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Reis MG, Ferreira AJF, Sohouli MH, Taimeirão DR, Vieira RAL, Guimarães NS. Effect of cannabis and subproducts on anthropometric measures: a systematic review and meta-analysis. Int J Obes (Lond) 2024; 48:44-54. [PMID: 37935909 DOI: 10.1038/s41366-023-01399-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 09/18/2023] [Accepted: 10/10/2023] [Indexed: 11/09/2023]
Abstract
BACKGROUND Obesity poses a significant public health challenge. Research has examined the impact of cannabis and subproducts on health but varying results have hindered a consensus. AIM This study aimed to evaluated the effects of cannabis and subproducts on body measurements. METHODS For searching randomized controlled trials evaluating cannabis and/or subproducts use and changes in anthropometric measures, a systematic search at MEDLINE, Embase, Cochrane Library and Web of Science was conducted until March 2023. The outcomes included changes in body weight, body mass index (BMI) and waist circumference (WC). Meta-analysis was realized using R software (version 4.2.1). RESULTS In general, cannabis use reduced weight by 1.87 kg (95% CI: -3.71 to -0.03) and WC (mean difference = -2.19, 95% CI: -4.44 to 0.06). When examining subgroups, longer follow-up periods were associated with a more pronounced BMI reduction (mean difference = -1.10, 95% CI: -2.23 to 0.03). Cannabinoid CB1 exhibited an increase in body fat (mean difference = 1.70, 95% CI: 0.66-2.74). CONCLUSION These findings suggest that cannabis and subproducts could be considered adjuncts in obesity treatment by helping to reduce relevant anthropometric measurements.
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Affiliation(s)
- Marcela Gomes Reis
- Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, Brazil
- Observatório de Pesquisa em Epidemiologia, Nutrição e Saúde (OPeNS), Belo Horizonte, Brazil
| | - Andrea J F Ferreira
- Observatório de Pesquisa em Epidemiologia, Nutrição e Saúde (OPeNS), Belo Horizonte, Brazil
- The Ubuntu Center on Racism, Global Movements, and Population Health Equity, Dornsife School of Public Health, Drexel University, Philadelphia, PA, USA
| | | | - Diego Ribeiro Taimeirão
- Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, Brazil
- Observatório de Pesquisa em Epidemiologia, Nutrição e Saúde (OPeNS), Belo Horizonte, Brazil
| | - Renata Adrielle Lima Vieira
- Observatório de Pesquisa em Epidemiologia, Nutrição e Saúde (OPeNS), Belo Horizonte, Brazil
- Universidade Federal de Ouro Preto, Ouro Preto, Brazil
| | - Nathalia Sernizon Guimarães
- Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, Brazil.
- Observatório de Pesquisa em Epidemiologia, Nutrição e Saúde (OPeNS), Belo Horizonte, Brazil.
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Maliszewska K, Miniewska K, Godlewski A, Gosk W, Mojsak M, Kretowski A, Ciborowski M. Changes in plasma endocannabinoids concentrations correlate with 18F-FDG PET/MR uptake in brown adipocytes in humans. Front Mol Biosci 2023; 10:1073683. [PMID: 37564131 PMCID: PMC10411954 DOI: 10.3389/fmolb.2023.1073683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 07/13/2023] [Indexed: 08/12/2023] Open
Abstract
Introduction: Recent data suggest a possible role of endocannabinoids in the regulation of brown adipose tissue (BAT) activity. Those findings indicate potential treatment options for obesity. The aim of this study was to evaluate the relationship between plasma endocannabinoids concentrations and the presence of BAT in humans. Methods: The study group consisted of 25 subjects divided into two groups: BAT positive BAT(+), (n = 17, median age = 25 years) and BAT negative BAT(-), (n = 8, median age = 28 years). BAT was estimated using 18F-FDG PET/MR after 2 h of cold exposure. The level of plasma endocannabinoids was assessed at baseline, 60 min and 120 min of cold exposure. Results: In both groups, BAT(+) and BAT(-), during the cooling, we observed a decrease of the same endocannabinoids: arachidonoylethanolamide (AEA), eicosapentaenoyl ethanolamide (EPEA) and oleoyl ethanolamide (OEA) with a much more profound decline in BAT(+) subjects. Statistically significant fall of PEA (palmitoylethanolamide) and SEA (stearoylethanolamide) concentrations after 60 min (FC = 0.7, p = 0.007 and FC = 0.8, p = 0.03, respectively) and 120 min (FC = 0.81, p = 0.004, and FC = 0.9, p = 0.01, respectively) of cooling was observed only in individuals with BAT. Conclusion: We noticed the profound decline of endocannabinoids concentrations in subjects with increased 18F-FDG PET/MR uptake in BAT. Identification of a new molecules related to BAT activity may create a new target for obesity treatment.
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Affiliation(s)
- Katarzyna Maliszewska
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Katarzyna Miniewska
- Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
| | - Adrian Godlewski
- Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
| | - Wioleta Gosk
- Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
| | - Malgorzata Mojsak
- Independent Laboratory of Molecular Imaging, Medical University of Bialystok, Bialystok, Poland
| | - Adam Kretowski
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
| | - Michal Ciborowski
- Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
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3
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Hirsch S, Hinden L, Naim MBD, Baraghithy S, Permyakova A, Azar S, Nasser T, Portnoy E, Agbaria M, Nemirovski A, Golomb G, Tam J. Hepatic targeting of the centrally active cannabinoid 1 receptor (CB 1R) blocker rimonabant via PLGA nanoparticles for treating fatty liver disease and diabetes. J Control Release 2023; 353:254-269. [PMID: 36442615 PMCID: PMC9900386 DOI: 10.1016/j.jconrel.2022.11.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 11/10/2022] [Accepted: 11/22/2022] [Indexed: 12/05/2022]
Abstract
Over-activation of the endocannabinoid/CB1R system is a hallmark feature of obesity and its related comorbidities, most notably type 2 diabetes (T2D), and non-alcoholic fatty liver disease (NAFLD). Although the use of drugs that widely block the CB1R was found to be highly effective in treating all metabolic abnormalities associated with obesity, they are no longer considered a valid therapeutic option due to their adverse neuropsychiatric side effects. Here, we describe a novel nanotechnology-based drug delivery system for repurposing the abandoned first-in-class global CB1R antagonist, rimonabant, by encapsulating it in polymeric nanoparticles (NPs) for effective hepatic targeting of CB1Rs, enabling effective treatment of NAFLD and T2D. Rimonabant-encapsulated NPs (Rimo-NPs) were mainly distributed in the liver, spleen, and kidney, and only negligible marginal levels of rimonabant were found in the brain of mice treated by iv/ip administration. In contrast to freely administered rimonabant treatment, no CNS-mediated behavioral activities were detected in animals treated with Rimo-NPs. Chronic treatment of diet-induced obese mice with Rimo-NPs resulted in reduced hepatic steatosis and liver injury as well as enhanced insulin sensitivity, which were associated with enhanced cellular uptake of the formulation into hepatocytes. Collectively, we successfully developed a method of encapsulating the centrally acting CB1R blocker in NPs with desired physicochemical properties. This novel drug delivery system allows hepatic targeting of rimonabant to restore the metabolic advantages of blocking CB1R in peripheral tissues, especially in the liver, without the negative CB1R-mediated neuropsychiatric side effects.
