|
1
|
Mullassaril P, Brodkin L, Brodkin J. Monlunabant suppresses appetite through a central mechanism. Behav Pharmacol 2025; 36:156-160. [PMID: 39969070 DOI: 10.1097/fbp.0000000000000818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/20/2025]
Abstract
This study aimed to determine whether the second-generation cannabinoid receptor subtype 1 (CB 1 ) antagonist, monlunabant - designed to treat obesity by targeting peripheral receptors - might actually exert its effects through CB 1 receptors in the central nervous system. In adult male mice, both monlunabant and rimonabant reduced appetite and antagonized CB 1 agonist-induced hypothermia. Monlunabant was consistently less potent than rimonabant in both appetite suppression and blocking hypothermia. The cannabinoid agonist HU-210 produced profound hypothermia, which was significantly attenuated by 10 mg/kg of either drug and by 3 mg/kg of rimonabant. Similarly, both drugs reduced appetite in food-deprived mice with limited access to preferred food at the same doses that were effective in the hypothermia assay. Lower doses of monlunabant, which likely saturated peripheral receptors, had no effect on appetite. These findings suggest that monlunabant suppresses appetite mainly through antagonism of central CB 1 receptors. Consequently, monlunabant and other second-generation CB 1 antagonists being developed for obesity may carry a similar risk of adverse psychiatric effects, as previously observed with rimonabant.
Collapse
|
|
2
|
Hu J, Cao Y, Duan L, Peng J. What is holding back preclinical GPR119 agonists from their potential as the therapeutics of type 2 diabetes? Expert Opin Ther Targets 2024; 28:825-828. [PMID: 39470103 DOI: 10.1080/14728222.2024.2421751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 10/23/2024] [Indexed: 10/30/2024]
Affiliation(s)
- Jing Hu
- Department of Nephropathy, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu Cao
- Department of Nephropathy, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lianxiang Duan
- Department of Nephropathy, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jinghua Peng
- Institute of Liver diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine, Ministry of Education, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| |
Collapse
|
|
3
|
Jung KM, Lin L, Piomelli D. Overactivation of the Endocannabinoid System in Adolescence Disrupts Adult Adipose Organ Function in Mice. Cells 2024; 13:461. [PMID: 38474425 PMCID: PMC10930932 DOI: 10.3390/cells13050461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 02/29/2024] [Accepted: 03/05/2024] [Indexed: 03/14/2024] Open
Abstract
Cannabis use stimulates calorie intake, but epidemiological studies show that people who regularly use it are leaner than those who don't. Two explanations have been proposed for this paradoxical finding. One posits that Δ9-tetrahydrocannabinol (THC) in cannabis desensitizes adipose CB1 cannabinoid receptors, stopping their stimulating effects on lipogenesis and adipogenesis. Another explanation is that THC exposure in adolescence, when habitual cannabis use typically starts, produces lasting changes in the developing adipose organ, which impacts adult systemic energy use. Here, we consider these possibilities in the light of a study which showed that daily THC administration in adolescent mice produces an adult metabolic phenotype characterized by reduced fat mass, partial resistance to obesity and dyslipidemia, and impaired thermogenesis and lipolysis. The phenotype, whose development requires activation of CB1 receptors in differentiated adipocytes, is associated with overexpression of myocyte proteins in the adipose organ with unchanged CB1 expression. We propose that adolescent exposure to THC causes lasting adipocyte dysfunction and the consequent emergence of a metabolic state that only superficially resembles healthy leanness. A corollary of this hypothesis, which should be addressed in future studies, is that CB1 receptors and their endocannabinoid ligands may contribute to the maintenance of adipocyte differentiation during adolescence.
Collapse
Affiliation(s)
- Kwang-Mook Jung
- Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697, USA; (K.-M.J.); (L.L.)
| | - Lin Lin
- Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697, USA; (K.-M.J.); (L.L.)
| | - Daniele Piomelli
- Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697, USA; (K.-M.J.); (L.L.)
- Department of Biological Chemistry, University of California, Irvine, CA 92697, USA
- Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, USA
| |
Collapse
|
|
4
|
Ahmed R, de Souza RJ, Li V, Banfield L, Anand SS. Twenty years of participation of racialised groups in type 2 diabetes randomised clinical trials: a meta-epidemiological review. Diabetologia 2024; 67:443-458. [PMID: 38177564 PMCID: PMC10844363 DOI: 10.1007/s00125-023-06052-w] [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: 07/27/2023] [Accepted: 10/16/2023] [Indexed: 01/06/2024]
Abstract
AIMS/HYPOTHESIS Type 2 diabetes mellitus prevalence is increasing globally and the greatest burden is borne by racialised people. However, there are concerns that the enrolment of racialised people into RCTs is limited, resulting in a lack of ethnic and racial diversity. This may differ depending whether an RCT is government funded or industry funded. The aim of this study was to review the proportions of racialised and white participants included in large RCTs of type 2 diabetes pharmacotherapies relative to the disease burden of type 2 diabetes in these groups. METHODS The Ovid MEDLINE database was searched from 1 January 2000 to 31 December 2020. English language reports of RCTs of type 2 diabetes pharmacotherapies published in select medical journals were included. Studies were included in this review if they had a sample size of at least 100 participants and all participants were adults with type 2 diabetes. Industry-funded trials must have recruited participants from at least two countries. Government-funded trials were not held to the same standard because they are typically conducted in a single country. Data including the numbers and proportions of participants by ethnicity and race were extracted from trial reports. The participation-to-prevalence ratio (PPR) was calculated for each trial by dividing the percentage of white and racialised participants in each trial by the percentage of white and racialised participants with type 2 diabetes, respectively, for the regions of recruitment. A random-effects meta-analysis was used to generate the pooled PPRs and 95% CIs across study types. A PPR <0.80 indicates under-representation and a PPR >1.20 indicates over-representation. Risk of bias assessments were not conducted for this study as the objective was to examine recruitment of racialised and white participants rather than evaluate the trustworthiness of clinical trial outcomes. RESULTS A total of 83 trials were included, involving 283,122 participants, of which 15 were government-funded and 68 were industry-funded trials. In government-funded trials, the PPR for white participants was 1.11 (95% CI 0.99, 1.24) and the PPR for racialised participants was 0.72 (95% CI 0.60, 0.86). In industry-funded trials, the PPR for white participants was 1.95 (95% CI 1.74, 2.18) and the PPR for racialised participants was 0.36 (95% CI 0.32, 0.42). The limitations of this study include the reliance on investigator-reported ethnicity and race to classify participants as 'white' or 'racialised', the use of estimates for type 2 diabetes prevalence and demographic data, and the high levels of heterogeneity of pooled estimates. However, despite these limitations, the results were consistent with respect to direction. CONCLUSIONS/INTERPRETATION Racialised participants are under-represented in government- and industry-funded type 2 diabetes trials. Strategies to improve recruitment and enrolment of racialised participants into RCTs should be developed. REGISTRATION Open Science Framework registration no. f59mk ( https://osf.io/f59mk ) FUNDING: The authors received no financial support for this research or authorship of the article.
Collapse
Affiliation(s)
- Rabeeyah Ahmed
- Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
- Chanchlani Research Centre, McMaster University, Hamilton, ON, Canada
| | - Russell J de Souza
- Chanchlani Research Centre, McMaster University, Hamilton, ON, Canada
- Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada
| | - Vincent Li
- Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Laura Banfield
- Health Sciences Library, McMaster University, Hamilton, ON, Canada
| | - Sonia S Anand
- Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
- Chanchlani Research Centre, McMaster University, Hamilton, ON, Canada.
- Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada.
| |
Collapse
|
|
5
|
Yang W, Gong X, Sun H, Wu C, Suo J, Ji J, Jiang X, Shen J, He Y, Aisa HA. Discovery of a CB 2 and 5-HT 1A receptor dual agonist for the treatment of depression and anxiety. Eur J Med Chem 2024; 265:116048. [PMID: 38150961 DOI: 10.1016/j.ejmech.2023.116048] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/29/2023] [Accepted: 12/11/2023] [Indexed: 12/29/2023]
Abstract
Cannabinoid CB2R agonists have gained considerable attention as potential novel therapies for psychiatric disorders due to their non-psychoactive nature, in contrast to CB1R agonists. In this study, we employed molecular docking to design and synthesize 23 derivatives of cannabidiol (CBD) with the aim of discovering potent CB2R agonists rather than CB2R antagonists or inverse agonists. Structure-activity relationship (SAR) investigations highlighted the critical importance of the amide group at the C-3' site and the cycloalkyl group at the C-4' site for CB2R activation. Interestingly, three CBD derivatives, namely 2o, 6g, and 6h, exhibited substantial partial agonistic activity towards the CB2 receptor, in contrast to the inverse agonistic property of CBD. Among these, 2o acted as a CB2R and 5-HT1AR dual agonist, albeit with some undesired antagonist activity for CB1R. It demonstrated significant CB2R partial agonism while maintaining a level of 5-HT1AR agonistic and CB1R antagonistic activity similar to CBD. Pharmacokinetic experiments confirmed that 2o possesses favorable pharmacokinetic properties. Behavioral studies further revealed that 2o elicits significant antidepressant-like and anxiolytic-like effects while maintaining a good safety profile.
