Highlights
- •CB1 receptor modulates energy homeostasis via both central and peripheral mechanisms.
- •Blockade of CB1 receptor in periphery ameliorates the development of visceral obesity.
- •Hepatic CB1 receptor regulates lipogenesis and fatty acid oxidation in the liver.
- •Activating renal CB1 receptor promotes the development of chronic kidney diseases.
- •Modulating skeletal CB1 receptor may be beneficial in a range of skeletal disorders.
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.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to European Journal of Internal MedicineAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Cannabis: effects on hunger and thirst.Behav Biol. 1975; 15: 255-281
- Isolation, structure and partial synthesis of an active constituent of hashish.J Am Chem Soc. 1964; 86: 1646-1647
- Determination and characterization of a cannabinoid receptor in rat brain.Mol Pharmacol. 1988; 34: 605-613
- Structure of a cannabinoid receptor and functional expression of the cloned cDNA.Nature. 1990; 346: 561-564
- Molecular characterization of a peripheral receptor for cannabinoids.Nature. 1993; 365: 61-65
- Crystal structure of the human cannabinoid receptor CB1.Cell. 2016; 167e714
- High-resolution crystal structure of the human CB1 cannabinoid receptor.Nature. 2016; 540: 602-606
- Cannabinoid receptor signaling.Handb Exp Pharmacol. 2005; : 53-79
- Isolation and structure of a brain constituent that binds to the cannabinoid receptor.Science. 1992; 258: 1946-1949
- Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors.Biochem Pharmacol. 1995; 50: 83-90
- 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain.Biochem Biophys Res Commun. 1995; 215: 89-97
- The pharmacology of the cannabinoid system—a question of efficacy and selectivity.Mol Neurobiol. 2007; 36: 15-25
- Structure and function of fatty acid amide hydrolase.Annu Rev Biochem. 2005; 74: 411-432
- Brain monoglyceride lipase participating in endocannabinoid inactivation.Proc Natl Acad Sci U S A. 2002; 99: 10819-10824
- MECHANISMS IN ENDOCRINOLOGY: endocannabinoids and metabolism: past, present and future.Eur J Endocrinol. 2017; 176: R309-R324
- Leptin-regulated endocannabinoids are involved in maintaining food intake.Nature. 2001; 410: 822-825
- Role of endogenous cannabinoids in synaptic signaling.Physiol Rev. 2003; 83: 1017-1066
- The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells.Mol Pharmacol. 2003; 63: 908-914
- Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity.J Clin Invest. 2005; 115: 1298-1305
- The emerging role of the endocannabinoid system in endocrine regulation and energy balance.Endocr Rev. 2006; 27: 73-100
- Expression of cannabinoid receptors in human kidney.Histol Histopathol. 2010; 25: 1133-1138
- Involvement of neuronal cannabinoid receptor CB1 in regulation of bone mass and bone remodeling.Mol Pharmacol. 2006; 70: 786-792
- Cannabinoids inhibit insulin secretion and cytosolic Ca2+ oscillation in islet beta-cells via CB1 receptors.Regul Pept. 2008; 145: 49-53
- Appetite suppression and weight loss after the cannabinoid antagonist SR 141716.Life Sci. 1998; 63: PL113-117
- Effects of SR141716A, a central cannabinoid receptor antagonist, on food-maintained responding.Pharmacol Biochem Behav. 2000; 67: 265-270
- SR 141716, a CB1 cannabinoid receptor antagonist, selectively reduces sweet food intake in marmoset.Behav Pharmacol. 1998; 9: 179-181
- Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors.Psychopharmacology (Berl). 1999; 143: 315-317
- Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia.N Engl J Med. 2005; 353: 2121-2134
- Effect of rimonabant on the high-triglyceride/low-HDL-cholesterol dyslipidemia, intraabdominal adiposity, and liver fat: the ADAGIO-lipids trial.Arterioscler Thromb Vasc Biol. 2009; 29: 416-423
- Effect of rimonabant on glycemic control in insulin-treated type 2 diabetes: the ARPEGGIO trial.Diabetes Care. 2010; 33: 605-607
- Effect of rimonabant, 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: 761-775
- SERENADE: the study evaluating rimonabant efficacy in drug-naive diabetic patients: effects of monotherapy with rimonabant, the first selective CB1 receptor antagonist, on glycemic control, body weight, and lipid profile in drug-naive type 2 diabetes.Diabetes Care. 2008; 31: 2169-2176
- Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study.Lancet. 2006; 368: 1660-1672
- Effects of the cannabinoid-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: 1389-1397
- The endocannabinoid system as an emerging target of pharmacotherapy.Pharmacol Rev. 2006; 58: 389-462
- Endocannabinoid control of food intake and energy balance.Nat Neurosci. 2005; 8: 585-589
- Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials.Lancet. 2007; 370: 1706-1713
- End of the line for cannabinoid receptor 1 as an anti-obesity target?.Nat Rev Drug Discov. 2008; 7: 961-962
- CB1 antagonism exerts specific molecular effects on visceral and subcutaneous fat and reverses liver steatosis in diet-induced obese mice.Diabetes. 2010; 59: 926-934
- Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice.J Clin Invest. 2008; 118: 3160-3169
- CB(1) signaling in forebrain and sympathetic neurons is a key determinant of endocannabinoid actions on energy balance.Cell Metab. 2010; 11: 273-285
- Proximal tubular cannabinoid-1 receptor regulates obesity-induced CKD.J Am Soc Nephrol. 2017; 28: 3518-3532
- Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes.Nat Med. 2013; 19: 1132-1140
- Cannabinoid CB1 receptor expression in relation to visceral adipose depots, endocannabinoid levels, microvascular damage, and the presence of the Cnr1 A3813G variant in humans.Metabolism. 2010; 59: 734-741
- Circulating endocannabinoids in insulin sensitive vs. insulin resistant obese postmenopausal women. A MONET group study.Obesity (Silver Spring). 2014; 22: 211-216
- Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity.Diabetes. 2006; 55: 3053-3060
- Role of insulin as a negative regulator of plasma endocannabinoid levels in obese and nonobese subjects.Eur J Endocrinol. 2009; 161: 715-722
- Activation of the peripheral endocannabinoid system in human obesity.Diabetes. 2005; 54: 2838-2843
- Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome.Mol Metab. 2016; 5: 1187-1199
- The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis.J Clin Invest. 2003; 112: 423-431
- Localization of CaMKIIalpha in rat primary sensory neurons: increase in inflammation.Brain Res. 2002; 947: 252-259
- Pharmacological interactions between calcium/calmodulin-dependent kinase II alpha and TRPV1 receptors in rat trigeminal sensory neurons.Neurosci Lett. 2005; 389: 94-98
- Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity.J Clin Invest. 2010; 120: 2953-2966
- Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity.Physiol Behav. 2017; 171: 32-39
- A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome.Proc Natl Acad Sci U S A. 2015; 112: 285-290
- 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: 629-642
- Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity.FASEB J. 2014; 28: 5361-5375
- Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance.Cell Metab. 2012; 16: 167-179
- Hypothalamic POMC neurons promote cannabinoid-induced feeding.Nature. 2015; 519: 45-50
- Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signaling.Mol Metab. 2017; 6: 1113-1125
- Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages.J Clin Invest. 2017; 127: 4148-4162
- Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations.Eur J Biochem. 1995; 232: 54-61
- Expression of the CB1 and CB2 receptor messenger RNAs during embryonic development in the rat.Neuroscience. 1998; 82: 1131-1149
- Hepatic expression of endocannabinoid receptors and their novel polymorphisms in primary biliary cirrhosis.J Gastroenterol. 2010; 45: 68-76
- Overexpression of cannabinoid receptors CB1 and CB2 correlates with improved prognosis of patients with hepatocellular carcinoma.Cancer Genet Cytogenet. 2006; 171: 31-38
- The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen species.FASEB J. 2007; 21: 2798-2806
- Hepatic cannabinoid-1 receptors mediate diet-induced insulin resistance by increasing de novo synthesis of long-chain ceramides.Hepatology. 2014; 59: 143-153
- Antagonism of peripheral hepatic cannabinoid receptor-1 improves liver lipid metabolism in mice: evidence from cultured explants.Hepatology. 2012; 55: 790-799
- Inhibiting CB1 receptors improves lipogenesis in an in vitro non-alcoholic fatty liver disease model.Lipids Health Dis. 2014; 13: 173
- Role of adiponectin in the metabolic effects of cannabinoid type 1 receptor blockade in mice with diet-induced obesity.Am J Physiol Endocrinol Metab. 2014; 306: E457-468