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Affiliation(s)
- Shira Hirsch
- Obesity and Metabolism Laboratory, POB 12065, Jerusalem 9112001, Israel
| | - Liad Hinden
- Obesity and Metabolism Laboratory, POB 12065, Jerusalem 9112001, Israel
| | - Meital Ben-David Naim
- The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
| | - Saja Baraghithy
- Obesity and Metabolism Laboratory, POB 12065, Jerusalem 9112001, Israel
| | - Anna Permyakova
- Obesity and Metabolism Laboratory, POB 12065, Jerusalem 9112001, Israel
| | - Shahar Azar
- Obesity and Metabolism Laboratory, POB 12065, Jerusalem 9112001, Israel
| | - Taher Nasser
- The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
| | - Emma Portnoy
- Department of Biochemistry, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Israel
| | - Majd Agbaria
- The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
| | - Alina Nemirovski
- The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
| | - Gershon Golomb
- The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
| | - Joseph Tam
- Obesity and Metabolism Laboratory, POB 12065, Jerusalem 9112001, Israel; The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
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Ferrulli A, Terruzzi I, Senesi P, Succi M, Cannavaro D, Luzi L. Turning the clock forward: New pharmacological and non pharmacological targets for the treatment of obesity. Nutr Metab Cardiovasc Dis 2022; 32:1320-1334. [PMID: 35354547 DOI: 10.1016/j.numecd.2022.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/21/2022] [Accepted: 02/25/2022] [Indexed: 11/26/2022]
Abstract
AIMS Obesity and its main metabolic complication, type 2 diabetes, have attained the status of a global pandemic; there is need for novel strategies aimed at treating obesity and preventing the development of diabetes. A healthy diet and exercise are basic for treatment of obesity but often not enough. Pharmacotherapy can be helpful in maintaining compliance, ameliorating obesity-related health risks, and improving quality of life. In the last two decades, the knowledge of central and peripheral mechanisms underlying homeostatic and hedonic aspects of food intake has significantly increased. Dysregulation of one or more of these components could lead to obesity. DATA SYNTHESIS In order to better understand how potential innovative treatment options can affect obesity, homeostatic and reward mechanisms that regulate energy balance has been firstly illustrated. Then, an overview of potential therapeutic targets for obesity, distinguished according to the level of regulation of feeding behavior, has been provided. Moreover, several non-drug therapies have been recently tested in obesity, such as non-invasive neurostimulation: Transcranial Magnetic Stimulation or Transcranial Direct Current Stimulation. All of them are promising for obesity treatment and are almost devoid of side effects, constituting a potential resource for the prevention of metabolic diseases. CONCLUSIONS The plethora of current anti-obesity therapies creates the unique challenge for physicians to customize the intervention, according to the specific obesity characteristics and the intervention side effect profiles; moreover, it allows multimodal approaches addressed to treat obesity and metabolic adaptation with complementary mechanisms.
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Affiliation(s)
- Anna Ferrulli
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, MI, Italy; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Ileana Terruzzi
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, MI, Italy; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Pamela Senesi
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, MI, Italy; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Massimiliano Succi
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Daniele Cannavaro
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Livio Luzi
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, MI, Italy; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.
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Meah F, Lundholm M, Emanuele N, Amjed H, Poku C, Agrawal L, Emanuele MA. The effects of cannabis and cannabinoids on the endocrine system. Rev Endocr Metab Disord 2022; 23:401-420. [PMID: 34460075 DOI: 10.1007/s11154-021-09682-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/15/2021] [Indexed: 01/24/2023]
Abstract
With the increase in cannabis use due to policy changes and areas of decriminalization, it is important to recognize the potential impact of these substances on endocrine processes. Cannabinoids have many effects by activating the endocannabinoid system. This system plays a role in the normal functioning of nearly every organ and consists of the body's natural endocannabinoids, the cannabinoid receptors, and the enzymes and processes that regulate endocannabinoids. Exogenous cannabinoids such as Δ9-tetrahydrocannabinol (THC) are known to act through cannabinoid type 1 and 2 receptors, and have been shown to mimic endocannabinoid signaling and affect receptor expression. This review summarizes the known impacts of cannabis on thyroid, adrenal, and gonadal function in addition to glucose control, lipids, and bone metabolism, including: reduced female fertility, increased risk of adverse pregnancy outcomes, reduced sperm counts and function, lower thyroid hormone levels with acute use, blunting of stress response with chronic use, increased risk of prediabetes but lower risk of diabetes, suggested improvement of high density lipoproteins and triglycerides, and modest increase in fracture risk. The known properties of endocannabinoids, animal data, population data, and the possible benefits and concerns of cannabinoid use on hormonal function are discussed. The interconnectivity of the endocrine and endocannabinoid systems suggests opportunities for future therapeutic modalities which are an area of active investigation.
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Affiliation(s)
- Farah Meah
- Endocrinology Section, Medical Service, VA Hospital, Hines, Illinois, USA
| | - Michelle Lundholm
- Department of Internal Medicine, Loyola University Medical Center, Maywood, IL, USA
| | - Nicholas Emanuele
- Endocrinology Section, Medical Service, VA Hospital, Hines, Illinois, USA
| | - Hafsa Amjed
- Department of Medicine, Division of Endocrinology, Loyola University Health Care System, Maywood, Illinois, USA
| | - Caroline Poku
- Department of Medicine, Division of Endocrinology, Loyola University Health Care System, Maywood, Illinois, USA
| | - Lily Agrawal
- Endocrinology Section, Medical Service, VA Hospital, Hines, Illinois, USA
| | - Mary Ann Emanuele
- Department of Medicine, Division of Endocrinology, Loyola University Health Care System, Maywood, Illinois, USA.
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6
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El-Azab MF, Wakiel AE, Nafea YK, Youssef ME. Role of cannabinoids and the endocannabinoid system in modulation of diabetic cardiomyopathy. World J Diabetes 2022; 13:387-407. [PMID: 35664549 PMCID: PMC9134026 DOI: 10.4239/wjd.v13.i5.387] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/18/2021] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic complications, chiefly seen in long-term situations, are persistently deleterious to a large extent, requiring multi-factorial risk reduction strategies beyond glycemic control. Diabetic cardiomyopathy is one of the most common deleterious diabetic complications, being the leading cause of mortality among diabetic patients. The mechanisms of diabetic cardiomyopathy are multi-factorial, involving increased oxidative stress, accumulation of advanced glycation end products (AGEs), activation of various pro-inflammatory and cell death signaling pathways, and changes in the composition of extracellular matrix with enhanced cardiac fibrosis. The novel lipid signaling system, the endocannabinoid system, has been implicated in the pathogenesis of diabetes and its complications through its two main receptors: Cannabinoid receptor type 1 and cannabinoid receptor type 2, alongside other components. However, the role of the endocannabinoid system in diabetic cardiomyopathy has not been fully investigated. This review aims to elucidate the possible mechanisms through which cannabinoids and the endocannabinoid system could interact with the pathogenesis and the development of diabetic cardiomyopathy. These mechanisms include oxidative/ nitrative stress, inflammation, accumulation of AGEs, cardiac remodeling, and autophagy. A better understanding of the role of cannabinoids and the endocannabinoid system in diabetic cardiomyopathy may provide novel strategies to manipulate such a serious diabetic complication.