Collapse
Affiliation(s)
- Wenjiao Yang
- State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, and Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xudong Gong
- Vigonvita Shanghai Co., Ltd, Shanghai, 201210, China
| | - Haiguo Sun
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Chunhui Wu
- Vigonvita Shanghai Co., Ltd, Shanghai, 201210, China
| | - Jin Suo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jing Ji
- State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, and Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiangrui Jiang
- University of Chinese Academy of Sciences, Beijing, 100049, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jingshan Shen
- University of Chinese Academy of Sciences, Beijing, 100049, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Yang He
- University of Chinese Academy of Sciences, Beijing, 100049, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Haji Akber Aisa
- State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, and Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
| |
Collapse
|
|
6
|
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.
Collapse
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.
| |
Collapse
|
|
7
|
Cortes-Justo E, Garfias-Ramírez SH, Vilches-Flores A. The function of the endocannabinoid system in the pancreatic islet and its implications on metabolic syndrome and diabetes. Islets 2023; 15:1-11. [PMID: 36598083 PMCID: PMC9815253 DOI: 10.1080/19382014.2022.2163826] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
The following review focuses on the scientific studies related to the role of endocannabinoid system (ECS) in pancreatic islet physiology and dysfunction. Different natural or synthetic agonists and antagonists have been suggested as an alternative treatment for diabetes, obesity and metabolic syndrome. Therapeutic use of Cannabis led to the discovery and characterization of the ECS, a signaling complex involved in regulation of various physiological processes, including food intake and metabolism. After the development of different agonists and antagonists, evidence have demonstrated the presence and activity of cannabinoid receptors in several organs and tissues, including pancreatic islets. Insulin and glucagon expression, stimulated secretion, and the development of diabetes and other metabolic disorders have been associated with the activity and modulation of ECS in pancreatic islets. However, according to the animal model and experimental design, either endogenous or pharmacological ligands of cannabinoid receptors have guided to contradictory and paradoxical results that suggest a complex physiological interaction. In consensus, ECS activity modulates insulin and glucagon secretions according to glucose in media; over-stimulation of cannabinoid receptors affects islets negatively, leading to glucose intolerance, meanwhile the treatment with antagonists in diabetic models and humans suggests an improvement in islets function.
Collapse
Affiliation(s)
- Edgardo Cortes-Justo
- Posgrado e Investigación, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico NacionalMexico CityMexico
| | - Sergio H Garfias-Ramírez
- Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Coyoacán, Mexico
| | - Alonso Vilches-Flores
- Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Coyoacán, Mexico
- CONTACT Alonso Vilches-Flores Universidad Nacional Autónoma de México, Facultad de Estudios Superiores Iztacala. Edif.A4 Lab 4, Los Reyes Iztacala, Tlalnepantla54090, Mexico
| |
Collapse
|
|
8
|
Hassan FU, Liu C, Mehboob M, Bilal RM, Arain MA, Siddique F, Chen F, Li Y, Zhang J, Shi P, Lv B, Lin Q. Potential of dietary hemp and cannabinoids to modulate immune response to enhance health and performance in animals: opportunities and challenges. Front Immunol 2023; 14:1285052. [PMID: 38111585 PMCID: PMC10726122 DOI: 10.3389/fimmu.2023.1285052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 11/17/2023] [Indexed: 12/20/2023] Open
Abstract
Cannabinoids are a group of bioactive compounds abundantly present in Cannabis sativa plant. The active components of cannabis with therapeutic potential are known as cannabinoids. Cannabinoids are divided into three groups: plant-derived cannabinoids (phytocannabinoids), endogenous cannabinoids (endocannabinoids), and synthetic cannabinoids. These compounds play a crucial role in the regulation various physiological processes including the immune modulation by interacting with the endocannabinoid system (A complex cell-signaling system). Cannabinoid receptor type 1 (CB1) stimulates the binding of orexigenic peptides and inhibits the attachment of anorexigenic proteins to hypothalamic neurons in mammals, increasing food intake. Digestibility is unaffected by the presence of any cannabinoids in hemp stubble. Endogenous cannabinoids are also important for the peripheral control of lipid processing in adipose tissue, in addition to their role in the hypothalamus regulation of food intake. Regardless of the kind of synaptic connection or the length of the transmission, endocannabinoids play a crucial role in inhibiting synaptic transmission through a number of mechanisms. Cannabidiol (CBD) mainly influences redox equilibrium through intrinsic mechanisms. Useful effects of cannabinoids in animals have been mentioned e.g., for disorders of the cardiovascular system, pain treatment, disorders of the respiratory system or metabolic disorders. Dietary supplementation of cannabinoids has shown positive effects on health, growth and production performance of small and large animals. Animal fed diet supplemented with hemp seeds (180 g/day) or hemp seed cake (143 g/kg DM) had achieved batter performance without any detrimental effects. But the higher level of hemp or cannabinoid supplementation suppress immune functions and reduce productive performance. With an emphasis on the poultry and ruminants, this review aims to highlight the properties of cannabinoids and their derivatives as well as their significance as a potential feed additive in their diets to improve the immune status and health performance of animals.
Collapse
Affiliation(s)
- Faiz-ul Hassan
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
- Faculty of Animal Production and Technology, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan
| | - Chunjie Liu
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Maryam Mehboob
- Department of Zoology, Wildlife and Fisheries, University of Agriculture, Faisalabad, Pakistan
| | - Rana Muhammad Bilal
- Faculty of Animal Production and Technology, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan
| | - Muhammad Asif Arain
- Faculty of Veterinary and Animal Sciences, Lasbela University of Agriculture, Water and Marine Sciences, Uthal, Balochistan, Pakistan
| | - Faisal Siddique
- Faculty of Animal Production and Technology, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan
| | - Fengming Chen
- Hunan Provincial Key Laboratory of the TCM Agricultural Biogenomics, Changsha Medical University, Changsha, China
| | - Yuying Li
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Jingmeng Zhang
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Pengjun Shi
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Biguang Lv
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Qian Lin
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| |
Collapse
|
|
9
|
Colak DK, Coskun Yazici ZM, Bolkent S. Chronic administration of delta9-tetrahydrocannabinol protects hyperinsulinemic gastric tissue in rats. Cell Biochem Funct 2023; 41:1543-1551. [PMID: 38032085 DOI: 10.1002/cbf.3894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 11/15/2023] [Accepted: 11/17/2023] [Indexed: 12/01/2023]
Abstract
Hyperinsulinemia (HI) can result from some reasons such as an increase in basal/fasting circulating insulin and/or potentiation of postprandial insulin production. Diabetes mellitus (DM) is indirectly related to HI since it both causes and results from insulin resistance. Understanding the causes of HI and treating this is crucial for preventing DM. Previous research has shown that delta9-tetrahydrocannabinol (THC) has medicinal benefits. In light of this, the relationship between THC and oxidative stress, DNA repair mechanism, apoptosis, and its regulatory impact on appetite hormones in the gastric tissue of hyperinsulinemic rats has been investigated for the first time. Male rats (Spraque-Dawley, total = 32) were used, and they were randomly divided into the following groups (n = 8 in each group): control (CTRL), HI, THC administered control (THC, 1.5 mg/kg/day, during 4 weeks), and THC administered HI (HI + THC) groups. The number of poly (ADP-ribose) polymerase-1 and proliferating cell nuclear antigen (PCNA) and caspase-3 immunopositive cells in the HI group was significantly reduced compared to the CTRL group. The number of PCNA and caspase-9 immunopositive cells was significantly increased in the HI + THC group compared to the HI group. Obestatin immunopositive cell numbers in the HI + THC group were higher than in the HI and CTRL groups. The results show that THC administration may affect the regulation of appetite hormones and regeneration in the fundus of rats with HI. Glutathione (GSH) levels were higher in the HI + THC group than in the HI group. Both immunohistochemical and biochemical analyses revealed that THC promotes regeneration and regulates appetite hormones in hyperinsulinemic gastric tissues.
Collapse
Affiliation(s)
- Dilara Kamer Colak
- Department of Medical Biology, Faculty of Cerrahpaşa Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkey
| | - Zeynep Mine Coskun Yazici
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Demiroglu Bilim University, Istanbul, Turkey
| | - Sema Bolkent
- Department of Medical Biology, Faculty of Cerrahpaşa Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkey
| |
Collapse
|
|
10
|
Stumpf MAM, Cercato C, de Melo ME, Santos RD, Mancini MC. Down the rabbit hole: reviewing the evidence for primary prevention of cardiovascular disease in people with obesity. Eur J Prev Cardiol 2023; 30:1895-1905. [PMID: 37648659 DOI: 10.1093/eurjpc/zwad280] [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: 05/14/2023] [Revised: 08/22/2023] [Accepted: 08/25/2023] [Indexed: 09/01/2023]
Abstract
Obesity is a prevalent chronic disorder and a well-known risk factor for cardiovascular disease. However, the evidence of treating obesity for primary prevention of major cardiovascular events is still scarce and controversial. In this review, we provided a comprehensive description of the current evidence in treating obesity regarding cardiovascular protection. Bariatric surgery appears to be the most robust method to reduce events in people without established cardiovascular disease. High compliance to lifestyle interventions can further reduce cardiovascular risk. Concerning pharmacological therapies, a post hoc analysis from SUSTAIN-6 and a meta-analysis from STEP trials suggest that semaglutide, a GLP-1 receptor agonist, could reduce cardiovascular events in people without established cardiovascular disease. The first study addressed specifically a high-risk population with diabetes and, the second, low- or intermediary-risk individuals without diabetes. Tirzepatide, a novel dual GIP/GLP-1 agonist, although not yet tested in specific cardiovascular outcomes trials, could be an alternative since it induces loss in weight similar to the achieved by bariatric surgery. Therefore, extrapolated data in distinct baseline cardiovascular risk populations suggest that these two drugs could be used in primary prevention with the aim of preventing cardiovascular events, but the grade of this evidence is still low. Specifically designed studies are needed to address this specific topic.
