK, Rey AA, Cardinal P, Tedesco L, et al.
Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alter-
natively activated macrophages. J Clin Invest 2017;127:414862.
[62] Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, et al.
Expression of central and peripheral cannabinoid receptors in human immune
tissues and leukocyte subpopulations. Eur J Biochem 1995;232:5461.
[63] Buckley NE, Hansson S, Harta G, Mezey E. Expression of the CB1 and CB2 receptor
messenger RNAs during embryonic development in the rat. Neuroscience
1998;82:113149.
[64] Floreani A, Lazzari R, Macchi V, Porzionato A, Variola A, Colavito D, et al. Hepatic
expression of endocannabinoid receptors and their novel polymorphisms in pri-
mary biliary cirrhosis. J Gastroenterol 2010;45:6876.
[65] Xu X, Liu Y, Huang S, Liu G, Xie C, Zhou J, et al. Overexpression of cannabinoid
receptors CB1 and CB2 correlates with improved prognosis of patients with he-
patocellular carcinoma. Cancer Genet Cytogenet 2006;171:318.
[66] Siegmund SV, Qian T, de Minicis S, Harvey-White J, Kunos G, Vinod KY, et al. The
endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells
via mitochondrial reactive oxygen species. FASEB J 2007;21:2798806.
[67] Cinar R, Godlewski G, Liu J, Tam J, Jourdan T, Mukhopadhyay B, et al. Hepatic
cannabinoid-1 receptors mediate diet-induced insulin resistance by increasing de
novo synthesis of long-chain ceramides. Hepatology 2014;59:14353.
[68] Jourdan T, Demizieux L, Gresti J, Djaouti L, Gaba L, Verges B, et al. Antagonism of
peripheral hepatic cannabinoid receptor-1 improves liver lipid metabolism in
mice: evidence from cultured explants. Hepatology 2012;55:7909.
[69] Shi D, Zhan X, Yu X, Jia M, Zhang Y, Yao J, et al. Inhibiting CB1 receptors im-
proves lipogenesis in an in vitro non-alcoholic fatty liver disease model. Lipids
Health Dis 2014;13:173.
[70] Tam J, Godlewski G, Earley BJ, Zhou L, Jourdan T, Szanda G, et al. Role of adi-
ponectin in the metabolic eects of cannabinoid type 1 receptor blockade in mice
with diet-induced obesity. Am J Physiol Endocrinol Metab 2014;306:E45768.
[71] Wu HM, Yang YM, Kim SG. Rimonabant, a cannabinoid receptor type 1 inverse
agonist, inhibits hepatocyte lipogenesis by activating liver kinase B1 and AMP-
activated protein kinase axis downstream of Galpha i/o inhibition. Mol Pharmacol
2011;80:85969.
[72] Gary-Bobo M, Elachouri G, Gallas JF, Janiak P, Marini P, Ravinet-Trillou C, et al.
Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic
syndrome in obese Zucker fa/fa rats. Hepatology 2007;46:1229.
[73] Wierzbicki AS, Pendleton S, McMahon Z, Dar A, Oben J, Crook MA, et al.
J. Tam et al. European Journal of Internal Medicine xxx (xxxx) xxx–xxx
5
Rimonabant improves cholesterol, insulin resistance and markers of non-alcoholic
fatty liver in morbidly obese patients: a retrospective cohort study. Int J Clin Pract
2011;65:7135.
[74] Chorvat RJ, Berbaum J, Seriacki K, McElroy JF. JD-5006 and JD-5037: periph-
erally restricted (PR) cannabinoid-1 receptor blockers related to SLV-319
(Ibipinabant) as metabolic disorder therapeutics devoid of CNS liabilities. Bioorg
Med Chem Lett 2012;22:617380.
[75] Zhao W, Fong O, Muise ES, Thompson JR, Weingarth D, Qian S, et al. Genome-
wide expression proling revealed peripheral eects of cannabinoid receptor 1
inverse agonists in improving insulin sensitivity and metabolic parameters. Mol
Pharmacol 2010;78:3509.
[76] Westerbacka J, Kotronen A, Fielding BA, Wahren J, Hodson L, Perttila J, et al.
Splanchnic balance of free fatty acids, endocannabinoids, and lipids in subjects
with nonalcoholic fatty liver disease. Gastroenterology
2010;139(19611971):e1961.
[77] Zelber-Sagi S, Azar S, Nemirovski A, Webb M, Halpern Z, Shibolet O, et al. Serum
levels of endocannabinoids are independently associated with nonalcoholic fatty
liver disease. Obesity (Silver Spring) 2017;25:94101.
[78] Cote M, Matias I, Lemieux I, Petrosino S, Almeras N, Despres JP, et al. Circulating
endocannabinoid levels, abdominal adiposity and related cardiometabolic risk
factors in obese men. Int J Obes (Lond) 2007;31:6929.
[79] Di Marzo V, Cote M, Matias I, Lemieux I, Arsenault BJ, Cartier A, et al. Changes in
plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle
modication programme and waist circumference reduction: associations with
changes in metabolic risk factors. Diabetologia 2009;52:2137.
[80] Hsu CY, McCulloch CE, Iribarren C, Darbinian J, Go AS. Body mass index and risk
for end-stage renal disease. Ann Intern Med 2006;144:218.
[81] Nguyen S, Hsu CY. Excess weight as a risk factor for kidney failure. Curr Opin
Nephrol Hypertens 2007;16:716.
[82] Wang Y, Chen X, Song Y, Caballero B, Cheskin LJ. Association between obesity and
kidney disease: a systematic review and meta-analysis. Kidney Int 2008;73:1933.