- 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: 859-869
- Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats.Hepatology. 2007; 46: 122-129
- 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: 713-715
- JD-5006 and JD-5037: peripherally 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: 6173-6180
- Genome-wide expression profiling revealed peripheral effects of cannabinoid receptor 1 inverse agonists in improving insulin sensitivity and metabolic parameters.Mol Pharmacol. 2010; 78: 350-359
- Splanchnic balance of free fatty acids, endocannabinoids, and lipids in subjects with nonalcoholic fatty liver disease.Gastroenterology. 2010; 139e1961
- Serum levels of endocannabinoids are independently associated with nonalcoholic fatty liver disease.Obesity (Silver Spring). 2017; 25: 94-101
- Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men.Int J Obes (Lond). 2007; 31: 692-699
- Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors.Diabetologia. 2009; 52: 213-217
- Body mass index and risk for end-stage renal disease.Ann Intern Med. 2006; 144: 21-28
- Excess weight as a risk factor for kidney failure.Curr Opin Nephrol Hypertens. 2007; 16: 71-76
- Association between obesity and kidney disease: a systematic review and meta-analysis.Kidney Int. 2008; 73: 19-33
- Renal risk and renoprotection among ethnic groups with type 2 diabetic nephropathy: a post hoc analysis of RENAAL.Kidney Int. 2006; 69: 1675-1682
- Prevention and treatment of diabetic renal disease in type 2 diabetes: the BENEDICT study.J Am Soc Nephrol. 2006; 17: S90-97
- High-fat-diet-induced obesity causes an inflammatory and tumor-promoting microenvironment in the rat kidney.Dis Model Mech. 2012; 5: 627-635
- 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: 1217-1228
- Early events leading to renal injury in obese Zucker (fatty) rats with type II diabetes.Kidney Int. 2000; 57: 167-182
- Structural and functional changes in the kidneys of high-fat diet-induced obese mice.Am J Physiol Renal Physiol. 2009; 296: F118-126
- Low-density lipoprotein stimulates the expression of macrophage colony-stimulating factor in glomerular mesangial cells.Kidney Int. 1995; 48: 1254-1262
- Dysregulation of peripheral endocannabinoid levels in hyperglycemia and obesity: effect of high fat diets.Mol Cell Endocrinol. 2008; 286: S66-78
- Blockade of cannabinoid CB1 receptors improves renal function, metabolic profile, and increased survival of obese Zucker rats.Kidney Int. 2007; 72: 1345-1357
- Chronic administration with AM251 improves albuminuria and renal tubular structure in obese rats.J Endocrinol. 2015; 225: 113-124
- The emerging role of the endocannabinoid system in the pathogenesis and treatment of kidney diseases.J Basic Clin Physiol Pharmacol. 2016; 27: 267-276
- AMPK mediates the initiation of kidney disease induced by a high-fat diet.J Am Soc Nephrol. 2011; 22: 1846-1855
- Regulation of lipid accumulation by AMP-activated kinase [corrected] in high fat diet-induced kidney injury.Kidney Int. 2014; 85: 611-623
- Cannabinoid receptor 1 blockade ameliorates albuminuria in experimental diabetic nephropathy.Diabetes. 2010; 59: 1046-1054
- 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: 256-262
- Blockade of cannabinoid receptor 1 improves insulin resistance, lipid metabolism, and diabetic nephropathy in db/db mice.Endocrinology. 2012; 153: 1387-1396
- Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy.Proc Natl Acad Sci U S A. 2014; 111: E5420-5428
- Dual therapy targeting the endocannabinoid system prevents experimental diabetic nephropathy.Nephrol Dial Transplant. 2017; 32: 1655-1665
- Cannabinoid-1 receptor deletion in podocytes mitigates both glomerular and tubular dysfunction in a mouse model of diabetic nephropathy.Diabetes Obes Metab. 2017; https://doi.org/10.1111/dom.13150
- 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: 895-906
- AT1R-CB(1)R heteromerization reveals a new mechanism for the pathogenic properties of angiotensin II.EMBO J. 2011; 30: 2350-2363
- 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: F179-188
- Cannabinoid receptor 1 disturbance of PPARgamma2 augments hyperglycemia induction of mesangial inflammation and fibrosis in renal glomeruli.J Mol Med (Berl). 2014; 92: 779-792