Collapse
Affiliation(s)
- Matheo A M Stumpf
- Obesity Unit, Division of Endocrinology and Metabolism, University of São Paulo Medical School Hospital, Street Dr. Ovídio Pires de Campos, 05403-010, São Paulo, Brazil
| | - Cintia Cercato
- Obesity Unit, Division of Endocrinology and Metabolism, University of São Paulo Medical School Hospital, Street Dr. Ovídio Pires de Campos, 05403-010, São Paulo, Brazil
| | - Maria E de Melo
- Obesity Unit, Division of Endocrinology and Metabolism, University of São Paulo Medical School Hospital, Street Dr. Ovídio Pires de Campos, 05403-010, São Paulo, Brazil
| | - Raul D Santos
- Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, Brazil
- Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Marcio C Mancini
- Obesity Unit, Division of Endocrinology and Metabolism, University of São Paulo Medical School Hospital, Street Dr. Ovídio Pires de Campos, 05403-010, São Paulo, Brazil
| |
Collapse
|
|
11
|
Vasincu A, Rusu RN, Ababei DC, Neamțu M, Arcan OD, Macadan I, Beșchea Chiriac S, Bild W, Bild V. Exploring the Therapeutic Potential of Cannabinoid Receptor Antagonists in Inflammation, Diabetes Mellitus, and Obesity. Biomedicines 2023; 11:1667. [PMID: 37371762 DOI: 10.3390/biomedicines11061667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/31/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Recently, research has greatly expanded the knowledge of the endocannabinoid system (ECS) and its involvement in several therapeutic applications. Cannabinoid receptors (CBRs) are present in nearly every mammalian tissue, performing a vital role in different physiological processes (neuronal development, immune modulation, energy homeostasis). The ECS has an essential role in metabolic control and lipid signaling, making it a potential target for managing conditions such as obesity and diabetes. Its malfunction is closely linked to these pathological conditions. Additionally, the immunomodulatory function of the ECS presents a promising avenue for developing new treatments for various types of acute and chronic inflammatory conditions. Preclinical investigations using peripherally restricted CBR antagonists that do not cross the BBB have shown promise for the treatment of obesity and metabolic diseases, highlighting the importance of continuing efforts to discover novel molecules with superior safety profiles. The purpose of this review is to examine the roles of CB1R and CB2Rs, as well as their antagonists, in relation to the above-mentioned disorders.
Collapse
Affiliation(s)
- Alexandru Vasincu
- Department of Pharmacodynamics and Clinical Pharmacy, "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Răzvan-Nicolae Rusu
- Department of Pharmacodynamics and Clinical Pharmacy, "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Daniela-Carmen Ababei
- Department of Pharmacodynamics and Clinical Pharmacy, "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Monica Neamțu
- Department of Pharmacodynamics and Clinical Pharmacy, "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Oana Dana Arcan
- Department of Pharmacodynamics and Clinical Pharmacy, "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Ioana Macadan
- Department of Pharmacodynamics and Clinical Pharmacy, "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Sorin Beșchea Chiriac
- Department of Toxicology, "Ion Ionescu de la Brad" University of Life Sciences, 8 M. Sadoveanu Alley, 700489 Iasi, Romania
| | - Walther Bild
- Department of Physiology, "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
- Center of Biomedical Research of the Romanian Academy, 700506 Iasi, Romania
| | - Veronica Bild
- Department of Pharmacodynamics and Clinical Pharmacy, "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
- Center of Biomedical Research of the Romanian Academy, 700506 Iasi, Romania
- Center for Advanced Research and Development in Experimental Medicine (CEMEX), "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| |
Collapse
|
|
12
|
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.
Collapse
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.
| |
Collapse
|
|
13
|
Therapeutics in Metabolic Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1396:255-273. [DOI: 10.1007/978-981-19-5642-3_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
|
|
14
|
Spyridakos D, Mastrodimou N, Vemuri K, Ho TC, Nikas SP, Makriyannis A, Thermos K. Blockade of CB1 or Activation of CB2 Cannabinoid Receptors Is Differentially Efficacious in the Treatment of the Early Pathological Events in Streptozotocin-Induced Diabetic Rats. Int J Mol Sci 2022; 24:240. [PMID: 36613692 PMCID: PMC9820336 DOI: 10.3390/ijms24010240] [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: 10/03/2022] [Revised: 12/19/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Oxidative stress, neurodegeneration, neuroinflammation, and vascular leakage are believed to play a key role in the early stage of diabetic retinopathy (ESDR). The aim of this study was to investigate the blockade of cannabinoid receptor 1 (CB1R) and activation of cannabinoid receptor 2 (CB2R) as putative therapeutics for the treatment of the early toxic events in DR. Diabetic rats [streptozotocin (STZ)-induced] were treated topically (20 μL, 10 mg/mL), once daily for fourteen days (early stage DR model), with SR141716 (CB1R antagonist), AM1710 (CB2R agonist), and the dual treatment SR141716/AM1710. Immunohistochemical-histological, ELISA, and Evans-Blue analyses were performed to assess the neuroprotective and vasculoprotective properties of the pharmacological treatments on diabetes-induced retinal toxicity. Activation of CB2R or blockade of CB1R, as well as the dual treatment, attenuated the nitrative stress induced by diabetes. Both single treatments protected neural elements (e.g., RGC axons) and reduced vascular leakage. AM1710 alone reversed all toxic insults. These findings provide new knowledge regarding the differential efficacies of the cannabinoids, when administered topically, in the treatment of ESDR. Cannabinoid neuroprotection of the diabetic retina in ESDR may prove therapeutic in delaying the development of the advanced stage of the disease.
Collapse
Affiliation(s)
- Dimitris Spyridakos
- Department of Pharmacology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Niki Mastrodimou
- Department of Pharmacology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Kiran Vemuri
- Center for Drug Discovery, Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
| | - Thanh C. Ho
- Center for Drug Discovery, Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
| | - Spyros P. Nikas
- Center for Drug Discovery, Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
| | - Alexandros Makriyannis
- Center for Drug Discovery, Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
| | - Kyriaki Thermos
- Department of Pharmacology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| |
Collapse
|
|
15
|
Kim H, Shah K, Buettner C. Use of Patient-Reported Outcomes for Assessing Diabetes Outcomes. Endocrinol Metab Clin North Am 2022; 51:781-793. [PMID: 36244693 DOI: 10.1016/j.ecl.2022.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The treatment of diabetes can be complex and overwhelming for patients as it demands persistent attention to lifestyle management, adherence to medications, monitoring of side effects of drugs, and management of devices for glucose monitoring and/or insulin infusion. Therefore, understanding patient-reported outcomes (PROs) that provide direct insight into the patient's experience with diabetes is crucial for optimizing diabetes management.This review provides an overview of commonly used PRO questionnaires that assess different aspects of diabetes management.
Collapse
Affiliation(s)
- Hyon Kim
- Department of Medicine, Division of Endocrinology, Metabolism and Nutrition Rutgers, The State University of New Jersey, One Robert Wood Johnson Place, Medical Education Boulevard, 384, New Brunswick, NJ 08901, USA.
| | - Kunal Shah
- Department of Medicine, Division of Endocrinology, Metabolism and Nutrition Rutgers, The State University of New Jersey, One Robert Wood Johnson Place, Medical Education Boulevard, 384, New Brunswick, NJ 08901, USA.
| | - Christoph Buettner
- Department of Medicine, Division of Endocrinology, Metabolism and Nutrition Rutgers, The State University of New Jersey, One Robert Wood Johnson Place, Medical Education Boulevard, 384, New Brunswick, NJ 08901, USA.
| |
Collapse
|
|
16
|
CB1 Ligand AM251 Induces Weight Loss and Fat Reduction in Addition to Increased Systemic Inflammation in Diet-Induced Obesity. Int J Mol Sci 2022; 23:ijms231911447. [PMID: 36232744 PMCID: PMC9569643 DOI: 10.3390/ijms231911447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/16/2022] [Accepted: 09/20/2022] [Indexed: 11/30/2022] Open
Abstract
Diet-induced obesity (DIO) reduces fatty acid oxidation in skeletal muscle and decreases circulating levels of adiponectin. Endocannabinoid signaling is overactive in obesity, with some effects abated by antagonism of cannabinoid receptor 1 (CB1). This research aimed to determine if treatment with the global CB1 antagonist/inverse agonist, AM251, in high-fat diet (HFD) fed rats influenced adiponectin signaling in skeletal muscle and a “browning” of white adipose tissue (WAT) defined by UCP1 expression levels. Male Sprague Dawley rats consumed an HFD (21% fat) for 9 weeks before receiving daily intraperitoneal injections with vehicle or AM251 (3 mg/kg) for 6 weeks. mRNA expression of genes involved in metabolic functions were measured in skeletal muscle and adipose tissue, and blood was harvested for the measurement of hormones and cytokines. Muscle citrate synthase activity was also measured. AM251 treatment decreased fat pad weight (epididymal, peri-renal, brown), and plasma levels of leptin, glucagon, ghrelin, and GLP-1, and increased PAI-1 along with a range of pro-inflammatory and anti-inflammatory cytokines; however, AM251 did not alter plasma adiponectin levels, skeletal muscle citrate synthase activity or mRNA expression of the genes measured in muscle. AM251 treatment had no effect on white fat UCP1 expression levels. AM251 decreased fat pad mass, altered plasma hormone levels, but did not induce browning of WAT defined by UCP1 mRNA levels or alter gene expression in muscle treated acutely with adiponectin, demonstrating the complexity of the endocannabinoid system and metabolism. The CB1 ligand AM251 increased systemic inflammation suggesting limitations on its use in metabolic disorders.