[83] de Zeeuw D, Ramjit D, Zhang Z, Ribeiro AB, Kurokawa K, Lash JP, et al. Renal risk
and renoprotection among ethnic groups with type 2 diabetic nephropathy: a post
hoc analysis of RENAAL. Kidney Int 2006;69:167582.
[84] Remuzzi G, Macia M, Ruggenenti P. Prevention and treatment of diabetic renal
disease in type 2 diabetes: the BENEDICT study. J Am Soc Nephrol 2006;17:S907.
[85] Stemmer K, Perez-Tilve D, Ananthakrishnan G, Bort A, Seeley RJ, Tschop MH,
et al. High-fat-diet-induced obesity causes an inammatory and tumor-promoting
microenvironment in the rat kidney. Dis Model Mech 2012;5:62735.
[86] Lee W, Eom DW, Jung Y, Yamabe N, Lee S, Jeon Y, et al. Dendrobium moniliforme
attenuates high-fat diet-induced renal damage in mice through the regulation of
lipid-induced oxidative stress. Am J Chin Med 2012;40:121728.
[87] Coimbra TM, Janssen U, Grone HJ, Ostendorf T, Kunter U, Schmidt H, et al. Early
events leading to renal injury in obese Zucker (fatty) rats with type II diabetes.
Kidney Int 2000;57:16782.
[88] Deji N, Kume S, Araki S, Soumura M, Sugimoto T, Isshiki K, et al. Structural and
functional changes in the kidneys of high-fat diet-induced obese mice. Am J
Physiol Renal Physiol 2009;296:F11826.
[89] Pai R, Kirschenbaum MA, Kamanna VS. Low-density lipoprotein stimulates the
expression of macrophage colony-stimulating factor in glomerular mesangial cells.
Kidney Int 1995;48:125462.
[90] Matias I, Petrosino S, Racioppi A, Capasso R, Izzo AA, Di Marzo V. Dysregulation of
peripheral endocannabinoid levels in hyperglycemia and obesity: eect of high fat
diets. Mol Cell Endocrinol 2008;286:S6678.
[91] Janiak P, Poirier B, Bidouard JP, Cadrouvele C, Pierre F, Gouraud L, et al. Blockade
of cannabinoid CB1 receptors improves renal function, metabolic prole, and in-
creased survival of obese Zucker rats. Kidney Int 2007;72:134557.
[92] Jenkin KA, O'Keefe L, Simcocks A, Grinfeld E, Mathai M, McAinch A, et al. Chronic
administration with AM251 improves albuminuria and renal tubular structure in
obese rats. J Endocrinol 2015;225:11324.
[93] Tam J. The emerging role of the endocannabinoid system in the pathogenesis and
treatment of kidney diseases. J Basic Clin Physiol Pharmacol 2016;27:26776.
[94] Decleves AE, Mathew AV, Cunard R, Sharma K. AMPK mediates the initiation of
kidney disease induced by a high-fat diet. J Am Soc Nephrol 2011;22:184655.
[95] Decleves AE, Zolkipli Z, Satriano J, Wang L, Nakayama T, Rogac M, et al.
Regulation of lipid accumulation by AMP-activated kinase [corrected] in high fat
diet-induced kidney injury. Kidney Int 2014;85:61123.
[96] Barutta F, Corbelli A, Mastrocola R, Gambino R, Di Marzo V, Pinach S, et al.
Cannabinoid receptor 1 blockade ameliorates albuminuria in experimental dia-
betic nephropathy. Diabetes 2010;59:104654.
[97] Jenkin KA, McAinch AJ, Zhang Y, Kelly DJ, Hryciw DH. Elevated cannabinoid
receptor 1 and G protein-coupled receptor 55 expression in proximal tubule cells
and whole kidney exposed to diabetic conditions. Clin Exp Pharmacol Physiol
2015;42:25662.
[98] Nam DH, Lee MH, Kim JE, Song HK, Kang YS, Lee JE, et al. Blockade of canna-
binoid receptor 1 improves insulin resistance, lipid metabolism, and diabetic ne-
phropathy in db/db mice. Endocrinology 2012;153:138796.
[99] Jourdan T, Szanda G, Rosenberg AZ, Tam J, Earley BJ, Godlewski G, et al.
Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephro-
pathy. Proc Natl Acad Sci U S A 2014;111:E54208.
[100] Barutta F, Grimaldi S, Gambino R, Vemuri K, Makriyannis A, Annaratone L, et al.
Dual therapy targeting the endocannabinoid system prevents experimental dia-
betic nephropathy. Nephrol Dial Transplant 2017;32:165565.
[101] Jourdan T, Park JK, Varga ZV, Paloczi J, Coey NJ, Rosenberg AZ, et al.
Cannabinoid-1 receptor deletion in podocytes mitigates both glomerular and
tubular dysfunction in a mouse model of diabetic nephropathy. Diabetes Obes
Metab 2017. http://dx.doi.org/10.1111/dom.13150.
[102] Lim SK, Park SH. The high glucose-induced stimulation of B1R and B2R expression
via CB(1)R activation is involved in rat podocyte apoptosis. Life Sci
2012;91:895906.
[103] Rozenfeld R, Gupta A, Gagnidze K, Lim MP, Gomes I, Lee-Ramos D, et al. AT1R-CB
(1)R heteromerization reveals a new mechanism for the pathogenic properties of
angiotensin II. EMBO J 2011;30:235063.
[104] Lim JC, Lim SK, Park MJ, Kim GY, Han HJ, Park SH. Cannabinoid receptor 1
mediates high glucose-induced apoptosis via endoplasmic reticulum stress in
primary cultured rat mesangial cells. Am J Physiol Renal Physiol
2011;301:F17988.