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Affiliation(s)
- Mona F El-Azab
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Ahmed E Wakiel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Yossef K Nafea
- Program of Biochemistry, McMaster University, Hamilton L8S 4L8, Ontario, Canada
| | - Mahmoud E Youssef
- Department of Pharmacology and Biochemistry, Delta University for Science and Technology, Mansoura 35511, New Cairo, Egypt
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Lee K, Hardy DB. Metabolic Consequences of Gestational Cannabinoid Exposure. Int J Mol Sci 2021; 22:9528. [PMID: 34502436 PMCID: PMC8430813 DOI: 10.3390/ijms22179528] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 08/29/2021] [Accepted: 08/30/2021] [Indexed: 12/20/2022] Open
Abstract
Up to 20% of pregnant women ages 18-24 consume cannabis during pregnancy. Moreover, clinical studies indicate that cannabis consumption during pregnancy leads to fetal growth restriction (FGR), which is associated with an increased risk of obesity, type II diabetes (T2D), and cardiovascular disease in the offspring. This is of great concern considering that the concentration of Δ9- tetrahydrocannabinol (Δ9-THC), a major psychoactive component of cannabis, has doubled over the last decade and can readily cross the placenta and enter fetal circulation, with the potential to negatively impact fetal development via the endocannabinoid (eCB) system. Cannabis exposure in utero could also lead to FGR via placental insufficiency. In this review, we aim to examine current pre-clinical and clinical findings on the direct effects of exposure to cannabis and its constituents on fetal development as well as indirect effects, namely placental insufficiency, on postnatal metabolic diseases.
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Affiliation(s)
- Kendrick Lee
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, London, ON N6A 5C1, Canada;
- The Children’s Health Research Institute, The Lawson Health Research Institute, London, ON N6A 5C1, Canada
| | - Daniel B. Hardy
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, London, ON N6A 5C1, Canada;
- The Children’s Health Research Institute, The Lawson Health Research Institute, London, ON N6A 5C1, Canada
- Department of Obstetrics and Gynaecology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1151 Richmond Street, London, ON N6A 5C1, Canada
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8
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Ruz-Maldonado I, Liu B, Atanes P, Pingitore A, Huang GC, Choudhary P, Persaud SJ. The cannabinoid ligands SR141716A and AM251 enhance human and mouse islet function via GPR55-independent signalling. Cell Mol Life Sci 2020; 77:4709-4723. [PMID: 31925452 PMCID: PMC7599183 DOI: 10.1007/s00018-019-03433-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 12/02/2019] [Accepted: 12/18/2019] [Indexed: 12/16/2022]
Abstract
AIMS Endocannabinoids are lipid mediators involved in the regulation of glucose homeostasis. They interact with the canonical cannabinoid receptors CB1 and CB2, and it is now apparent that some cannabinoid receptor ligands are also agonists at GPR55. Thus, CB1 antagonists such as SR141716A, also known as rimonabant, and AM251 act as GPR55 agonists in some cell types. The complex pharmacological properties of cannabinoids make it difficult to fully identify the relative importance of CB1 and GPR55 in the functional effects of SR141716A, and AM251. Here, we determine whether SR141716A and AM251 regulation of mouse and human islet function is through their action as GPR55 agonists. METHODS Islets isolated from Gpr55+/+ and Gpr55-/- mice and human donors were incubated in the absence or presence of 10 µM SR141716A or AM251, concentrations that are known to activate GPR55. Insulin secretion, cAMP, IP1, apoptosis and β-cell proliferation were quantified by standard techniques. RESULTS Our results provide the first evidence that SR141716A and AM251 are not GPR55 agonists in islets, as their effects are maintained in islets isolated from Gpr55-/- mice. Their signalling through Gq-coupled cascades to induce insulin secretion and human β-cell proliferation, and protect against apoptosis in vitro, indicate that they have direct beneficial effects on islet function. CONCLUSION These observations may be useful in directing development of peripherally restricted novel therapeutics that are structurally related to SR141716A and AM251, and which potentiate glucose-induced insulin secretion and stimulate β-cell proliferation.
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Affiliation(s)
- Inmaculada Ruz-Maldonado
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London, SE1 1UL, UK.
| | - Bo Liu
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London, SE1 1UL, UK
| | - Patricio Atanes
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London, SE1 1UL, UK
| | - Attilio Pingitore
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London, SE1 1UL, UK
| | - Guo Cai Huang
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London, SE1 1UL, UK
| | - Pratik Choudhary
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London, SE1 1UL, UK
| | - Shanta J Persaud
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London, SE1 1UL, UK.
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Druggable Targets in Endocannabinoid Signaling. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1274:177-201. [PMID: 32894511 DOI: 10.1007/978-3-030-50621-6_8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cannabis and cannabinoid-based extracts have long been utilized for their perceived therapeutic value, and support for the legalization of cannabis for medicinal purposes continues to increase worldwide. Since the discovery of Δ9-tetrahydrocannabinol (THC) as the primary psychoactive component of cannabis over 50 years ago, substantial effort has been directed toward detection of endogenous mediators of cannabinoid activity. The discovery of anandamide and 2-arachidonoylglycerol as two endogenous lipid mediators of cannabinoid-like effects (endocannabinoids) has inspired exponential growth in our understanding of this essential pathway, as well as the pathological conditions that result from dysregulated endocannabinoid signaling. This review examines current knowledge of the endocannabinoid system including metabolic enzymes involved in biosynthesis and degradation and their receptors, and evaluates potential druggable targets for therapeutic intervention.
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10
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Murphy T, Le Foll B. Targeting the Endocannabinoid CB1 Receptor to Treat Body Weight Disorders: A Preclinical and Clinical Review of the Therapeutic Potential of Past and Present CB1 Drugs. Biomolecules 2020; 10:biom10060855. [PMID: 32512776 PMCID: PMC7356944 DOI: 10.3390/biom10060855] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/29/2020] [Accepted: 06/01/2020] [Indexed: 12/12/2022] Open
Abstract
Obesity rates are increasing worldwide and there is a need for novel therapeutic treatment options. The endocannabinoid system has been linked to homeostatic processes, including metabolism, food intake, and the regulation of body weight. Rimonabant, an inverse agonist for the cannabinoid CB1 receptor, was effective at producing weight loss in obese subjects. However, due to adverse psychiatric side effects, rimonabant was removed from the market. More recently, we reported an inverse relationship between cannabis use and BMI, which has now been duplicated by several groups. As those results may appear contradictory, we review here preclinical and clinical studies that have studied the impact on body weight of various cannabinoid CB1 drugs. Notably, we will review the impact of CB1 inverse agonists, agonists, partial agonists, and neutral antagonists. Those findings clearly point out the cannabinoid CB1 as a potential effective target for the treatment of obesity. Recent preclinical studies suggest that ligands targeting the CB1 may retain the therapeutic potential of rimonabant without the negative side effect profile. Such approaches should be tested in clinical trials for validation.