Collapse
|
|
17
|
Contribution of specific ceramides to obesity-associated metabolic diseases. Cell Mol Life Sci 2022; 79:395. [PMID: 35789435 PMCID: PMC9252958 DOI: 10.1007/s00018-022-04401-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/20/2022] [Accepted: 05/26/2022] [Indexed: 12/04/2022]
Abstract
Ceramides are a heterogeneous group of bioactive membrane sphingolipids that play specialized regulatory roles in cellular metabolism depending on their characteristic fatty acyl chain lengths and subcellular distribution. As obesity progresses, certain ceramide molecular species accumulate in metabolic tissues and cause cell-type-specific lipotoxic reactions that disrupt metabolic homeostasis and lead to the development of cardiometabolic diseases. Several mechanisms for ceramide action have been inferred from studies in vitro, but only recently have we begun to better understand the acyl chain length specificity of ceramide-mediated signaling in the context of physiology and disease in vivo. New discoveries show that specific ceramides affect various metabolic pathways and that global or tissue-specific reduction in selected ceramide pools in obese rodents is sufficient to improve metabolic health. Here, we review the tissue-specific regulation and functions of ceramides in obesity, thus highlighting the emerging concept of selectively inhibiting production or action of ceramides with specific acyl chain lengths as novel therapeutic strategies to ameliorate obesity-associated diseases.
Collapse
|
|
18
|
Busquets-García A, Bolaños JP, Marsicano G. Metabolic Messengers: endocannabinoids. Nat Metab 2022; 4:848-855. [PMID: 35817852 DOI: 10.1038/s42255-022-00600-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 06/07/2022] [Indexed: 11/09/2022]
Affiliation(s)
- Arnau Busquets-García
- Cell-type mechanisms in normal and pathological behavior Research Group. IMIM-Hospital del Mar Medical Research Institute, PRBB, Barcelona, Spain.
| | - Juan P Bolaños
- Institute of Functional Biology and Genomics, University of Salamanca, CSIC, Salamanca, Spain.
- Centro de Investigación Biomédica en Red sobre Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain.
- Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, University of Salamanca, CSIC, Salamanca, Spain.
| | - Giovanni Marsicano
- INSERM, U1215 NeuroCentre Magendie, Bordeaux, France.
- University of Bordeaux, Bordeaux, France.
| |
Collapse
|
|
19
|
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.
Collapse
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.
| |
Collapse
|
|
20
|
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.
Collapse
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
| |
Collapse
|
|
21
|
Angelidi AM, Belanger MJ, Kokkinos A, Koliaki CC, Mantzoros CS. Novel Noninvasive Approaches to the Treatment of Obesity: From Pharmacotherapy to Gene Therapy. Endocr Rev 2022; 43:507-557. [PMID: 35552683 PMCID: PMC9113190 DOI: 10.1210/endrev/bnab034] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Indexed: 02/08/2023]
Abstract
Recent insights into the pathophysiologic underlying mechanisms of obesity have led to the discovery of several promising drug targets and novel therapeutic strategies to address the global obesity epidemic and its comorbidities. Current pharmacologic options for obesity management are largely limited in number and of modest efficacy/safety profile. Therefore, the need for safe and more efficacious new agents is urgent. Drugs that are currently under investigation modulate targets across a broad range of systems and tissues, including the central nervous system, gastrointestinal hormones, adipose tissue, kidney, liver, and skeletal muscle. Beyond pharmacotherapeutics, other potential antiobesity strategies are being explored, including novel drug delivery systems, vaccines, modulation of the gut microbiome, and gene therapy. The present review summarizes the pathophysiology of energy homeostasis and highlights pathways being explored in the effort to develop novel antiobesity medications and interventions but does not cover devices and bariatric methods. Emerging pharmacologic agents and alternative approaches targeting these pathways and relevant research in both animals and humans are presented in detail. Special emphasis is given to treatment options at the end of the development pipeline and closer to the clinic (ie, compounds that have a higher chance to be added to our therapeutic armamentarium in the near future). Ultimately, advancements in our understanding of the pathophysiology and interindividual variation of obesity may lead to multimodal and personalized approaches to obesity treatment that will result in safe, effective, and sustainable weight loss until the root causes of the problem are identified and addressed.
Collapse
Affiliation(s)
- Angeliki M Angelidi
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA
- Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Matthew J Belanger
- Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Alexander Kokkinos
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Chrysi C Koliaki
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Christos S Mantzoros
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA
- Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
22
|
Silvério R, Barth R, Heimann AS, Reckziegel P, dos Santos GJ, Romero-Zerbo SY, Bermúdez-Silva FJ, Rafacho A, Ferro ES. Pep19 Has a Positive Effect on Insulin Sensitivity and Ameliorates Both Hepatic and Adipose Tissue Phenotype of Diet-Induced Obese Mice. Int J Mol Sci 2022; 23:ijms23084082. [PMID: 35456900 PMCID: PMC9030859 DOI: 10.3390/ijms23084082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 03/29/2022] [Accepted: 04/01/2022] [Indexed: 12/10/2022] Open
Abstract
Peptide DIIADDEPLT (Pep19) has been previously suggested to improve metabolic parameters, without adverse central nervous system effects, in a murine model of diet-induced obesity. Here, we aimed to further evaluate whether Pep19 oral administration has anti-obesogenic effects, in a well-established high-fat diet-induced obesity model. Male Swiss mice, fed either a standard diet (SD) or high-fat diet (HFD), were orally administrated for 30 consecutive days, once a day, with saline vehicle or Pep19 (1 mg/kg). Next, several metabolic, morphological, and behavioral parameters were evaluated. Oral administration of Pep19 attenuated HFD body-weight gain, reduced in approximately 40% the absolute mass of the endocrine pancreas, and improved the relationship between circulating insulin and peripheral insulin sensitivity. Pep19 treatment of HFD-fed mice attenuated liver inflammation, hepatic fat distribution and accumulation, and lowered plasma alanine aminotransferase activity. The inguinal fat depot from the SD group treated with Pep19 showed multilocular brown-fat-like cells and increased mRNA expression of uncoupling protein 1 (UCP1), suggesting browning on inguinal white adipose cells. Morphological analysis of brown adipose tissue (BAT) from HFD mice showed the presence of larger white-like unilocular cells, compared to BAT from SD, Pep19-treated SD or HFD mice. Pep19 treatment produced no alterations in mice behavior. Oral administration of Pep19 ameliorates some metabolic traits altered by diet-induced obesity in a Swiss mice model.
Collapse
Affiliation(s)
- Renata Silvério
- Graduate Program in Pharmacology, Federal University of Santa Catarina (UFSC), Florianópolis 88040-900, Brazil;
- Laboratory of Investigation in Chronic Diseases, Department of Physiological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis 88040-900, Brazil; (R.B.); (G.J.d.S.)
| | - Robson Barth
- Laboratory of Investigation in Chronic Diseases, Department of Physiological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis 88040-900, Brazil; (R.B.); (G.J.d.S.)
- Multicenter Graduate Program in Physiological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis 88040-900, Brazil
| | - Andrea S. Heimann
- Proteimax BioTechnology Israel LTD, 4 Duvdevan Street, Pardes Hana, Haifa 3708973, Israel;
| | - Patrícia Reckziegel
- Department of Pharmacology, Biomedical Science Institute, University of São Paulo (USP), São Paulo 05508-000, Brazil;
| | - Gustavo J. dos Santos
- Laboratory of Investigation in Chronic Diseases, Department of Physiological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis 88040-900, Brazil; (R.B.); (G.J.d.S.)
- Multicenter Graduate Program in Physiological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis 88040-900, Brazil
| | - Silvana Y. Romero-Zerbo
- Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición Hospital Regional Universitario de Málaga, Universidad de Málaga, 29009 Málaga, Spain; (S.Y.R.-Z.); (F.J.B.-S.)
- Biomedical Research Center for Diabetes and Associated Metabolic Diseases (CIBERDEM), 28029 Madrid, Spain
| | - Francisco J. Bermúdez-Silva
- Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición Hospital Regional Universitario de Málaga, Universidad de Málaga, 29009 Málaga, Spain; (S.Y.R.-Z.); (F.J.B.-S.)
- Biomedical Research Center for Diabetes and Associated Metabolic Diseases (CIBERDEM), 28029 Madrid, Spain
| | - Alex Rafacho
- Graduate Program in Pharmacology, Federal University of Santa Catarina (UFSC), Florianópolis 88040-900, Brazil;
- Laboratory of Investigation in Chronic Diseases, Department of Physiological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis 88040-900, Brazil; (R.B.); (G.J.d.S.)