[105] Lin CL, Hsu YC, Lee PH, Lei CC, Wang JY, Huang YT, et al. Cannabinoid receptor 1
disturbance of PPARgamma2 augments hyperglycemia induction of mesangial
inammation and brosis in renal glomeruli. J Mol Med (Berl) 2014;92:77992.
[106] Vallon V. The proximal tubule in the pathophysiology of the diabetic kidney. Am J
Physiol Regul Integr Comp Physiol 2011;300:R100922.
[107] Cohen M, Kitsberg D, Tsytkin S, Shulman M, Aroeti B, Nahmias Y. Live imaging of
GLUT2 glucose-dependent tracking and its inhibition in polarized epithelial
cysts. Open Biol 2014;4.
[108] Marks J, Carvou NJ, Debnam ES, Srai SK, Unwin RJ. Diabetes increases facilitative
glucose uptake and GLUT2 expression at the rat proximal tubule brush border
membrane. J Physiol 2003;553:13745.
[109] Chichger H, Cleasby ME, Srai SK, Unwin RJ, Debnam ES, Marks J. Experimental
type II diabetes and related models of impaired glucose metabolism dierentially
regulate glucose transporters at the proximal tubule brush border membrane. Exp
Physiol 2016;101:73142.
[110] Goestemeyer AK, Marks J, Srai SK, Debnam ES, Unwin RJ. GLUT2 protein at the
rat proximal tubule brush border membrane correlates with protein kinase C
(PKC)-betal and plasma glucose concentration. Diabetologia 2007;50:220917.
[111] Larkins RG, Dunlop ME. The link between hyperglycaemia and diabetic nephro-
pathy. Diabetologia 1992;35:499504.
[112] Wolf G, Thaiss F. Hyperglycaemiapathophysiological aspects at the cellular
level. Nephrol Dial Transplant 1995;10:110912.
[113] Hinden L, Udi S, Drori A, Gammal A, Nemirovski A, Hadar R, et al. Modulation of
renal GLUT2 by the Cannabinoid-1 receptor: implications for the treatment of
diabetic nephropathy. J Am Soc Nephrol 2017. http://dx.doi.org/10.1681/ASN.
2017040371.
[114] Bab I. Themed issue on cannabinoids in biology and medicine. Br J Pharmacol
2011;163:13278.
[115] Bab I, Ofek O, Tam J, Rehnelt J, Zimmer A. Endocannabinoids and the regulation
of bone metabolism. J Neuroendocrinol 2008;20:6974.
[116] Partt A. The coupling of bone formation to bone resorption: a critical analysis of
the concept and of its relevance to the pathogenesis of osteoporosis. Metab Bone
Dis Relat Res 1982;4:16.
[117] Rossi F, Siniscalco D, Luongo L, De Petrocellis L, Bellini G, Petrosino S, et al. The
endovanilloid/endocannabinoid system in human osteoclasts: possible involve-
ment in bone formation and resorption. Bone 2009;44:47684.
[118] Sophocleous A, Landao-Bassonga E, Van't Hof RJ, Idris AI, Ralston SH. The type 2
cannabinoid receptor regulates bone mass and ovariectomy-induced bone loss by
aecting osteoblast dierentiation and bone formation. Endocrinology
2011;152:21419.
[119] Tam J, Trembovler V, Di Marzo V, Petrosino S, Leo G, Alexandrovich A, et al. The
cannabinoid CB1 receptor regulates bone formation by modulating adrenergic
signaling. FASEB J 2008;22:28594.
[120] Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, et al. Peripheral
cannabinoid receptor, CB2, regulates bone mass. Proc Natl Acad Sci U S A
2006;103:696701.
[121] Raphael B, Gabet Y. The skeletal endocannabinoid system: clinical and experi-
mental insights. J Basic Clin Physiol Pharmacol 2016;27:23745.
[122] Ofek O, Attar-Namdar M, Kram V, Dvir-Ginzberg M, Mechoulam R, Zimmer A,
et al. CB2 cannabinoid receptor targets mitogenic Gi proteincyclin D1 axis in
osteoblasts. J Bone Miner Res 2011;26:30816.
[123] Smoum R, Baraghithy S, Chourasia M, Breuer A, Mussai N, Attar-Namdar M, et al.
CB2 cannabinoid receptor agonist enantiomers HU-433 and HU-308: an inverse
relationship between binding anity and biological potency. Proc Natl Acad Sci
2015;112:87749.
[124] Karsak M, Malkin I, Toliat MR, Kubisch C, Nurnberg P, Zimmer A, et al. The
cannabinoid receptor type 2 (CNR2) gene is associated with hand bone strength
phenotypes in an ethnically homogeneous family sample. Hum Genet
2009;126:62936.
[125] Yamada Y, Ando F, Shimokata H. Association of candidate gene polymorphisms
with bone mineral density in community-dwelling Japanese women and men. Int J
Mol Med 2007;19:791801.
[126] Karsak M, Cohen-Solal M, Freudenberg J, Ostertag A, Morieux C, Kornak U, et al.
Cannabinoid receptor type 2 gene is associated with human osteoporosis. Hum
Mol Genet 2005;14:338996.
[127] Idris AI, Sophocleous A, Landao-Bassonga E, van't Hof RJ, Ralston SH. Regulation
of bone mass, osteoclast function, and ovariectomy-induced bone loss by the type
2 cannabinoid receptor. Endocrinology 2008;149:561926.
[128] Idris AI, van't Hof RJ, Greig IR, Ridge SA, Baker D, Ross RA, et al. Regulation of
bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat Med
2005;11:7749.
[129] Idris AI, Sophocleous A, Landao-Bassonga E, Canals M, Milligan G, Baker D, et al.
Cannabinoid receptor type 1 protects against age-related osteoporosis by reg-
ulating osteoblast and adipocyte dierentiation in marrow stromal cells. Cell
Metab 2009;10:13947.