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Affiliation(s)
- Thomas Murphy
- Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, University of Toronto, 33 Russell Street, Toronto, ON M5S 2S1, Canada;
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Bernard Le Foll
- Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, University of Toronto, 33 Russell Street, Toronto, ON M5S 2S1, Canada;
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Acute Care Program, Centre for Addiction and Mental Health, Toronto, ON M6J 1H4, Canada
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5S 2S1, Canada
- Department of Family and Community Medicine, University of Toronto, Toronto, ON M5G 1V7, Canada
- Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON M5T 1R8, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada
- Correspondence: ; Tel.: +1-416-535-8501
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11
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Tsilingiris D, Liatis S, Dalamaga M, Kokkinos A. The Fight Against Obesity Escalates: New Drugs on the Horizon and Metabolic Implications. Curr Obes Rep 2020; 9:136-149. [PMID: 32388792 DOI: 10.1007/s13679-020-00378-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW There is currently a steep rise in the global prevalence of obesity. Pharmaceutical therapy is a valuable component of conservative obesity therapy. Herein, medications currently in the phase of preclinical or clinical testing are reviewed, along with an overview of the mechanisms that regulate energy intake and expenditure. In addition, the current and potential future directions of obesity drug therapy are discussed. RECENT FINDINGS Although the current arsenal of obesity pharmacotherapy is limited, a considerable number of agents that exert their actions through a variety of pharmacodynamic targets and mechanisms are in the pipeline. This expansion shapes a potential near future of obesity conservative management, characterized by tailored combined therapeutic regimens, targeting not only weight loss but also improved overall health outcomes. The progress regarding the elucidation of the mechanisms which regulate the bodily energy equilibrium has led to medications which mimic hormonal adaptations that follow bariatric surgery, in the quest for a "Medical bypass." These, combined with agents which could increase energy expenditure, point to a brilliant future in the conservative treatment of obesity.
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Affiliation(s)
- Dimitrios Tsilingiris
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 17 Ag. Thoma Street, 11527, Athens, Greece
| | - Stavros Liatis
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 17 Ag. Thoma Street, 11527, Athens, Greece
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Alexander Kokkinos
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 17 Ag. Thoma Street, 11527, Athens, Greece.
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Quarta C, Cota D. Anti-obesity therapy with peripheral CB1 blockers: from promise to safe(?) practice. Int J Obes (Lond) 2020; 44:2179-2193. [PMID: 32317751 DOI: 10.1038/s41366-020-0577-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/03/2020] [Accepted: 03/27/2020] [Indexed: 12/25/2022]
Abstract
Pharmacological blockers of the cannabinoid receptor type-1 (CB1) have been considered for a long time as the holy grail of obesity pharmacotherapy. These agents were hastily released in the clinical setting, due to their clear-cut therapeutic efficacy. However, the first generation of these drugs, which were able to target both the brain and peripheral tissues, had serious neuropsychiatric effects, leading authorities to ban their clinical use. New peripherally restricted CB1 blockers, characterized by low brain penetrance, have been developed over the past 10 years. In preclinical studies, these molecules seem to overcome the neuropsychiatric negative effects previously observed with brain-penetrant CB1 inhibitors, while retaining or even outperforming their efficacy. The mechanisms of action of these peripherally restricted compounds are only beginning to emerge, and a balanced discussion of the risk/benefits ratio associated to their possible clinical use is urgently needed, in order to avoid repeating past mistakes. Here, we will critically discuss the advantages and the possible hidden threats associated with the use of peripheral CB1 blockers for the pharmacotherapy of obesity and its associated metabolic complications. We will address whether this novel pharmacological approach might 'compete' with current pharmacotherapies for obesity and diabetes, while also conceptualizing future CB1-based pharmacological trends that may significantly lower the risk/benefits ratio associated with the use of these drugs.
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Affiliation(s)
- Carmelo Quarta
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000, Bordeaux, France. .,University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000, Bordeaux, France.
| | - Daniela Cota
- INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000, Bordeaux, France. .,University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, F-33000, Bordeaux, France.
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Bielawiec P, Harasim-Symbor E, Chabowski A. Phytocannabinoids: Useful Drugs for the Treatment of Obesity? Special Focus on Cannabidiol. Front Endocrinol (Lausanne) 2020; 11:114. [PMID: 32194509 PMCID: PMC7064444 DOI: 10.3389/fendo.2020.00114] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 02/21/2020] [Indexed: 12/13/2022] Open
Abstract
Currently, an increasing number of diseases related to insulin resistance and obesity is an alarming problem worldwide. It is well-known that the above states can lead to the development of type 2 diabetes, hypertension, and cardiovascular diseases. An excessive amount of triacylglycerols (TAGs) in a diet also evokes adipocyte hyperplasia and subsequent accumulation of lipids in peripheral organs (liver, cardiac muscle). Therefore, new therapeutic methods are constantly sought for the prevention, treatment and alleviation of symptoms of the above mentioned diseases. Currently, much attention is paid to Cannabis derivatives-phytocannabinoids, which interact with the endocannabinoid system (ECS) constituents. Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the most abundant compounds of Cannabis plants and their therapeutic application has been suggested. CBD is considered as a potential therapeutic agent due to its anti-inflammatory, anti-oxidant, anti-tumor, neuroprotective, and potential anti-obesity properties. Therefore, in this review, we especially highlight pharmacological properties of CBD as well as its impact on obesity in different tissues.
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El-Atawneh S, Hirsch S, Hadar R, Tam J, Goldblum A. Prediction and Experimental Confirmation of Novel Peripheral Cannabinoid-1 Receptor Antagonists. J Chem Inf Model 2019; 59:3996-4006. [PMID: 31433190 DOI: 10.1021/acs.jcim.9b00577] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Small molecules targeting peripheral CB1 receptors have therapeutic potential in a variety of disorders including obesity-related, hormonal, and metabolic abnormalities, while avoiding the psychoactive effects in the central nervous system. We applied our in-house algorithm, iterative stochastic elimination, to produce a ligand-based model that distinguishes between CB1R antagonists and random molecules by physicochemical properties only. We screened ∼2 million commercially available molecules and found that about 500 of them are potential candidates to antagonize the CB1R. We applied a few criteria for peripheral activity and narrowed that set down to 30 molecules, out of which 15 could be purchased. Ten out of those 15 showed good affinity to the CB1R and two of them with nanomolar affinities (Ki of ∼400 nM). The eight molecules with top affinities were tested for activity: two compounds were pure antagonists, and five others were inverse agonists. These molecules are now being examined in vivo for their peripheral versus central distribution and subsequently will be tested for their effects on obesity in small animals.
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Cannabis: From a Plant That Modulates Feeding Behaviors toward Developing Selective Inhibitors of the Peripheral Endocannabinoid System for the Treatment of Obesity and Metabolic Syndrome. Toxins (Basel) 2019; 11:toxins11050275. [PMID: 31096702 PMCID: PMC6563239 DOI: 10.3390/toxins11050275] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 05/10/2019] [Accepted: 05/12/2019] [Indexed: 12/15/2022] Open
Abstract
In this review, we discuss the role of the endocannabinoid (eCB) system in regulating energy and metabolic homeostasis. Endocannabinoids, via activating the cannabinoid type-1 receptor (CB1R), are commonly known as mediators of the thrifty phenotype hypothesis due to their activity in the central nervous system, which in turn regulates food intake and underlies the development of metabolic syndrome. Indeed, these findings led to the clinical testing of globally acting CB1R blockers for obesity and various metabolic complications. However, their therapeutic potential was halted due to centrally mediated adverse effects. Recent observations that highlighted the key role of the peripheral eCB system in metabolic regulation led to the preclinical development of various novel compounds that block CB1R only in peripheral organs with very limited brain penetration and without causing behavioral side effects. These unique molecules, which effectively ameliorate obesity, type II diabetes, fatty liver, insulin resistance, and chronic kidney disease in several animal models, are likely to be further developed in the clinic and may revive the therapeutic potential of blocking CB1R once again.