- Multicenter Graduate Program in Physiological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis 88040-900, Brazil
- Correspondence: (A.R.); (E.S.F.)
| | - Emer S. Ferro
- Department of Pharmacology, Biomedical Science Institute, University of São Paulo (USP), São Paulo 05508-000, Brazil;
- Correspondence: (A.R.); (E.S.F.)
| |
Collapse
|
|
23
|
Abstract
The endocannabinoid system is found in most, if not all, mammalian organs and is involved in a variety of physiological functions, ranging from the control of synaptic plasticity in the brain to the modulation of smooth muscle motility in the gastrointestinal tract. This signaling complex consists of G protein-coupled cannabinoid receptors, endogenous ligands for those receptors (endocannabinoids) and enzymes/transporters responsible for the formation and deactivation of these ligands. There are two subtypes of cannabinoid receptors, CB1 and CB2, and two major endocannabinoids, arachidonoylethanolamide (anandamide) and 2-arachidonoyl-sn-glycerol (2-AG), which are produced upon demand through cleavage of distinct phospholipid precursors. All molecular components of the endocannabinoid system are represented in the adipose organ, where endocannabinoid signals are thought to regulate critical homeostatic processes, including adipogenesis, lipogenesis and thermogenesis. Importantly, obesity was found to be associated with excess endocannabinoid activity in visceral fat depots, and the therapeutic potential of normalizing such activity by blocking CB1 receptors has been the focus of substantial preclinical and clinical research. Results have been mixed thus far, mostly owing to the emergence of psychiatric side effects rooted in the protective functions served by brain endocannabinoids in mood and affect regulation. Further studies about the roles played by the endocannabinoid system in the adipose organ will offer new insights into the pathogenesis of obesity and might help identify new ways to leverage this signaling complex for therapeutic benefit.
Collapse
Affiliation(s)
- Kwang-Mook Jung
- Department of Anatomy and Neurobiology, University of California, Irvine, 3101 Gillespie NRF, Irvine, CA, 92697-1275, USA
| | - Lin Lin
- Department of Anatomy and Neurobiology, University of California, Irvine, 3101 Gillespie NRF, Irvine, CA, 92697-1275, USA
| | - Daniele Piomelli
- Department of Anatomy and Neurobiology, University of California, Irvine, 3101 Gillespie NRF, Irvine, CA, 92697-1275, USA.
- Department of Pharmacology, University of California, Irvine, Irvine, CA, 92697, USA.
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, 92697, USA.
| |
Collapse
|
|
24
|
Di Prospero NA, Yee J, Frustaci ME, Samtani MN, Alba M, Fleck P. Efficacy and safety of glucagon-like peptide-1/glucagon receptor co-agonist JNJ-64565111 in individuals with type 2 diabetes mellitus and obesity: A randomized dose-ranging study. Clin Obes 2021; 11:e12433. [PMID: 33475251 DOI: 10.1111/cob.12433] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 11/17/2020] [Accepted: 11/29/2020] [Indexed: 12/15/2022]
Abstract
Weight loss has been shown to improve metabolic parameters and cardiovascular risk in people with type 2 diabetes mellitus (T2DM). This phase 2 study evaluated the safety and efficacy of JNJ-64565111, a dual agonist of GLP-1 and glucagon receptors, in individuals with T2DM and class II/III obesity. In this randomized, double-blind study, participants with T2DM (HbA1c 6.5%-9.5%), body mass index of 35 to 50 kg/m2 and stable weight were randomly assigned (1:1:1:1) to placebo or JNJ-64565111 (5.0 mg, 7.4 mg or 10.0 mg). The primary endpoint was percent change from baseline in body weight at week 12. Of 195 dosed participants, 144 (73.8%) completed treatment. At week 12, placebo-subtracted body weight changes were -4.6%, -5.9% and -7.2% with JNJ-64565111 5.0 mg, 7.4 mg and 10.0 mg, respectively. All JNJ-64565111 doses were associated with no change in HbA1c and slight numerical elevation of fasting insulin. Numerical increases in fasting plasma glucose were observed with JNJ-64565111 5.0 mg and 7.4 mg. Incidence of treatment-emergent adverse events, especially nausea and vomiting, was higher with JNJ-64565111 vs placebo. Overall, JNJ-64565111 significantly reduced body weight in a dose-dependent manner vs placebo but was associated with greater incidence of treatment-emergent adverse events, no HbA1c reductions, and increased fasting plasma glucose and fasting insulin.
Collapse
Affiliation(s)
| | - Jaqueline Yee
- Janssen Research & Development, LLC, Raritan, New Jersey, USA
| | - Mary E Frustaci
- Janssen Research & Development, LLC, Spring House, Pennsylvania, USA
| | | | - Maria Alba
- Janssen Research & Development, LLC, Raritan, New Jersey, USA
| | - Penny Fleck
- Janssen Research & Development, LLC, Raritan, New Jersey, USA
| |
Collapse
|
|
25
|
Mielnik CA, Lam VM, Ross RA. CB 1 allosteric modulators and their therapeutic potential in CNS disorders. Prog Neuropsychopharmacol Biol Psychiatry 2021; 106:110163. [PMID: 33152384 DOI: 10.1016/j.pnpbp.2020.110163] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/30/2020] [Accepted: 10/29/2020] [Indexed: 01/05/2023]
Abstract
CB1 is the most abundant GPCR found in the mammalian brain. It has garnered considerable attention as a potential therapeutic drug target. CB1 is involved in a wide range of physiological and psychiatric processes and has the potential to be targeted in a wide range of disease states. However, most of the selective and non-selective synthetic CB1 agonists and antagonists/inverse agonists developed to date are primarily used as research tools. No novel synthetic cannabinoids are currently in the clinic for use in psychiatric illness; synthetic analogues of the phytocannabinoid THC are on the market to treat nausea and vomiting caused by cancer chemotherapy, along with off-label use for pain. Novel strategies are being explored to target CB1, but with emphasis on the elimination or mitigation of the potential psychiatric adverse effects that are observed by central agonism/antagonism of CB1. New pharmacological options are being pursued that may avoid these adverse effects while preserving the potential therapeutic benefits of CB1 modulation. Allosteric modulation of CB1 is one such approach. In this review, we will summarize and critically analyze both the in vitro characterization and in vivo validation of CB1 allosteric modulators developed to date, with a focus on CNS therapeutic effects.
Collapse
Affiliation(s)
- Catharine A Mielnik
- Department of Pharmacology & Toxicology, University of Toronto, ON M5S 1A8, Canada
| | - Vincent M Lam
- Department of Pharmacology & Toxicology, University of Toronto, ON M5S 1A8, Canada
| | - Ruth A Ross
- Department of Pharmacology & Toxicology, University of Toronto, ON M5S 1A8, Canada.
| |
Collapse
|
|
26
|
What Role Does the Endocannabinoid System Play in the Pathogenesis of Obesity? Nutrients 2021; 13:nu13020373. [PMID: 33530406 PMCID: PMC7911032 DOI: 10.3390/nu13020373] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/19/2021] [Accepted: 01/22/2021] [Indexed: 02/07/2023] Open
Abstract
The endocannabinoid system (ECS) is an endogenous signaling system formed by specific receptors (cannabinoid type 1 and type 2 (CB1 and CB2)), their endogenous ligands (endocannabinoids), and enzymes involved in their synthesis and degradation. The ECS, centrally and peripherally, is involved in various physiological processes, including regulation of energy balance, promotion of metabolic process, food intake, weight gain, promotion of fat accumulation in adipocytes, and regulation of body homeostasis; thus, its overactivity may be related to obesity. In this review, we try to explain the role of the ECS and the impact of genetic factors on endocannabinoid system modulation in the pathogenesis of obesity, which is a global and civilizational problem affecting the entire world population regardless of age. We also emphasize that the search for potential new targets for health assessment, treatment, and the development of possible therapies in obesity is of great importance.