J. Tam et al. European Journal of Internal Medicine xxx (xxxx) xxx–xxx
6
[130] Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, et al. Leptin regulation
of bone resorption by the sympathetic nervous system and CART. Nature
2005;434:51420.
[131] Yirmiya R, Goshen I, Bajayo A, Kreisel T, Feldman S, Tam J, et al. Depression
induces bone loss through stimulation of the sympathetic nervous system.
Proceedings of the. 103. National Academy of Sciences; 2006. p. 1687681.
[132] Busquets-Garcia A, Gomis-Gonzalez M, Srivastava RK, Cutando L, Ortega-Alvaro
A, Ruehle S, et al. Peripheral and central CB1 cannabinoid receptors control stress-
induced impairment of memory consolidation. Proc Natl Acad Sci U S A
2016;113:99049.
[133] Deis S, Srivastava RK, de Azua IR, Bindila L, Baraghithy S, Lutz B, et al. Age-
related regulation of bone formation by the sympathetic cannabinoid CB1 re-
ceptor. Bone 2017;108:3442.
[134] Wasserman E, Tam J, Mechoulam R, Zimmer A, Maor G, Bab I. CB1 cannabinoid
receptors mediate endochondral skeletal growth attenuation by Δ9-tetra-
hydrocannabinol. Ann N Y Acad Sci 2015;1335:1109.
[135] El Marroun H, Tiemeier H, Steegers EA, Jaddoe VW, Hofman A, Verhulst FC, et al.
Intrauterine cannabis exposure aects fetal growth trajectories: the generation R
study. J Am Acad Child Adolesc Psychiatry 2009;48:117381.
[136] Zuckerman B, Frank DA, Hingson R, Amaro H, Levenson SM, Kayne H, et al.
Eects of maternal marijuana and cocaine use on fetal growth. N Engl J Med
1989;320:7628.
J. Tam et al. European Journal of Internal Medicine xxx (xxxx) xxx–xxx
7
... 7,[12][13][14] In recent years, there has been a growing interest in blocking CB 1 R in peripheral organs for treatment of many pathologies mainly associated with metabolic syndrome (reviewed in Refs. 15,16 ). Moreover, CB 1 R antagonism was suggested as a potential therapeutic intervention for acute cisplatin-induced renal dysfunction, 17 a disease associated with enhanced inflammation, oxidative/nitrosative stress, and cell death. ...
Article
Full-text available
Background: The endocannabinoid system (ECS) plays a key physiological role in bladder function and it has been suggested as a potential target for relieving lower urinary tract symptoms (LUTSs). Whereas most studies indicate that activating the ECS has some beneficial effects on the bladder, some studies imply the opposite. In this study, we investigated the therapeutic potential of peripheral cannabinoid-1 receptor (CB1R) blockade in a mouse model for LUTSs. Materials and Methods: To this end, we used the cyclophosphamide (CYP; 300 mg/kg, intraperitoneal)-induced cystitis model of bladder dysfunction, in which 12-week-old, female C57BL/6 mice were treated with the peripherally restricted CB1R antagonist, JD5037 (3 mg/kg), or vehicle for three consecutive days. Bladder dysfunction was assessed using the noninvasive voiding spot assay (VSA) as well as the bladder-to-body weight (BW) ratio and gene and protein expression levels; ECS tone was assessed at the end of the study. Results: Peripheral CB1R blockade significantly ameliorated the severity of CYP-induced cystitis, manifested by reduced urination events measured in the VSA and an increased bladder-to-BW ratio. Moreover, JD5037 normalized CYP-mediated bladder ECS tone imbalance by affecting both the expression of CB1R and the endocannabinoid levels. These effects were associated with the ability of JD5037 to reduce CYP-induced inflammatory response, manifested by a reduction in levels of the proinflammatory cytokine, tumor necrosis factor alpha (TNFα), in the bladder and serum. Conclusions: Collectively, our results highlight the therapeutic relevance of peripheral CB1R blockade in ameliorating CYP-induced cystitis; they may further support the preclinical development and clinical use of peripherally restricted CB1R antagonism for treatment of LUTSs.
... Accumulating evidence indicates that peripheral CB1R blockade improves lipid and carbohydrate homeostasis acting simultaneously on several peripheral organs [3,45]. Thus, activation of hepatocyte CB1R has been shown to induce liver lipogenesis and decrease ß-oxidation [46,47]. ...
Article
Full-text available
Targeting cannabinoid 1 receptors (CB1R) with peripherally restricted antagonists (or inverse agonists) shows promise to improve metabolic disorders associated with obesity. In this context, we designed and synthetized JM-00266, a new CB1R blocker with limited blood–brain barrier (BBB) permeability. Pharmacokinetics were tested with SwissADME and in vivo in rodents after oral and intraperitoneal administration of JM-00266 in comparison with Rimonabant. In silico predictions indicated JM-00266 is a non-brain penetrant compound and this was confirmed by brain/plasma ratios and brain uptake index values. JM-00266 had no impact on food intake, anxiety-related behavior and body temperature suggesting an absence of central activity. cAMP assays performed in CB1R-transfected HEK293T/17 cells showed that the drug exhibited inverse agonist activity on CB1R. In addition, JM-00266 counteracted anandamide-induced gastroparesis indicating substantial peripheral activity. Acute administration of JM-00266 also improved glucose tolerance and insulin sensitivity in wild-type mice, but not in CB1R−/− mice. Furthermore, the accumulation of JM-00266 in adipose tissue was associated with an increase in lipolysis. In conclusion, JM-00266 or derivatives can be predicted as a new candidate for modulating peripheral endocannabinoid activity and improving obesity-related metabolic disorders.