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Pepper I, Vinik A, Lattanzio F, McPheat W, Dobrian A. Countering the Modern Metabolic Disease Rampage With Ancestral Endocannabinoid System Alignment. Front Endocrinol (Lausanne) 2019; 10:311. [PMID: 31156558 PMCID: PMC6533883 DOI: 10.3389/fendo.2019.00311] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 04/30/2019] [Indexed: 12/18/2022] Open
Abstract
When primitive vertebrates evolved from ancestral members of the animal kingdom and acquired complex locomotive and neurological toolsets, a constant supply of energy became necessary for their continued survival. To help fulfill this need, the endocannabinoid (eCB) system transformed drastically with the addition of the cannabinoid-1 receptor (CB1R) to its gene repertoire. This established an eCB/CB1R signaling mechanism responsible for governing the whole organism's energy balance, with its activation triggering a shift toward energy intake and storage in the brain and the peripheral organs (i.e., liver and adipose). Although this function was of primal importance for humans during their pre-historic existence as hunter-gatherers, it became expendable following the successive lifestyle shifts of the Agricultural and Industrial Revolutions. Modernization of the world has further increased food availability and decreased energy expenditure, thus shifting the eCB/CB1R system into a state of hyperactive deregulated signaling that contributes to the 21st century metabolic disease pandemic. Studies from the literature supporting this perspective come from a variety of disciplines, including biochemistry, human medicine, evolutionary/comparative biology, anthropology, and developmental biology. Consideration of both biological and cultural evolution justifies the design of improved pharmacological treatments for obesity and Type 2 diabetes (T2D) that focus on peripheral CB1R antagonism. Blockade of peripheral CB1Rs, which universally promote energy conservation across the vertebrate lineage, represents an evolutionary medicine strategy for clinical management of present-day metabolic disorders.
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Affiliation(s)
- Ian Pepper
- Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, United States
- *Correspondence: Ian Pepper
| | - Aaron Vinik
- Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, VA, United States
| | - Frank Lattanzio
- Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, United States
| | - William McPheat
- Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, United States
| | - Anca Dobrian
- Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, United States
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Tam J, Hinden L, Drori A, Udi S, Azar S, Baraghithy S. The therapeutic potential of targeting the peripheral endocannabinoid/CB 1 receptor system. Eur J Intern Med 2018; 49:23-29. [PMID: 29336868 DOI: 10.1016/j.ejim.2018.01.009] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 01/03/2018] [Accepted: 01/04/2018] [Indexed: 02/07/2023]
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.
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Affiliation(s)
- Joseph Tam
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel.
| | - Liad Hinden
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Adi Drori
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Shiran Udi
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Shahar Azar
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Saja Baraghithy
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
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Hernández-Vázquez E, Ocampo-Montalban H, Cerón-Romero L, Cruz M, Gómez-Zamudio J, Hiriart-Valencia G, Villalobos-Molina R, Flores-Flores A, Estrada-Soto S. Antidiabetic, antidyslipidemic and toxicity profile of ENV-2: A potent pyrazole derivative against diabetes and related diseases. Eur J Pharmacol 2017; 803:159-166. [DOI: 10.1016/j.ejphar.2017.03.036] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2016] [Revised: 03/13/2017] [Accepted: 03/16/2017] [Indexed: 01/11/2023]
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Jourdan T, Godlewski G, Kunos G. Endocannabinoid regulation of β-cell functions: implications for glycaemic control and diabetes. Diabetes Obes Metab 2016; 18:549-57. [PMID: 26880114 PMCID: PMC5045244 DOI: 10.1111/dom.12646] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 02/08/2016] [Accepted: 02/11/2016] [Indexed: 01/11/2023]
Abstract
Visceral obesity is a major risk factor for the development of insulin resistance which can progress to overt type 2 diabetes (T2D) with loss of β-cell function and, ultimately, loss of β-cells. Insulin secretion by β-cells of the pancreatic islets is tightly coupled to blood glucose concentration and modulated by a large number of blood-borne or locally released mediators, including endocannabinoids. Obesity and its complications, including T2D, are associated with increased activity of the endocannabinoid/CB1 receptor (CB1 R) system, as indicated by the therapeutic effects of CB1 R antagonists. Similar beneficial effects of CB1 R antagonists with limited brain penetrance indicate the important role of CB1 R in peripheral tissues, including the endocrine pancreas. Pancreatic β-cells express all of the components of the endocannabinoid system, and endocannabinoids modulate their function via both autocrine and paracrine mechanisms, which influence basal and glucose-induced insulin secretion and also affect β-cell proliferation and survival. The present brief review will survey available information on the modulation of these processes by endocannabinoids and their receptors, with an attempt to assess the contribution of such effects to glycaemic control in T2D and insulin resistance.
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Affiliation(s)
- T Jourdan
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - G Godlewski
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - G Kunos
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
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20
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Hernández-Vázquez E, Salgado-Barrera S, Ramírez-Espinosa JJ, Estrada-Soto S, Hernández-Luis F. Synthesis and molecular docking of N′-arylidene-5-(4-chlorophenyl)-1-(3,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbohydrazides as novel hypoglycemic and antioxidant dual agents. Bioorg Med Chem 2016; 24:2298-306. [DOI: 10.1016/j.bmc.2016.04.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 03/23/2016] [Accepted: 04/01/2016] [Indexed: 01/05/2023]
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21
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Lu D, Dopart R, Kendall DA. Controlled downregulation of the cannabinoid CB1 receptor provides a promising approach for the treatment of obesity and obesity-derived type 2 diabetes. Cell Stress Chaperones 2016; 21:1-7. [PMID: 26498013 PMCID: PMC4679742 DOI: 10.1007/s12192-015-0653-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 10/15/2015] [Accepted: 10/16/2015] [Indexed: 12/20/2022] Open
Abstract
Increased activity of the endocannabinoid system has emerged as a pathogenic factor in visceral obesity, which is a risk factor for type 2 diabetes mellitus (T2DM). The endocannabinoid system is composed of at least two Gprotein-coupled receptors (GPCRs), the cannabinoid receptor type 1 (CB1), and the cannabinoid receptor type 2 (CB2). Downregulation of CB1 activity in rodents and humans has proven efficacious to reduce food intake, abdominal adiposity, fasting glucose levels, and cardiometabolic risk factors. Unfortunately, downregulation of CB1 activity by universally active CB1 inverse agonists has been found to elicit psychiatric side effects, which led to the termination of using globally active CB1 inverse agonists to treat diet-induced obesity. Interestingly, preclinical studies have shown that downregulation of CB1 activity by CB1 neutral antagonists or peripherally restricted CB1 inverse agonists provided similar anorectic effects and metabolic benefits without psychiatric side effects seen in globally active CB1 inverse agonists. Furthermore, downregulation of CB1 activity may ease endoplasmic reticulum and mitochondrial stress which are contributors to obesity-induced insulin resistance and type 2 diabetes. This suggests new approaches for cannabinoid-based therapy in the management of obesity and obesity-related metabolic disorders including type 2 diabetes.
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Affiliation(s)
- Dai Lu
- Rangel College of Pharmacy, Health Science Center, Texas A&M University, Kingsville, TX, 78363, USA
| | - Rachel Dopart
- Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Road, Storrs, CT, 06269-3092, USA
| | - Debra A Kendall
- Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Road, Storrs, CT, 06269-3092, USA.