- The proximal tubule in the pathophysiology of the diabetic kidney.Am J Physiol Regul Integr Comp Physiol. 2011; 300: R1009-1022
- Live imaging of GLUT2 glucose-dependent trafficking and its inhibition in polarized epithelial cysts.Open Biol. 2014; 4
- Diabetes increases facilitative glucose uptake and GLUT2 expression at the rat proximal tubule brush border membrane.J Physiol. 2003; 553: 137-145
- Experimental type II diabetes and related models of impaired glucose metabolism differentially regulate glucose transporters at the proximal tubule brush border membrane.Exp Physiol. 2016; 101: 731-742
- GLUT2 protein at the rat proximal tubule brush border membrane correlates with protein kinase C (PKC)-betal and plasma glucose concentration.Diabetologia. 2007; 50: 2209-2217
- The link between hyperglycaemia and diabetic nephropathy.Diabetologia. 1992; 35: 499-504
- Hyperglycaemia—pathophysiological aspects at the cellular level.Nephrol Dial Transplant. 1995; 10: 1109-1112
- Modulation of renal GLUT2 by the Cannabinoid-1 receptor: implications for the treatment of diabetic nephropathy.J Am Soc Nephrol. 2017; https://doi.org/10.1681/ASN.2017040371
- Themed issue on cannabinoids in biology and medicine.Br J Pharmacol. 2011; 163: 1327-1328
- Endocannabinoids and the regulation of bone metabolism.J Neuroendocrinol. 2008; 20: 69-74
- 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: 1-6
- The endovanilloid/endocannabinoid system in human osteoclasts: possible involvement in bone formation and resorption.Bone. 2009; 44: 476-484
- The type 2 cannabinoid receptor regulates bone mass and ovariectomy-induced bone loss by affecting osteoblast differentiation and bone formation.Endocrinology. 2011; 152: 2141-2149
- The cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling.FASEB J. 2008; 22: 285-294
- Peripheral cannabinoid receptor, CB2, regulates bone mass.Proc Natl Acad Sci U S A. 2006; 103: 696-701
- The skeletal endocannabinoid system: clinical and experimental insights.J Basic Clin Physiol Pharmacol. 2016; 27: 237-245
- CB2 cannabinoid receptor targets mitogenic Gi protein–cyclin D1 axis in osteoblasts.J Bone Miner Res. 2011; 26: 308-316
- CB2 cannabinoid receptor agonist enantiomers HU-433 and HU-308: an inverse relationship between binding affinity and biological potency.Proc Natl Acad Sci. 2015; 112: 8774-8779
- The cannabinoid receptor type 2 (CNR2) gene is associated with hand bone strength phenotypes in an ethnically homogeneous family sample.Hum Genet. 2009; 126: 629-636
- Association of candidate gene polymorphisms with bone mineral density in community-dwelling Japanese women and men.Int J Mol Med. 2007; 19: 791-801
- Cannabinoid receptor type 2 gene is associated with human osteoporosis.Hum Mol Genet. 2005; 14: 3389-3396
- Regulation of bone mass, osteoclast function, and ovariectomy-induced bone loss by the type 2 cannabinoid receptor.Endocrinology. 2008; 149: 5619-5626
- Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors.Nat Med. 2005; 11: 774-779
- Cannabinoid receptor type 1 protects against age-related osteoporosis by regulating osteoblast and adipocyte differentiation in marrow stromal cells.Cell Metab. 2009; 10: 139-147
- Leptin regulation of bone resorption by the sympathetic nervous system and CART.Nature. 2005; 434: 514-520
- Depression induces bone loss through stimulation of the sympathetic nervous system. Proceedings of the.103. National Academy of Sciences, 2006: 16876-16881
- Peripheral and central CB1 cannabinoid receptors control stress-induced impairment of memory consolidation.Proc Natl Acad Sci U S A. 2016; 113: 9904-9909
- Age-related regulation of bone formation by the sympathetic cannabinoid CB1 receptor.Bone. 2017; 108: 34-42
- CB1 cannabinoid receptors mediate endochondral skeletal growth attenuation by Δ9-tetrahydrocannabinol.Ann N Y Acad Sci. 2015; 1335: 110-119
- Intrauterine cannabis exposure affects fetal growth trajectories: the generation R study.J Am Acad Child Adolesc Psychiatry. 2009; 48: 1173-1181
- Effects of maternal marijuana and cocaine use on fetal growth.N Engl J Med. 1989; 320: 762-768
Article info
Publication history
Published online: January 11, 2018
Accepted:
January 4,
2018
Received in revised form:
January 3,
2018
Received:
December 1,
2017
Identification
Copyright
© 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