... ECS activity is based on the interaction between the endocannabinoid molecules N-arachidonoylethanolamine (Anandamide, AEA) and 2-arachidonoylglycerol (2-AG), which are Arachidonic Acid (AA) derivates, and the well-known G-protein coupled cannabinoid receptors 1 (CB1) and 2 (CB2) [2]. CB1 is primarily expressed in the central nervous system and it was thought to be present exclusively in this district before the discovery of functionally relevant expression levels in peripheral organs such as liver, adipose tissue and kidney, among others [3]. CB2 was thought to be absent from the CNS and only present in peripheral organs and in the immune system, but early discoveries were able to pinpoint its presence also in the microglia where it apparently participates in the regulation of neuroinflammation [4,5]. ...
Article
Full-text available
The endocannabinoid system is a complex lipid signaling network that has evolved to be a key regulator of pro-homeostatic pathways for the organism. Its involvement in numerous processes has rendered it a very suitable target for pharmacological studies regarding metabolic syndrome, obesity and other lifestyle-related diseases. Cannabinomimetic molecules have been found in a large variety of foods, most of which are normally present in the Mediterranean diet. The majority of these compounds belong to the terpene and polyphenol classes. While it is known that they do not necessarily act directly on the cannabinoid receptors CB1 and CB2, their ability to regulate their expression levels has already been shown in some disease-related models, as well as their ability to modulate the activity of other components of the system. In this review, evidence was gathered to support the idea that phytocannabinoid dietary intake may indeed be a viable strategy for disease prevention and may be helpful in maintaining the health status. In an era where personalized nutrition is becoming more and more a reality, having new therapeutic targets could become an important resource.
... Antagonizing CB 1 R signaling specifically in peripheral organs is also emerging as an exciting novel approach for preventing CKD in diabetes and in obesity [Reviewed in [181]]. As the kidney is a major source of endocannabinoids (eCBs), and the fact that CB 1 R is highly expressed in many cells within the kidney, the possible involvement of the eCB/CB 1 R system in regulating diabesity-induced kidney injury has been the interest of several recent studies. ...
Article
Full-text available
Diabetes kidney disease (DKD) is a major health care problem associated with increased risk for developing end‐stage kidney disease (ESKD) and high mortality. It is widely accepted that DKD is primarily a glomerular disease. Recent findings however suggest that renal proximal tubule cells (KPTCs) may play a central role in the pathophysiology of DKD. In diabetes and obesity, KPTCs are exposed to nutrient overload, including glucose, free‐fatty acids (FFAs) and amino acids (AAs), which dysregulate nutrient and energy sensing by mTORC1 and AMPK, with subsequent induction of tubular injury, inflammation and fibrosis. Pharmacological treatments that modulate nutrient sensing and signaling in KPTCs, including cannabinoid‐1 receptor (CB1R) antagonists and sodium glucose transporter 2 (SGLT2) inhibitors, exert robust kidney protective effects. Shedding light on how nutrients are sensed and metabolized in KPTCs and in other kidney domains, and on their effects on signal transduction pathways that mediate kidney injury, is important for understanding the pathophysiology of DKD and for the development of novel therapeutic approaches in DKD and probably also in other forms of kidney disease.
... For the past decade our research group has focused on elucidating the role of the endocannabinoid (eCB) system in several physiological/pathological functions. Our findings indicate that this endogenous system has crucial effects on the maintenance of both glucose and bone homeostasis; thus, deviation from this homeostasis can cause two major disorders: Diabetes and osteoporosis, suggesting that modulating the activity of the eCB system holds therapeutic promise for treating these disorders [14][15][16][17]. Moreover, the eCB system is also involved in regulating kidney function. ...
Article
Full-text available
The renal proximal tubule cells (RPTCs), well-known for maintaining glucose and mineral homeostasis, play a critical role in the regulation of kidney function and bone remodeling. Deterioration in RPTC function may therefore lead to the development of diabetic kidney disease (DKD) and osteoporosis. Previously, we have shown that the cannabinoid-1 receptor (CB1R) modulates both kidney function as well as bone remodeling and mass via its direct role in RPTCs and bone cells, respectively. Here we employed genetic and pharmacological approaches that target CB1R, and found that its specific nullification in RPTCs preserves bone mass and remodeling both under normo- and hyper-glycemic conditions, and that its chronic blockade prevents the development of diabetes-induced bone loss. These protective effects of negatively targeting CB1R specifically in RPTCs were associated with its ability to modulate erythropoietin (EPO) synthesis, a hormone known to affect bone mass and remodeling. Our findings highlight a novel molecular mechanism by which CB1R in RPTCs remotely regulates skeletal homeostasis via a kidney-to-bone axis that involves EPO.
... A large body of evidence indicates that obesitya major risk factor for the development of type-2 diabetes, cardiovascular disease and liver steatosisis associated with central and peripheral hyperactivity of the endocannabinoid system, which can be effectively (albeit not safely) corrected by administration of globally active CB 1 receptor blockers. Excellent reviews of this field of research are available [86][87][88][89][90] but is important to point out in the present context that signs of excess endocannabinoid activity are clearly detectable both in the circulation and in visceral compartments of the adipose organ, whose pathogenic role in obesity is well recognized [71]. Circulating levels of 2-AG are significantly elevated in persons with obesity and are correlated with body mass index (BMI), visceral fat mass and fasting insulin and triglyceride concentrations [91,92]. ...