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Powell DR, Gay JP, Wilganowski N, Doree D, Savelieva KV, Lanthorn TH, Read R, Vogel P, Hansen GM, Brommage R, Ding ZM, Desai U, Zambrowicz B. Diacylglycerol Lipase α Knockout Mice Demonstrate Metabolic and Behavioral Phenotypes Similar to Those of Cannabinoid Receptor 1 Knockout Mice. Front Endocrinol (Lausanne) 2015; 6:86. [PMID: 26082754 PMCID: PMC4451644 DOI: 10.3389/fendo.2015.00086] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 05/12/2015] [Indexed: 12/16/2022] Open
Abstract
After creating >4,650 knockouts (KOs) of independent mouse genes, we screened them by high-throughput phenotyping and found that cannabinoid receptor 1 (Cnr1) KO mice had the same lean phenotype published by others. We asked if our KOs of DAG lipase α or β (Dagla or Daglb), which catalyze biosynthesis of the endocannabinoid (EC) 2-arachidonoylglycerol (2-AG), or Napepld, which catalyzes biosynthesis of the EC anandamide, shared the lean phenotype of Cnr1 KO mice. We found that Dagla KO mice, but not Daglb or Napepld KO mice, were among the leanest of 3651 chow-fed KO lines screened. In confirmatory studies, chow- or high fat diet-fed Dagla and Cnr1 KO mice were leaner than wild-type (WT) littermates; when data from multiple cohorts of adult mice were combined, body fat was 47 and 45% lower in Dagla and Cnr1 KO mice, respectively, relative to WT values. By contrast, neither Daglb nor Napepld KO mice were lean. Weanling Dagla KO mice ate less than WT mice and had body weight (BW) similar to pair-fed WT mice, and adult Dagla KO mice had normal activity and VO2 levels, similar to Cnr1 KO mice. Our Dagla and Cnr1 KO mice also had low fasting insulin, triglyceride, and total cholesterol levels, and after glucose challenge had normal glucose but very low insulin levels. Dagla and Cnr1 KO mice also showed similar responses to a battery of behavioral tests. These data suggest: (1) the lean phenotype of young Dagla and Cnr1 KO mice is mainly due to hypophagia; (2) in pathways where ECs signal through Cnr1 to regulate food intake and other metabolic and behavioral phenotypes observed in Cnr1 KO mice, Dagla alone provides the 2-AG that serves as the EC signal; and (3) small molecule Dagla inhibitors with a pharmacokinetic profile similar to that of Cnr1 inverse agonists are likely to mirror the ability of these Cnr1 inverse agonists to lower BW and improve glycemic control in obese patients with type 2 diabetes, but may also induce undesirable neuropsychiatric side-effects.
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Affiliation(s)
- David R. Powell
- Lexicon Pharmaceuticals, Inc., The Woodlands, TX, USA
- *Correspondence: David R. Powell, Lexicon Pharmaceuticals, Inc., 8800 Technology Forest Place, The Woodlands, TX 77381, USA,
| | - Jason P. Gay
- Lexicon Pharmaceuticals, Inc., The Woodlands, TX, USA
| | | | - Deon Doree
- Lexicon Pharmaceuticals, Inc., The Woodlands, TX, USA
| | | | | | - Robert Read
- Lexicon Pharmaceuticals, Inc., The Woodlands, TX, USA
| | - Peter Vogel
- Lexicon Pharmaceuticals, Inc., The Woodlands, TX, USA
| | | | | | - Zhi-Ming Ding
- Lexicon Pharmaceuticals, Inc., The Woodlands, TX, USA
| | - Urvi Desai
- Lexicon Pharmaceuticals, Inc., The Woodlands, TX, USA
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Shahidi M, Tay ESE, Read SA, Ramezani-Moghadam M, Chayama K, George J, Douglas MW. Endocannabinoid CB1 antagonists inhibit hepatitis C virus production, providing a novel class of antiviral host-targeting agents. J Gen Virol 2014; 95:2468-2479. [PMID: 25053565 DOI: 10.1099/vir.0.067231-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Direct-acting antivirals have significantly improved treatment outcomes in chronic hepatitis C (CHC), but side effects, drug resistance and cost mean that better treatments are still needed. Lipid metabolism is closely linked with hepatitis C virus (HCV) replication, and endocannabinoids are major regulators of lipid homeostasis. The cannabinoid 1 (CB1) receptor mediates these effects in the liver. We have previously shown upregulation of CB1 receptors in the livers of patients with CHC, and in a HCV cell-culture model. Here, we investigated whether CB1 blockade inhibited HCV replication. The antiviral effect of a CB1 antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), was examined in HCV strain JFH1 cell-culture and subgenomic replicon models. The effects on the expression of genes involved in lipid metabolism were also measured. CB1 short hairpin RNA (shRNA) was used to confirm that the effects were specific for the cannabinoid receptor. Treatment with AM251 strongly inhibited HCV RNA (~70 %), viral protein (~80 %), the production of new virus particles (~70 %) and virus infectivity (~90 %). As expected, AM251 reduced the expression of pro-lipogenic genes (SREBP-1c, FASN, SCD1 and ACC1) and stimulated genes promoting lipid oxidation (CPT1 and PPARα). This effect was mediated by AMP-activated protein kinase (AMPK). Stable CB1 knockdown of cells infected with HCV showed reduced levels of HCV RNA compared with controls. Thus, reduced CB1 signalling inhibits HCV replication using either pharmacological inhibitors or CB1 shRNA. This may be due, at least in part, to reduced lipogenesis, mediated by AMPK activation. We suggest that CB1 antagonists may represent an entirely new class of drug with activity against HCV.
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Affiliation(s)
- Mahsa Shahidi
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, Australia
| | - Enoch S E Tay
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, Australia
| | - Scott A Read
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, Australia
| | - Mehdi Ramezani-Moghadam
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, Australia
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima-shi, Japan
| | - Jacob George
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, Australia
| | - Mark W Douglas
- Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Sydney, Australia.,Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, Australia
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24
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Rizvi AA, Nikolic D, Sallam HS, Montalto G, Rizzo M, Abate N. Adipokines and Lipoproteins: Modulation by Antihyperglycemic and Hypolipidemic Agents. Metab Syndr Relat Disord 2014; 12:1-10. [DOI: 10.1089/met.2013.0090] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Affiliation(s)
- Ali A. Rizvi
- Division of Endocrinology, Diabetes and Metabolism, University of South Carolina School of Medicine, Columbia, South Carolina
| | - Dragana Nikolic
- Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Hanaa S. Sallam
- Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
- Department of Internal Medicine, Division of Endocrinology, University of Texas Medical Branch, Galveston, Texas
| | - Giuseppe Montalto
- Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Manfredi Rizzo
- Division of Endocrinology, Diabetes and Metabolism, University of South Carolina School of Medicine, Columbia, South Carolina
- Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
- Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
| | - Nicola Abate
- Department of Internal Medicine, Division of Endocrinology, University of Texas Medical Branch, Galveston, Texas
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25
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Pacher P, Kunos G. Modulating the endocannabinoid system in human health and disease--successes and failures. FEBS J 2013; 280:1918-43. [PMID: 23551849 PMCID: PMC3684164 DOI: 10.1111/febs.12260] [Citation(s) in RCA: 281] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Revised: 03/11/2013] [Accepted: 03/19/2013] [Indexed: 12/20/2022]
Abstract
The discovery of the endocannabinoid system, comprising the G-protein coupled cannabinoid 1 and 2 receptors (CB1/2), their endogenous lipid ligands or endocannabinoids, and synthetic and metabolizing enzymes, has triggered an avalanche of experimental studies implicating the endocannabinoid system in a growing number of physiological/pathological functions. These studies have also suggested that modulating the activity of the endocannabinoid system holds therapeutic promise for a broad range of diseases, including neurodegenerative, cardiovascular and inflammatory disorders; obesity/metabolic syndrome; cachexia; chemotherapy-induced nausea and vomiting; and tissue injury and pain, amongst others. However, clinical trials with globally acting CB1 antagonists in obesity/metabolic syndrome, and other studies with peripherally-restricted CB1/2 agonists and inhibitors of the endocannabinoid metabolizing enzyme in pain, have introduced unexpected complexities, suggesting that a better understanding of the pathophysiological role of the endocannabinoid system is required to devise clinically successful treatment strategies.