Collapse
|
|
27
|
Siebenhofer A, Winterholer S, Jeitler K, Horvath K, Berghold A, Krenn C, Semlitsch T. Long-term effects of weight-reducing drugs in people with hypertension. Cochrane Database Syst Rev 2021; 1:CD007654. [PMID: 33454957 PMCID: PMC8094237 DOI: 10.1002/14651858.cd007654.pub5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND This is the third update of this review, first published in July 2009. All major guidelines on treatment of hypertension recommend weight loss; anti-obesity drugs may be able to help in this respect. OBJECTIVES Primary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events).. Secondary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on change from baseline in systolic and diastolic blood pressure, and on body weight reduction. SEARCH METHODS For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to March 2020: the Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. The searches had no language restrictions. We contacted authors of relevant papers about further published and unpublished work. SELECTION CRITERIA Randomised controlled trials of at least 24 weeks' duration in adults with hypertension that compared approved long-term weight-loss medications to placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risks of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using a fixed-effect meta-analysis. When heterogeneity was present, we used the random-effects method and investigated the cause of the heterogeneity. MAIN RESULTS This third update of the review added one new trial, investigating the combination of naltrexone/bupropion versus placebo. Two medications, which were included in the previous versions of this review (rimonabant and sibutramine) are no longer considered relevant for this update, since their marketing approval was withdrawn in 2010 and 2009, respectively. The number of included studies in this review update is therefore six (12,724 participants in total): four RCTs comparing orlistat to placebo, involving a total of 3132 participants with high blood pressure and a mean age of 46 to 55 years; one trial comparing phentermine/topiramate to placebo, involving 1305 participants with high blood pressure and a mean age of 53 years; and one trial comparing naltrexone/bupropion to placebo, involving 8283 participants with hypertension and a mean age of 62 years. We judged the risks of bias to be unclear for the trials investigating orlistat or naltrexone/bupropion. and low for the trial investigating phentermine/topiramate. Only the study of naltrexone/bupropion included cardiovascular mortality and morbidity as predefined outcomes. There were no differences in the rates of all-cause or cardiovascular mortality, major cardiovascular events, or serious adverse events between naltrexone/bupropion and placebo. The incidence of overall adverse events was significantly higher in participants treated with naltrexone/bupropion. For orlistat, the incidence of gastrointestinal side effects was consistently higher compared to placebo. The most frequent side effects with phentermine/topiramate were dry mouth and paraesthesia. After six to 12 months, orlistat reduced systolic blood pressure compared to placebo by mean difference (MD) -2.6 mm Hg (95% confidence interval (CI) -3.8 to -1.4 mm Hg; 4 trials, 2058 participants) and diastolic blood pressure by MD -2.0 mm Hg (95% CI -2.7 to -1.2 mm Hg; 4 trials, 2058 participants). After 13 months of follow-up, phentermine/topiramate decreased systolic blood pressure compared to placebo by -2.0 to -4.2 mm Hg (1 trial, 1030 participants) (depending on drug dosage), and diastolic blood pressure by -1.3 to -1.9 mm Hg (1 trial, 1030 participants) (depending on drug dosage). There was no difference in the change in systolic or diastolic blood pressure between naltrexone/bupropion and placebo (1 trial, 8283 participants). We identified no relevant studies investigating liraglutide or lorcaserin in people with hypertension. AUTHORS' CONCLUSIONS In people with elevated blood pressure, orlistat, phentermine/topiramate and naltrexone/bupropion reduced body weight; the magnitude of the effect was greatest with phentermine/topiramate. In the same trials, orlistat and phentermine/topiramate, but not naltrexone/bupropion, reduced blood pressure. One RCT of naltrexone/bupropion versus placebo showed no differences in all-cause mortality or cardiovascular mortality or morbidity after two years. The European Medicines Agency refused marketing authorisation for phentermine/topiramate due to safety concerns, while for lorcaserin the application for European marketing authorisation was withdrawn due to a negative overall benefit/risk balance. In 2020 lorcaserin was also withdrawn from the US market. Two other medications (rimonabant and sibutramine) had already been withdrawn from the market in 2009 and 2010, respectively.
Collapse
Affiliation(s)
- Andrea Siebenhofer
- Institute of General Practice and Evidence-Based Health Services Research, Medical University of Graz, Graz, Austria
- Institute for General Practice, Goethe University, Frankfurt am Main, Germany
| | - Sebastian Winterholer
- Institute of General Practice and Evidence-Based Health Services Research, Medical University of Graz, Graz, Austria
| | - Klaus Jeitler
- Institute of General Practice and Evidence-Based Health Services Research, Medical University of Graz, Graz, Austria
- Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
| | - Karl Horvath
- Institute of General Practice and Evidence-Based Health Services Research, Medical University of Graz, Graz, Austria
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria
| | - Andrea Berghold
- Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
| | - Cornelia Krenn
- Institute of General Practice and Evidence-Based Health Services Research, Medical University of Graz, Graz, Austria
| | - Thomas Semlitsch
- Institute of General Practice and Evidence-Based Health Services Research, Medical University of Graz, Graz, Austria
| |
Collapse
|
|
28
|
Hanachi R, Ben Said R, Allal H, Rahali S, Alkhalifah MAM, Alresheedi F, Tangour B, Hochlaf M. Structural, QSAR, machine learning and molecular docking studies of 5-thiophen-2-yl pyrazole derivatives as potent and selective cannabinoid-1 receptor antagonists. NEW J CHEM 2021. [DOI: 10.1039/d1nj02261j] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
We performed a structural study followed by theoretical analysis of the chemical descriptors and biological activity of a series of 5-thiophen-2-yl pyrazole derivatives as potent and selective cannabinoid-1 (CB1) receptor antagonists.
Collapse
Affiliation(s)
- Riadh Hanachi
- Laboratoire de Caractérisations, Applications et Modélisations des Matériaux, Faculté des Sciences de Tunis, Université Tunis El Manar, Tunis, Tunisia
| | - Ridha Ben Said
- Laboratoire de Caractérisations, Applications et Modélisations des Matériaux, Faculté des Sciences de Tunis, Université Tunis El Manar, Tunis, Tunisia
- Department of Chemistry, College of Science and Arts, Qassim University, ArRass, Saudi Arabia
| | - Hamza Allal
- Department of Technology, Faculty of Technology, 20 August 1955 University of Skikda, P.O. Box 26, El Hadaik Road, 21000 Skikda, Algeria
- Research Unit of Environmental Chemistry and Molecular Structural (CHEMS), University of Constantine-1, 25000, Constantine, Algeria
| | - Seyfeddine Rahali
- Department of Chemistry, College of Science and Arts, Qassim University, ArRass, Saudi Arabia
- Research Unit of Modelization on Fundamental Sciences and Didactics. Universitéde Tunis El Manar, Tunis 2092, Tunisia
| | | | - Faisal Alresheedi
- Department of Physics, College of Science, Qassim University, Buraidah 51452, Saudi Arabia
| | - Bahoueddine Tangour
- Research Unit of Modelization on Fundamental Sciences and Didactics. Universitéde Tunis El Manar, Tunis 2092, Tunisia
| | - Majdi Hochlaf
- Université Gustave Eiffel, COSYS/LISIS, 5 Bd Descartes, 77454, Champs sur Marne, France
| |
Collapse
|
|
29
|
Boswell RG, Potenza MN, Grilo CM. The Neurobiology of Binge-eating Disorder Compared with Obesity: Implications for Differential Therapeutics. Clin Ther 2021; 43:50-69. [PMID: 33257092 PMCID: PMC7902428 DOI: 10.1016/j.clinthera.2020.10.014] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 10/30/2020] [Accepted: 10/30/2020] [Indexed: 12/13/2022]
Abstract
PURPOSE Emerging work indicates divergence in the neurobiologies of binge-eating disorder (BED) and obesity despite their frequent co-occurrence. This review highlights specific distinguishing aspects of BED, including elevated impulsivity and compulsivity possibly involving the mesocorticolimbic dopamine system, and discusses implications for differential therapeutics for BED. METHODS This narrative review describes epidemiologic, clinical, genetic, and preclinical differences between BED and obesity. Subsequently, this review discusses human neuroimaging work reporting differences in executive functioning, reward processing, and emotion reactivity in BED compared with obesity. Finally, on the basis of the neurobiology of BED, this review identifies existing and new therapeutic agents that may be most promising given their specific targets based on putative mechanisms of action relevant specifically to BED. FINDINGS BED is characterized by elevated impulsivity and compulsivity compared with obesity, which is reflected in divergent neurobiological characteristics and effective pharmacotherapies. Therapeutic agents that influence both reward and executive function systems may be especially effective for BED. IMPLICATIONS Greater attention to impulsivity/compulsivity-related, reward-related, and emotion reactivity-related processes may enhance conceptualization and treatment approaches for patients with BED. Consideration of these distinguishing characteristics and processes could have implications for more targeted pharmacologic treatment research and interventions.
Collapse
Affiliation(s)
- Rebecca G Boswell
- Yale School of Medicine, Department of Psychiatry, New Haven, CT, USA.
| | - Marc N Potenza
- Yale School of Medicine, Department of Psychiatry, New Haven, CT, USA; Connecticut Mental Health Center, New Haven, CT, USA; Connecticut Council on Problem Gambling, Wethersfield, CT, USA; Yale School of Medicine, Child Study Center, New Haven, CT, USA; Yale University, Department of Neuroscience, New Haven, CT, USA
| | - Carlos M Grilo
- Yale School of Medicine, Department of Psychiatry, New Haven, CT, USA; Yale University, Department of Psychology, New Haven, CT, USA
| |
Collapse
|
|
30
|
Jorgačević B, Vučević D, Samardžić J, Mladenović D, Vesković M, Vukićević D, Ješić R, Radosavljević T. The Effect of CB1 Antagonism on Hepatic Oxidative/Nitrosative Stress and Inflammation in Nonalcoholic Fatty Liver Disease. Curr Med Chem 2021; 28:169-180. [PMID: 32124686 DOI: 10.2174/0929867327666200303122734] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 10/17/2019] [Accepted: 01/25/2020] [Indexed: 02/08/2023]
Abstract
Dysfunction of the endocannabinoid system (ES) has been identified in nonalcoholic fatty liver disease (NAFLD) and associated metabolic disorders. Cannabinoid receptor type 1 (CB1) expression is largely dependent on nutritional status. Thus, individuals suffering from NAFLD and metabolic syndrome (MS) have a significant increase in ES activity. Furthermore, oxidative/ nitrosative stress and inflammatory process modulation in the liver are highly influenced by the ES. Numerous experimental studies indicate that oxidative and nitrosative stress in the liver is associated with steatosis and portal inflammation during NAFLD. On the other hand, inflammation itself may also contribute to reactive oxygen species (ROS) production due to Kupffer cell activation and increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The pathways by which endocannabinoids and their lipid-related mediators modulate oxidative stress and lipid peroxidation represent a significant area of research that could yield novel pharmaceutical strategies for the treatment of NAFLD. Cumulative evidence suggested that the ES, particularly CB1 receptors, may also play a role in inflammation and disease progression toward steatohepatitis. Pharmacological inactivation of CB1 receptors in NAFLD exerts multiple beneficial effects, particularly due to the attenuation of hepatic oxidative/nitrosative stress parameters and significant reduction of proinflammatory cytokine production. However, further investigations regarding precise mechanisms by which CB1 blockade influences the reduction of hepatic oxidative/nitrosative stress and inflammation are required before moving toward the clinical phase of the investigation.