Article
Full-text available
The endocannabinoid system is found in most, if not all, mammalian organs and is involved in a variety of physiological functions, ranging from the control of synaptic plasticity in the brain to the modulation of smooth muscle motility in the gastrointestinal tract. This signaling complex consists of G protein-coupled cannabinoid receptors, endogenous ligands for those receptors (endocannabinoids) and enzymes/transporters responsible for the formation and deactivation of these ligands. There are two subtypes of cannabinoid receptors, CB1 and CB2, and two major endocannabinoids, arachidonoylethanolamide (anandamide) and 2-arachidonoyl-sn-glycerol (2-AG), which are produced upon demand through cleavage of distinct phospholipid precursors. All molecular components of the endocannabinoid system are represented in the adipose organ, where endocannabinoid signals are thought to regulate critical homeostatic processes, including adipogenesis, lipogenesis and thermogenesis. Importantly, obesity was found to be associated with excess endocannabinoid activity in visceral fat depots, and the therapeutic potential of normalizing such activity by blocking CB1 receptors has been the focus of substantial preclinical and clinical research. Results have been mixed thus far, mostly owing to the emergence of psychiatric side effects rooted in the protective functions served by brain endocannabinoids in mood and affect regulation. Further studies about the roles played by the endocannabinoid system in the adipose organ will offer new insights into the pathogenesis of obesity and might help identify new ways to leverage this signaling complex for therapeutic benefit.
Thesis
L’obésité est une pathologie dont la fréquence est en constante augmentation. Elle correspond à un excès de tissu adipeux (TA) dont les fonctions peuvent être altérées. Parmi les dérégulations métaboliques, il peut exister une hyperactivation du système endocannabinoïde (SEC). Ce système, composé de récepteurs aux cannabinoïdes (CB1R et CB2R), de leurs ligands endogènes (EndoCannabinoïdes – ECs) et des enzymes impliquées dans leur biosynthèse et leur dégradation, est présent dans le système nerveux central ainsi que dans divers tissus périphériques.Le blocage des CB1R par le Rimonabant, premier antagoniste commercialisé en 2006, s’est révélé être une approche thérapeutique efficace en réduisant la prise alimentaire, la masse corporelle et en améliorant significativement les paramètres métaboliques. Néanmoins, les troubles psychiatriques sévères associés, consécutifs aux effets centraux, ont valu à ce composé d’être retiré du marché 2 ans plus tard.Depuis, l’utilisation d’antagonistes ne franchissant pas la barrière hémato-encéphalique a permis de démontrer que l’inactivation des CB1R périphériques était suffisante pour diminuer le risque cardio-métabolique chez la souris obèse. Compte tenu du rôle central joué par le TA dans l’étiologie des pathologies associées à l’obésité, il apparait important de préciser la relation existante entre le SEC et le métabolisme adipocytaire. Dans ce contexte, ces travaux de thèse ont pour objectifs de préciser le rôle des ECs sur l’activité lipolytique adipocytaire, d’évaluer les capacités sécrétoires des différents dépôts de TA et d’étudier l’impact d’agonistes et d’antagonistes des CB1R sur l’adipogenèse. Une dernière partie, est consacrée à la caractérisation de l’activité biologique de nouveaux antagonistes des CB1R.Tout d’abord, l’étude des conséquences de la modulation du SEC sur l’activité lipolytique a permis de démontrer que l’activation des CB1R, en stimulant la voie de signalisation PI3K/Akt, conduit à une diminution de la lipolyse. Les résultats suggèrent également que les ECs produits par le TA, pourraient alimenter le pool d’ECs circulants et être à l’origine d’effets exocrines néfastes.L’étude de la production des ECs in vitro, par des explants de TA viscéral et sous-cutané chez la souris et chez l’Homme obèses, a confirmé la modification des capacités sécrétoires en ECs. Ces résultats préliminaires valident une approche méthodologique originale qui nous permet d’envisager une exploration plus poussée des mécanismes de la production des ECs.Par ailleurs, le rôle des ECs sur la différenciation de cellules souches issues de la fraction stroma-vasculaire de TA sain et pathologique de souris a été étudié. Des essais préliminaires ont permis de suggérer l’existence d’un lien entre différenciation adipocytaire et activité des CB1R.Enfin, les études de caractérisation de nouveaux antagonistes des CB1R ont démontré des effets intéressants des molécules JM-00266 et HR-0133 sur la masse corporelle et le métabolisme glucido-lipidique. Toutefois, l’optimisation, le développement et la caractérisation de ces nouveaux types d’antagonistes à des fins thérapeutiques apparait essentiel dans la lutte contre l’obésité et ses complications.Mots clés : Obésité, Système Endocannabinoïde, Tissu Adipeux, Métabolisme glucido-lipidique
Article
ZUSAMMENFASSUNG Hintergrund Bei Patienten mit Störungen aus dem schizophrenen Formenkreis ist der Konsum von Cannabis und anderen psychoaktiven Substanzen weit verbreitet. Es besteht eine wissenschaftliche Evidenz, dass der hochdosierte und regelmäßige Freizeitkonsum von Cannabis mit nachteiligen Langzeitfolgen assoziiert ist. Und dennoch könnte die physiologische Bedeutung des Endocannabinoidsystems (ECS) den Einsatz von Cannabispräparaten – womöglich mit einem hohen Gehalt an Cannabidiol (CBD) – zur Therapie neuropsychiatrischer Erkrankungen als nützlich erscheinen lassen. Ziel Darstellung der Grundlagen für die Wirksamkeit von medizinischem Cannabis bei neuropsychiatrischen Erkrankungen – insbesondere Störungen aus dem schizophrenen Formenkreis – und kritische Nutzen-Risiko-Bewertung. Ergebnisse und Diskussion Die beiden wichtigsten neuroaktiven Bestandteile von Cannabis sind CBD und Tetrahydrocannabinol (THC). THC scheint psychose- und angstfördernd zu wirken und die Kognition zu beeinträchtigen. Basierend auf einer Recherche aktueller Literatur ist anzunehmen, dass CBD im Gegensatz zu THC nicht euphorisierend, sondern antikonvulsiv, analgetisch, angstlösend und antipsychotisch wirken könnte und möglicherweise die kognitive Leistungsfähigkeit verbessern kann. Somit wäre CBD ein natürlicher Antagonist von THC. Während es eine hinreichende Evidenz gibt, dass der Freizeitkonsum von meist THC-lastigem Cannabis die psychische Gesundheit nachteilig beeinflusst und Psychosen fördert, gibt es Studien, die darauf hindeuten, dass CBD protektiv sein könnte. Allerdings mangelt es an hochwertigen kontrollierten klinischen Studien mit größeren Patientenzahlen und guter Methodik, um eine ausreichende Evidenz für den Einsatz von Cannabidiol in der klinischen Praxis zu begründen.