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Affiliation(s)
- Pál Pacher
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9413, USA.
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Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver morbidity and mortality with no proven effective therapy as of yet. Its prevalence is increasing globally in parallel with obesity and metabolic syndrome pandemic. The endocannabinoid (EC) system has been implicated in the pathogenesis of several diseases, including fatty liver diseases. This system refers to the cannabinoid receptors type 1 (CB1) and type 2 (CB2), with both their endogenous ligands and machinery dedicated to EC synthesis and degradation. There is accumulating evidence on the role CB1 as a key mediator of insulin resistance and liver lipogenesis in both animals and humans. On the other hand, CB2 receptors have been shown to promote inflammation with anti-fibrogenic properties. The pharmacological modulation of the EC system activity for the treatment of metabolic syndrome and NAFLD are promising yet premature. The initial limited success due to deleterious central nervous system side-effects are likely to be bypassed with the use of peripherally restricted drugs.
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Affiliation(s)
- Khalid A. Alswat
- Department of Medicine, Liver Disease Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia,Address for correspondence: Dr. Khalid A. Alswat, Department of Medicine, College of Medicine, Liver Disease Research Center, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia. E-mail:
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27
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Abstract
A safe and effective antiobesity drug is needed to combat the global obesity epidemic. The discovery of cannabinoids from medicinal herbs has revealed the endocannabinoid system (ECS) in animals and humans, which regulates various physiological activities such as feeding, thermogenesis, and body weight (BW). Although cannabinoid receptors 1 (CB1) antagonists have shown antiobesity efficacies in animal models and in the clinic, they failed to establish as a treatment due to their psychological side effects. Recent studies indicate that CB1 in various peripheral tissues may mediate some of the therapeutic effects of CB1 antagonists, such as improved lipid and glucose homeostasis. It rationalizes the development of compounds with limited brain penetration, for minimizing the side effects while retaining the therapeutic efficacies. A survey of the literature has revealed some controversies about how the ECS affects obesity. This review summarizes the research progresses and discusses some future perspectives.
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Affiliation(s)
- Guoxun Chen
- Department of Nutrition, University of Tennessee at Knoxville, Knoxville, Tennessee, USA.
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Nam DH, Lee MH, Kim JE, Song HK, Kang YS, Lee JE, Kim HW, Cha JJ, Hyun YY, Kim SH, Han SY, Han KH, Han JY, Cha DR. Blockade of cannabinoid receptor 1 improves insulin resistance, lipid metabolism, and diabetic nephropathy in db/db mice. Endocrinology 2012; 153:1387-96. [PMID: 22234468 DOI: 10.1210/en.2011-1423] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The endocannabinoid system is important in the pathogenesis of obesity-related metabolic disorders. However, the effect of inhibiting the endocannabinoid system in type 2 diabetic nephropathy is unclear. Therefore, we examined the effect of the cannabinoid (CB)1 receptor antagonist, SR141716, on insulin resistance and diabetic nephropathy in db/db mice. Six-week-old db/db mice were treated with the CB1-specific antagonist SR141716 (10 mg/kg · d) for 3 months. Treatment with SR141716 significantly improved insulin resistance and lipid abnormalities. Concomitantly, CB1 antagonism improved cardiac functional and morphological abnormality, hepatic steatosis, and phenotypic changes of adipocytes into small differentiated forms, associated with increased adiponectin expression and decreased lipid hydroperoxide levels. CB1 receptor was overexpressed in diabetic kidneys, especially in podocytes. Treatment with the SR141716 markedly decreased urinary albumin excretion and mesangial expansion and suppressed profibrotic and proinflammatory cytokine synthesis. Furthermore, SR141716 improved renal lipid metabolism and decreased urinary 8-isoprostane levels, renal lipid hydroperoxide content, and renal lipid content. In cultured podocytes, high-glucose stimulation increased CB1 receptor expression, and SR141716 treatment abolished high-glucose-induced up-regulation of collagen and plasminogen activator inhibitor-1 synthesis. Additionally, knockdown of CB1 receptor expression by stealth small interfering RNA abolished high-glucose-induced sterol-regulatory element-binding protein-1 expression in podocytes. These findings suggest that CB1 blockade improves insulin resistance and protect against renal injury through both metabolic and antifibrotic effects in type 2 diabetic nephropathy. Targeting CB1 blockade could therefore provide a new therapeutic target to prevent type 2 diabetic nephropathy.
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Affiliation(s)
- D H Nam
- Department of Internal Medicine, Korea University, Ansan City, Kyungki-Do, 425-020, Korea
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Horváth B, Mukhopadhyay P, Haskó G, Pacher P. The endocannabinoid system and plant-derived cannabinoids in diabetes and diabetic complications. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 180:432-42. [PMID: 22155112 PMCID: PMC3349875 DOI: 10.1016/j.ajpath.2011.11.003] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2011] [Revised: 10/23/2011] [Accepted: 11/02/2011] [Indexed: 02/07/2023]
Abstract
Oxidative stress and inflammation play critical roles in the development of diabetes and its complications. Recent studies provided compelling evidence that the newly discovered lipid signaling system (ie, the endocannabinoid system) may significantly influence reactive oxygen species production, inflammation, and subsequent tissue injury, in addition to its well-known metabolic effects and functions. The modulation of the activity of this system holds tremendous therapeutic potential in a wide range of diseases, ranging from cancer, pain, neurodegenerative, and cardiovascular diseases to obesity and metabolic syndrome, diabetes, and diabetic complications. This review focuses on the role of the endocannabinoid system in primary diabetes and its effects on various diabetic complications, such as diabetic cardiovascular dysfunction, nephropathy, retinopathy, and neuropathy, particularly highlighting the mechanisms beyond the metabolic consequences of the activation of the endocannabinoid system. The therapeutic potential of targeting the endocannabinoid system and certain plant-derived cannabinoids, such as cannabidiol and Δ9-tetrahydrocannabivarin, which are devoid of psychotropic effects and possess potent anti-inflammatory and/or antioxidant properties, in diabetes and diabetic complications is also discussed.