Collapse
Affiliation(s)
- Bojan Jorgačević
- Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Danijela Vučević
- Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Janko Samardžić
- Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Dušan Mladenović
- Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Milena Vesković
- Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Dušan Vukićević
- Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Rada Ješić
- Institute of Digestive Diseases, Clinical Centre of Serbia, 11000 Belgrade, Serbia
| | - Tatjana Radosavljević
- Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| |
Collapse
|
|
31
|
Chen X, Huang W, Wei D, Ding DG, Jiao Y, Pan HL, Jin YT, Zheng YW, Zhang YJ, Zhang YR, Liu YR, Zhou ZY. Clinical effect of catgut implantation at acupoints for the treatment of simple obesity: A multicentre randomized controlled trial. Medicine (Baltimore) 2020; 99:e23390. [PMID: 33235115 PMCID: PMC7710253 DOI: 10.1097/md.0000000000023390] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 10/29/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Catgut implantation at acupoints (CIA) is a subtype of acupuncture that has been widely used to treat simple obesity, but evidence for its effectiveness remains scarce. The aim of this study is to evaluate the efficacy and safety of treating simple obesity with CIA. OBJECTIVE This clinical trial aims to evaluate the effectiveness and safety of CIA used for treatment of simple obesity. METHODS This is a multicentre, randomized, parallel, sham-controlled clinical trial. A total of 216 patients with simple obesity will be recruited. They will be randomly assigned in a 1:1 ratio to either the CIA group or the sham control group. All treatments will be given once every 2 weeks. The primary outcome measure is the rate of waistline reduction. Secondary outcome measures are the rates of reduction of body measurements, including weight, body mass index (BMI), hipline, waist-hip-ratio (WHR) and body fat percentage (BFP), the changes in scores on scales, including the Impact of Weight on Quality of Life Questionnaire (IWQOL-Lite), Short Form 36 (SF-36), the Hospital Anxiety and Depression Scale (HAD) and the Self-Esteem Scale (SES), Outcomes will be evaluated at baseline and at weeks 4, 8, 12, 16, 28, and 40, respectively. All adverse events that occur during this study will be recorded. If any participant withdraws from the trial, an intention-to-treat analysis (ITT) will be performed. CONCLUSION This is a randomized, sham-controlled trial of CIA treatment for simple obesity. The results of this trial will provide more evidence on whether CIA is efficacious and safe for treating obesity. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02936973. Registered on October 18, 2016.
Collapse
Affiliation(s)
- Xia Chen
- Department of Acupuncture, Hubei Provincial Hospital of Traditional Chinese Medicine
- Hubei Province Academy of Traditional Chinese Medicine
| | - Wei Huang
- Department of Acupuncture, Hubei Provincial Hospital of Traditional Chinese Medicine
- Hubei Province Academy of Traditional Chinese Medicine
- Hubei University of Chinese Medicine/The Co-innovation Center for Preventive Treatment of Disease of Acupuncture-moxibustion in Hubei Province, Wuhan, China
| | - Dan Wei
- Department of Acupuncture, Hubei Provincial Hospital of Traditional Chinese Medicine
- Hubei Province Academy of Traditional Chinese Medicine
| | - De-Guang Ding
- Department of Acupuncture, Hubei Provincial Hospital of Traditional Chinese Medicine
- Hubei Province Academy of Traditional Chinese Medicine
| | - Yang Jiao
- Department of Acupuncture, Hubei Provincial Hospital of Traditional Chinese Medicine
- Hubei Province Academy of Traditional Chinese Medicine
| | - Hong-Ling Pan
- Department of Acupuncture, Hubei Provincial Hospital of Traditional Chinese Medicine
- Hubei Province Academy of Traditional Chinese Medicine
| | - Yi-Ting Jin
- Hubei University of Chinese Medicine/The Co-innovation Center for Preventive Treatment of Disease of Acupuncture-moxibustion in Hubei Province, Wuhan, China
| | - Yi-Wei Zheng
- Department of Acupuncture, Hubei Provincial Hospital of Traditional Chinese Medicine
- Hubei Province Academy of Traditional Chinese Medicine
| | - Yan-Ji Zhang
- Hubei University of Chinese Medicine/The Co-innovation Center for Preventive Treatment of Disease of Acupuncture-moxibustion in Hubei Province, Wuhan, China
| | - Ying-Rong Zhang
- Hubei University of Chinese Medicine/The Co-innovation Center for Preventive Treatment of Disease of Acupuncture-moxibustion in Hubei Province, Wuhan, China
| | - Yi-Ran Liu
- Department of Acupuncture, Hubei Provincial Hospital of Traditional Chinese Medicine
- Hubei Province Academy of Traditional Chinese Medicine
| | - Zhong-Yu Zhou
- Department of Acupuncture, Hubei Provincial Hospital of Traditional Chinese Medicine
- Hubei Province Academy of Traditional Chinese Medicine
| |
Collapse
|
|
32
|
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.
Collapse
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.
| |
Collapse
|
|
33
|
Suraev AS, Marshall NS, Vandrey R, McCartney D, Benson MJ, McGregor IS, Grunstein RR, Hoyos CM. Cannabinoid therapies in the management of sleep disorders: A systematic review of preclinical and clinical studies. Sleep Med Rev 2020; 53:101339. [DOI: 10.1016/j.smrv.2020.101339] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 04/13/2020] [Accepted: 04/14/2020] [Indexed: 12/21/2022]
|
|
34
|
Castonguay-Paradis S, Lacroix S, Rochefort G, Parent L, Perron J, Martin C, Lamarche B, Raymond F, Flamand N, Di Marzo V, Veilleux A. Dietary fatty acid intake and gut microbiota determine circulating endocannabinoidome signaling beyond the effect of body fat. Sci Rep 2020; 10:15975. [PMID: 32994521 PMCID: PMC7524791 DOI: 10.1038/s41598-020-72861-3] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 08/27/2020] [Indexed: 02/08/2023] Open
Abstract
The endocannabinoidome encompasses several fatty acid (FA)-derived mediators, including the endocannabinoid anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), which served as targets for anti-obesity drug development, and their congener N-acyl-ethanolamines (NAEs) and 2-monoacyl-glycerols (2‑MAGs), which are involved in food intake and energy metabolism. Body weight and fat distribution have been suggested as determinants of peripheral endocannabinoid levels. We aimed at investigating factors, beyond body fat composition, that are associated with circulating NAE and 2-MAG levels in a heterogeneous human population. Plasma NAEs and 2-MAGs were measured using LC–MS/MS in a cross-sectional sample of healthy men and women (n = 195) covering a wide range of BMI and individuals before and after a 2-day Mediterranean diet (n = 21). Circulating levels of all 2-MAGs and NAEs, other than N-oleoyl-ethanolamine (OEA), correlated with body fat mass and visceral adipose tissue (0.26 < r < 0.54). NAE levels were elevated in individuals with elevated fat mass, while 2-MAGs were increased in individuals with predominantly visceral body fat distribution. Dietary intakes of specific FAs were associated with 2-AG and omega-3-FA-derived NAEs or 2-MAGs, irrespective of the body fat distribution. Some gut bacterial families (e.g. Veillonellaceae, Peptostreptococcaceae and Akkermansiaceae) were associated with variations in most NAEs or omega-3-FA-derived 2‑MAGs, independently of fat mass and dietary FA intake. Finally, a 2-day Mediterranean diet intervention increased circulating levels of NAEs and 2-MAGs in agreement with changes in FA intake (p < 0.01). Self-reported intake and short-term dietary intervention increased in oleic acid and EPA and DHA intake as well as certain gut microbiota taxa are associated to circulating NAEs and 2‑MAGs independently of adiposity measures, thus highlighting the potential importance of these variables in determining endocannabinoidome signaling in humans.