Article
‘Diabesity’ refers to a rising epidemic indicated by the intricate relationship between obesity and diabetes. The global prevalence of these coexisting, insidious diseases increases social and economic health burdens at a rapid pace. Numerous reports delineate the involvement of the underlying endocannabinoid (EC) signaling system through the cannabinoid-1 (CB1) receptor in the regulation of metabolism and adiposity. Conversely, EC inverse agonists can result in severe depression and suicidal thoughts through interactions with CB1/2 receptors in the brain. This review attempts to elucidate a possible mechanism for the amelioration of diabesity. Moreover, we also highlight the available targets of the CB1 receptor, which could pave the way for safe and effective therapy.
Article
Full-text available
Dysregulated adipocyte physiology leads to imbalanced energy storage, obesity, and associated diseases, imposing a costly burden on current health care. Cannabinoid receptor type-1 (CB1) plays a crucial role in controlling energy metabolism through central and peripheral mechanisms. In this work, adipocyte-specific inducible deletion of the CB1 gene (Ati-CB1-KO) was sufficient to protect adult mice from diet-induced obesity and associated metabolic alterations and to reverse the phenotype in already obese mice. Compared with controls, Ati-CB1-KO mice showed decreased body weight, reduced total adiposity, improved insulin sensitivity, enhanced energy expenditure, and fat depot-specific cellular remodeling toward lowered energy storage capacity and browning of white adipocytes. These changes were associated with an increase in alternatively activated macrophages concomitant with enhanced sympathetic tone in adipose tissue. Remarkably, these alterations preceded the appearance of differences in body weight, highlighting the causal relation between the loss of CB1 and the triggering of metabolic reprogramming in adipose tissues. Finally, the lean phenotype of Ati-CB1-KO mice and the increase in alternatively activated macrophages in adipose tissue were also present at thermoneutral conditions. Our data provide compelling evidence for a crosstalk among adipocytes, immune cells, and the sympathetic nervous system (SNS), wherein CB1 plays a key regulatory role.
Article
Full-text available
Altered glucose reabsorption via the facilitative glucose transporter 2 (GLUT2) during diabetes may lead to renal proximal tubule cell (RPTC) injury, inflammation, and interstitial fibrosis. These pathologies are also triggered by activating the cannabinoid-1 receptor (CB1R), which contributes to the development of diabetic nephropathy (DN). However, the link between CB1R and GLUT2 remains to be determined. Here, we show that chronic peripheral CB1R blockade or genetically inactivating CB1Rs in the RPTCs ameliorated diabetes-induced renal structural and functional changes, kidney inflammation, and tubulointerstitial fibrosis in mice. Inhibition of CB1R also downregulated GLUT2 expression, affected the dynamic translocation of GLUT2 to the brush border membrane of RPTCs, and reduced glucose reabsorption. Thus, targeting peripheral CB1R or inhibiting GLUT2 dynamics in RPTCs has the potential to treat and ameliorate DN. These findings may support the rationale for the clinical testing of peripherally restricted CB1R antagonists or the development of novel renal-specific GLUT2 inhibitors against DN.
Article
Full-text available
Obesity-related structural and functional changes in the kidney develop early in the course of obesity and occur independently of hypertension, diabetes, and dyslipidemia. Activating the renal cannabinoid-1 receptor (CB1R) induces nephropathy, whereas CB1R blockade improves kidney function. Whether these effects are mediated via a specific cell type within the kidney remains unknown. Here, we show that specific deletion of CB1R in the renal proximal tubule cells did not protect the mice from obesity, but markedly attenuated the obesity-induced lipid accumulation in the kidney and renal dysfunction, injury, inflammation, and fibrosis. These effects associated with increased activation of liver kinase B1 and the energy sensor AMP-activated protein kinase, as well as enhanced fatty acid β-oxidation. Collectively, these findings indicate that renal proximal tubule cell CB1R contributes to the pathogenesis of obesity-induced renal lipotoxicity and nephropathy by regulating the liver kinase B1/AMP-activated protein kinase signaling pathway.
Article
Full-text available
Objective: In visceral obesity, an overactive endocannabinoid/CB1 receptor (CB1R) system promotes increased caloric intake and decreases energy expenditure, which are mitigated by global or peripheral CB1R blockade. In mice with diet-induced obesity (DIO), inhibition of food intake by the peripherally restricted CB1R antagonist JD5037 could be attributed to endogenous leptin due to the rapid reversal of hyperleptinemia that maintains leptin resistance, but the signaling pathway engaged by leptin has remained to be determined. Methods: We analyzed the hypothalamic circuitry targeted by leptin following chronic treatment of DIO mice with JD5037. Results: Leptin treatment or an increase in endogenous leptin following fasting/refeeding induced STAT3 phosphorylation in neurons in the arcuate nucleus (ARC) in lean and JD5037-treated DIO mice, but not in vehicle-treated DIO animals. Co-localization of pSTAT3 in leptin-treated mice was significantly less common with NPY+ than with POMC+ ARC neurons. The hypophagic effect of JD5037 was absent in melanocortin-4 receptor (MC4R) deficient obese mice or DIO mice treated with a MC4R antagonist, but was maintained in NPY−/− mice kept on a high-fat diet. Conclusions: Peripheral CB1R blockade in DIO restores sensitivity to endogenous leptin, which elicits hypophagia via the re-activation of melanocortin signaling in the ARC.