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Affiliation(s)
- Béla Horváth
- Section on Oxidative Stress and Tissue Injury, Laboratory of Physiological Studies, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
- Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary
| | - Partha Mukhopadhyay
- Section on Oxidative Stress and Tissue Injury, Laboratory of Physiological Studies, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - György Haskó
- Department of Surgery, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey
| | - Pál Pacher
- Section on Oxidative Stress and Tissue Injury, Laboratory of Physiological Studies, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
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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 Gα i/o inhibition. Mol Pharmacol 2011; 80:859-69. [PMID: 21803969 DOI: 10.1124/mol.111.072769] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Liver X receptor-α (LXRα) and its target sterol regulatory element-binding protein-1c (SREBP-1c) play key roles in hepatic lipogenesis. Rimonabant, an inverse agonist of cannabinoid receptor type 1 (CB1), has been studied as an antiobesity drug. In view of the link between CB1 and energy metabolism, this study investigated the effect of rimonabant on LXRα-mediated lipogenesis in hepatocytes and the underlying basis. Rimonabant treatment inhibited CYP7A1-LXRα response element gene transactivation and an increase in LXRα mRNA level by the LXRα agonist N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317) in HepG2 cells. Rimonabant consistently attenuated the activation of SREBP-1c and its target gene induction. The reversal by CB1 agonists on rimonabant's repression of SREBP-1c supported the role of CB1 in this effect. Rimonabant inhibited the activation of SREBP-1c presumably via Gα(i/o) inhibition, as did pertussis toxin. Adenylyl cyclase activator forskolin or 8-bromo-cAMP treatment mimicked the action of rimonabant, suggesting that Gα(i/o) inhibition causes repression of SREBP-1c by increasing the cAMP level. Knockdown or chemical inhibition of protein kinase A (PKA) prevented the inhibition of LXRα by rimonabant, supporting the fact that an increase in cAMP content and PKA activation, which catalyzes LXRα inhibitory phosphorylation, might be responsible for the antilipogenic effect. In addition, rimonabant activated liver kinase B1 (LKB1), resulting in the activation of AMP-activated protein kinase responsible for LXRα repression. Moreover, PKA inhibition prevented the activation of LKB1, supporting the fact that PKA regulates LKB1. In conclusion, rimonabant has an antilipogenic effect in hepatocytes by inhibiting LXRα-dependent SREBP-1c induction, as mediated by an increase in PKA activity and PKA-mediated LKB1 activation downstream of CB1-coupled Gα(i/o) inhibition.
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Affiliation(s)
- Hong Min Wu
- Innovative Drug Research Center for Metabolic and Inflammatory Diseases, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
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Janero DR, Lindsley L, Vemuri VK, Makriyannis A. Cannabinoid 1 G protein-coupled receptor (periphero-)neutral antagonists: emerging therapeutics for treating obesity-driven metabolic disease and reducing cardiovascular risk. Expert Opin Drug Discov 2011; 6:995-1025. [DOI: 10.1517/17460441.2011.608063] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Kunos G, Tam J. The case for peripheral CB₁ receptor blockade in the treatment of visceral obesity and its cardiometabolic complications. Br J Pharmacol 2011; 163:1423-31. [PMID: 21434882 PMCID: PMC3165952 DOI: 10.1111/j.1476-5381.2011.01352.x] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2010] [Revised: 02/21/2011] [Accepted: 02/28/2011] [Indexed: 12/22/2022] Open
Abstract
In this review, we consider the role of endocannabinoids and cannabinoid-1 (CB(1)) cannabinoid receptors in metabolic regulation and as mediators of the thrifty phenotype that underlies the metabolic syndrome. We survey the actions of endocannabinoids on food intake and body weight, as well as on the metabolic complications of visceral obesity, including fatty liver, insulin resistance and dyslipidemias. Special emphasis is placed on weighing the relative importance of CB(1) receptors located in peripheral tissues versus the central nervous system in mediating the metabolic effects of endocannabinoids. Finally, we review recent observations that indicate that peripherally restricted CB(1) receptor antagonists retain efficacy in reducing weight and improving metabolic abnormalities in mouse models of obesity without causing behavioural effects predictive of neuropsychiatric side effects in humans.
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Affiliation(s)
- George Kunos
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9413, USA.
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Christopoulou FD, Kiortsis DN. An overview of the metabolic effects of rimonabant in randomized controlled trials: potential for other cannabinoid 1 receptor blockers in obesity. J Clin Pharm Ther 2011; 36:10-8. [PMID: 21198716 DOI: 10.1111/j.1365-2710.2010.01164.x] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Rimonabant, a cannabinoid receptor blocker, has recently been used in clinical practice for weight loss and weight maintenance. Our aim was to review the results of trials of the drug in relation to weight loss and maintenance, and its impact on cardio-metabolic risk factors. METHODS Randomized controlled trials with rimonabant were selected, through a Medline search, using the terms: rimonabant, endocannabinoid antagonist and obesity. Reports of studies on large numbers of patients and covering the topics related to this review were included. RESULTS AND DISCUSSION In all the trials, there was a considerable reduction in body weight in subjects taking 20 mg rimonabant daily varying from 2.6 to 6.3 kg (placebo-subtracted changes). Rimonabant was also associated with haemoglobin A(₁c) (HbA(₁c) ) reduction. In the Rimonabant in obesity (RIO)-diabetes study, diabetic patients taking metformin or sulphonylureas showed decrease in HbA(₁c) levels by 0.5-0.6 ± 0.8% when rimonabant was added, whereas in the Serenade trial patients with untreated diabetes showed a reduction in HbA(₁c) of 0.8% vs. 0.3% with placebo. Similar results were obtained in diabetic patients under insulin treatment. The lipidemic profile also improved in patients taking rimonabant 20 mg daily; levels of high density lipoprotein cholesterol (HDL-c) increased significantly while levels of triglycerides (TRG) decreased in all trials, and positive effects were also observed in patients with atherogenic or untreated dyslipidaemia. In all the RIO studies, prevalence of the metabolic syndrome decreased significantly. In addition, patients treated with 20 mg rimonabant daily exhibited increase in adiponectin. The metabolic changes observed were partly independent of the weight loss and could be attributed to independent peripheral effect of rimonabant. All these beneficial metabolic effects of rimonabant could lead to progress in the prevention of cardiovascular disease. However, in all the trials the incidence of adverse events leading to discontinuation was greater in the rimonabant treated patients than placebo, mainly because of psychiatric disorders (depression and anxiety), nausea and dizziness. WHAT IS NEW AND CONCLUSION Rimonabant is effective in reducing weight in the obese but may lead to intolerable adverse effects most notably psychiatric effects, which make it unsuitable for routine use. However, the drug provides useful proof of principle for this approach to weight loss. Novel cannabinoid type 1 receptor blockers with selectivity for peripheral receptors, may achieve similar metabolic results with decreased prevalence of psychiatric adverse effects.
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Affiliation(s)
- F D Christopoulou
- Laboratory of Physiology, Medical School, University of Ioannina, Ioannina, Greece
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Di Marzo V, Piscitelli F, Mechoulam R. Cannabinoids and endocannabinoids in metabolic disorders with focus on diabetes. Handb Exp Pharmacol 2011:75-104. [PMID: 21484568 DOI: 10.1007/978-3-642-17214-4_4] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
The cannabinoid receptors for Δ(9)-THC, and particularly, the CB(1) receptor, as well as its endogenous ligands, the endocannabinoids anandamide and 2-arachidonoylglycerol, are deeply involved in all aspects of the control of energy balance in mammals. While initially it was believed that this endocannabinoid signaling system would only facilitate energy intake, we now know that perhaps even more important functions of endocannabinoids and CB(1) receptors in this context are to enhance energy storage into the adipose tissue and reduce energy expenditure by influencing both lipid and glucose metabolism. Although normally well controlled by hormones and neuropeptides, both central and peripheral aspects of endocannabinoid regulation of energy balance can become dysregulated and contribute to obesity, dyslipidemia, and type 2 diabetes, thus raising the possibility that CB(1) antagonists might be used for the treatment of these metabolic disorders. On the other hand, evidence is emerging that some nonpsychotropic plant cannabinoids, such as cannabidiol, can be employed to retard β-cell damage in type 1 diabetes. These novel aspects of endocannabinoid research are reviewed in this chapter, with emphasis on the biological effects of plant cannabinoids and endocannabinoid receptor antagonists in diabetes.
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Affiliation(s)
- Vincenzo Di Marzo
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Via Campi Flegrei 34 Comprensorio Olivetti, 80078, Pozzuoli, NA, Italy
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