Article
The endocannabinoid (eCB) system, including its receptors, ligands, and their metabolizing enzymes, plays an important role in bone physiology. Skeletal cannabinoid type 1 (CB1) receptor signaling transmits retrograde signals that restrain norepinephrine (NE) release, thus transiently stimulating bone formation following an acute challenge, suggesting a feedback circuit between sympathetic nerve terminals and osteoblasts. To assess the effect of chronic in vivo occurrence of this circuit, we characterized the skeletal phenotype of mice with a conditional deletion of the CB1 receptor in adrenergic/noradrenergic cells, including sympathetic nerves. Whereas the deletion of the CB1 receptor did not affect bone mass accrual in the distal femoral metaphysis and in vertebral bodies of young, 12-week-old mice, it substantially increased bone mass in aged, 35-week-old mutant mice as compared to wild-type controls. Contrary to our expectations, specific deficiency of the CB1 receptor in sympathetic neurons led to a markedly increased bone mass phenotype, associated with an enhanced bone formation rate and reduced osteoclastogenesis. Mechanistically, the reduced skeletal eCB 'tone' in the null mice did not reflect in increased sympathetic tone and reduced bone formation, suggesting that constitutive genetic inactivation of sympathetic CB1 receptor disrupts the negative feedback loop between eCBs and NE signaling in bone.
Article
Aims: To determine the specific role of podocyte-expressed cannabinoid-1 receptor (CB1 R) in the development of diabetic nephropathy (DN), relative to CB1 R in other renal cell types. Material and methods: We developed a mouse model with a podocyte-specific deletion of CB1 R (pCB1Rko) and challenged this model with streptozotocin (STZ)-induced type-1 DN. We also assessed the podocyte response to high glucose in vitro and its effects on CB1 R activation. Results: High glucose exposure for 48h led to an increase in CB1 R gene expression (CNR1) and endocannabinoid production in cultured human podocytes. This was associated with podocyte injury reflected by decreased podocin and nephrin expression. These changes could be prevented by Cnr1-silencing, thus identifying CB1R as a key player in podocyte injury. After 12 weeks of chronic hyperglycemia, STZ-treated pCB1Rko mice showed similar elevated blood glucose as their wild-type littermates. However, they displayed less albuminuria and less podocyte loss than STZ-treated wild-type mice. Unexpectedly, pCB1Rko mice also have milder tubular dysfunction, fibrosis and reduction of cortical microcirculation compared to wild-type controls, which is partly mediated by podocyte-derived endocannabinoids acting via CB1 R on proximal tubular cells. Conclusions: Activation of CB1 R in podocytes contributes to both glomerular and tubular dysfunction in type-1 DN, which highlights the therapeutic potential of peripheral CB1 R blockade.
Article
Background.: The endocannabinoid system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effect of combined therapy with AM6545, a 'peripherally' restricted cannabinoid receptor type 1 (CB1R) neutral antagonist, and AM1241, a cannabinoid receptor type 2 (CB2R) agonist, in experimental DN. Methods.: Renal function and structure, podocyte proteins and markers of both fibrosis and inflammation were studied in streptozotocin-induced diabetic mice treated for 14 weeks with vehicle, AM6545, AM1241 and AM6545-AM1241. Results.: Single treatment with either AM6545 or AM1241 alone reduced diabetes-induced albuminuria and prevented nephrin loss both in vivo and in vitro in podocytes exposed to glycated albumin. Dual therapy performed better than monotherapies, as it abolished albuminuria, inflammation, tubular injury and markedly reduced renal fibrosis. Converging anti-inflammatory mechanisms provide an explanation for this greater efficacy as dual therapy abolished diabetes-induced renal monocyte infiltration and M1/M2 macrophage imbalance in vivo and abrogated the profibrotic effect of M1 macrophage-conditioned media on cultured mesangial cells. Conclusion.: 'Peripheral' CB1R blockade is beneficial in experimental DN and this effect is synergically magnified by CB2R activation.
Article
The endocannabinoid system (ECS), including cannabinoid type 1 and type 2 receptors (CB1R and CB2R), endogenous ligands called endocannabinoids and their related enzymatic machinery, is known to have a role in the regulation of energy balance. Past information generated on the ECS, mainly focused on the involvement of this system in the central nervous system regulation of food intake, while at the same time clinical studies pointed out the therapeutic efficacy of brain-penetrant CB1R antagonists like rimonabant for obesity and metabolic disorders. Rimonabant was removed from the market in 2009 and its obituary written due to its psychiatric side effects. However, in the meanwhile a number of investigations had started to highlight the roles of the peripheral ECS in the regulation of metabolism, bringing up new hope that the ECS might still represent target for treatment. Accordingly, peripherally-restricted CB1R antagonists or inverse agonists have shown to effectively reduce body weight, adiposity, insulin resistance and dyslipidemia in obese animal models. Very recent investigations have further expanded the possible toolbox for the modulation of the ECS, by demonstrating the existence of endogenous allosteric inhibitors of CB1R, the characterization of the structure of the human CB1R, and the likely involvement of CB2R in metabolic disorders. Here we give an overview of these findings, discussing what the future may hold in the context of strategies targeting the ECS in metabolic disease.