Collapse
Affiliation(s)
- Sophie Castonguay-Paradis
- Centre Nutrition, Santé et Société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, 2440, boulevard Hochelaga, Québec, QC, G1V 0A6, Canada.,École de nutrition, Faculté des sciences de l'agriculture et de l'alimentation (FSAA), Université Laval, Québec, QC, Canada.,Canada Research Excellence Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec, QC, Canada
| | - Sébastien Lacroix
- Centre Nutrition, Santé et Société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, 2440, boulevard Hochelaga, Québec, QC, G1V 0A6, Canada.,Canada Research Excellence Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec, QC, Canada
| | - Gabrielle Rochefort
- Centre Nutrition, Santé et Société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, 2440, boulevard Hochelaga, Québec, QC, G1V 0A6, Canada.,École de nutrition, Faculté des sciences de l'agriculture et de l'alimentation (FSAA), Université Laval, Québec, QC, Canada.,Canada Research Excellence Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec, QC, Canada
| | - Lydiane Parent
- École de nutrition, Faculté des sciences de l'agriculture et de l'alimentation (FSAA), Université Laval, Québec, QC, Canada.,Canada Research Excellence Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec, QC, Canada
| | - Julie Perron
- Centre Nutrition, Santé et Société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, 2440, boulevard Hochelaga, Québec, QC, G1V 0A6, Canada.,Canada Research Excellence Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec, QC, Canada
| | - Cyril Martin
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ), Université Laval, Québec, QC, Canada.,Canada Research Excellence Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec, QC, Canada
| | - Benoît Lamarche
- Centre Nutrition, Santé et Société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, 2440, boulevard Hochelaga, Québec, QC, G1V 0A6, Canada.,École de nutrition, Faculté des sciences de l'agriculture et de l'alimentation (FSAA), Université Laval, Québec, QC, Canada
| | - Frédéric Raymond
- Centre Nutrition, Santé et Société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, 2440, boulevard Hochelaga, Québec, QC, G1V 0A6, Canada.,École de nutrition, Faculté des sciences de l'agriculture et de l'alimentation (FSAA), Université Laval, Québec, QC, Canada.,Canada Research Excellence Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec, QC, Canada
| | - Nicolas Flamand
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ), Université Laval, Québec, QC, Canada.,Département de médecine, Faculté de Médecine, Université Laval, Québec, QC, Canada.,Canada Research Excellence Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec, QC, Canada
| | - Vincenzo Di Marzo
- Centre Nutrition, Santé et Société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, 2440, boulevard Hochelaga, Québec, QC, G1V 0A6, Canada.,Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ), Université Laval, Québec, QC, Canada.,École de nutrition, Faculté des sciences de l'agriculture et de l'alimentation (FSAA), Université Laval, Québec, QC, Canada.,Département de médecine, Faculté de Médecine, Université Laval, Québec, QC, Canada.,Joint International Unit on Chemical and Biomolecular Research on the Microbiome and Its Impact on Metabolic Health and Nutrition (UMI-MicroMeNu), Pozzuoli, Italy.,Canada Research Excellence Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec, QC, Canada
| | - Alain Veilleux
- Centre Nutrition, Santé et Société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, 2440, boulevard Hochelaga, Québec, QC, G1V 0A6, Canada. .,École de nutrition, Faculté des sciences de l'agriculture et de l'alimentation (FSAA), Université Laval, Québec, QC, Canada. .,Canada Research Excellence Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec, QC, Canada.
| |
Collapse
|
|
35
|
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.
Collapse
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
| |
Collapse
|
|
36
|
Effects of a High-Protein Diet on Cardiometabolic Health, Vascular Function, and Endocannabinoids-A PREVIEW Study. Nutrients 2020; 12:nu12051512. [PMID: 32455987 PMCID: PMC7284520 DOI: 10.3390/nu12051512] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 05/11/2020] [Accepted: 05/20/2020] [Indexed: 12/11/2022] Open
Abstract
An unfavorable lipid profile and being overweight are known mediators in the development of cardiovascular disease (CVD) risk. The effect of diet, particularly high in protein, remains under discussion. Therefore, this study examines the effects of a high-protein (HP) diet on cardiometabolic health and vascular function (i.e., endothelial function, arterial stiffness, and retinal microvascular structure), and the possible association with plasma endocannabinoids and endocannabinoid-related compounds in overweight participants. Thirty-eight participants (64.5 ± 5.9 (mean ± SD) years; body mass index (BMI) 28.9 ± 4.0 kg/m2) were measured for 48 h in a respiration chamber after body-weight maintenance for approximately 34 months following weight reduction. Diets with either a HP (n = 20) or moderate protein (MP; n = 18) content (25%/45%/30% vs. 15%/55%/30% protein/carbohydrate/fat) were provided in energy balance. Validated markers for cardiometabolic health (i.e., office blood pressure (BP) and serum lipoprotein concentrations) and vascular function (i.e., brachial artery flow-mediated vasodilation, pulse wave analysis and velocity, and retinal microvascular calibers) were measured before and after those 48 h. Additionally, 24 h ambulatory BP, plasma anandamide (AEA), 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and pregnenolone (PREG) were analyzed throughout the day. Office and ambulatory BP, serum lipoprotein concentrations, and vascular function markers were not different between the groups. Only heart rate (HR) was higher in the HP group. HR was positively associated with OEA, while OEA and PEA were also positively associated with total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol concentrations. Vascular function markers were not associated with endocannabinoids (or endocannabinoid-related substances). In conclusion, the HP diet did not affect cardiometabolic health and vascular function in overweight participants after completing a weight-loss intervention. Furthermore, our data indicate a possible association between OEA and PEA with TC and LDL cholesterol.
Collapse
|
|
37
|
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.
Collapse
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.
| |
Collapse
|
|
38
|
Stasiulewicz A, Znajdek K, Grudzień M, Pawiński T, Sulkowska JI. A Guide to Targeting the Endocannabinoid System in Drug Design. Int J Mol Sci 2020; 21:ijms21082778. [PMID: 32316328 PMCID: PMC7216112 DOI: 10.3390/ijms21082778] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 04/07/2020] [Accepted: 04/14/2020] [Indexed: 12/11/2022] Open
Abstract
The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and proliferation. Thus, ECS proteins, including cannabinoid receptors and their endogenous ligands’ synthesizing and degrading enzymes, are promising therapeutic targets. Their modulation has been employed in or extensively studied as a treatment of multiple diseases. However, due to a complex nature of ECS and its crosstalk with other biological systems, the development of novel drugs turned out to be a challenging task. In this review, we summarize potential therapeutic applications for ECS-targeting drugs, especially focusing on promising synthetic compounds and preclinical studies. We put emphasis on modulation of specific proteins of ECS in different pathophysiological areas. In addition, we stress possible difficulties and risks and highlight proposed solutions. By presenting this review, we point out information pivotal in the spotlight of ECS-targeting drug design, as well as provide an overview of the current state of knowledge on ECS-related pharmacodynamics and show possible directions for needed research.
Collapse
Affiliation(s)
- Adam Stasiulewicz
- Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland; (M.G.); (T.P.)
- Interdisciplinary Laboratory of Biological Systems Modelling, Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, Poland;
- Correspondence: (A.S.); (J.I.S.)
| | - Katarzyna Znajdek
- Interdisciplinary Laboratory of Biological Systems Modelling, Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, Poland;
- Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
| | - Monika Grudzień
- Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland; (M.G.); (T.P.)
| | - Tomasz Pawiński
- Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland; (M.G.); (T.P.)
| | - Joanna I. Sulkowska
- Interdisciplinary Laboratory of Biological Systems Modelling, Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, Poland;
- Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
- Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125, USA
- Correspondence: (A.S.); (J.I.S.)
| |
Collapse
|
|
39
|
Nava-Molina L, Uchida-Fuentes T, Ramos-Tovar H, Fregoso-Padilla M, Rodríguez-Monroy MA, Vega AV, Navarrete-Vázquez G, Andrade-Jorge E, Villalobos-Molina R, Ortiz-Ortega R, Vilches-Flores A. Novel CB1 receptor antagonist BAR-1 modifies pancreatic islet function and clinical parameters in prediabetic and diabetic mice. Nutr Diabetes 2020; 10:7. [PMID: 32132523 PMCID: PMC7055595 DOI: 10.1038/s41387-020-0110-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 01/02/2020] [Accepted: 01/16/2020] [Indexed: 01/24/2023] Open
Abstract
BACKGROUDS Cannabinoid receptor antagonists have been suggested as a novel treatment for obesity and diabetes. We have developed a synthetic cannabinoid receptor antagonist denominated BAR-1. As the function and integrity of a β-cell cellular structure are important keys for diabetes onset, we evaluated the effects of pharmacological administration of BAR-1 on prediabetic and diabetic rodents. METHODS CD-1 mice fed a hypercaloric diet or treated with streptozotocin were treated with 10 mg/kg BAR-1 for 2, 4 or 8 weeks. Body weight, oral glucose tolerance test, HbA1c, triglycerides and insulin in serum were measured. In isolated islets, we evaluated stimulated secretion and mRNA expression, and relative area of islets in fixed pancreases. Docking analysis of BAR-1 was complemented. RESULTS BAR-1 treatment slowed down weight gain in prediabetic mice. Fasting glucose-insulin relation also decreased in BAR-1-treated mice and glucose-stimulated insulin secretion was increased in isolated islets, without effects in oral test. Diabetic mice treated with BAR-1 showed a reduced glucose and a partial recovery of islet integrity. Gene expression of insulin and glucagon showed biphasic behaviour, increasing after 4 weeks of BAR-1 administration; however, after 8 weeks, mRNA abundance decreased significantly. Administration of BAR-1 also prevents changes in endocannabinoid element expression observed in prediabetic mice. No changes were detected in other parameters studied, including the histological structure. A preliminary in-silico study suggests a close interaction with CB1 receptor. CONCLUSIONS BAR-1 induces improvement of islet function, isolated from both prediabetic and diabetic mice. Effects of BAR-1 suggest a possible interaction with other cannabinoid receptors.
Collapse
Affiliation(s)
- Lesly Nava-Molina
- Unidad de Biomedicina, FES Iztacala, Universidad Nacional Autónoma de México. Av. de Los Barrios 1, Los Reyes Iztacala, C.P., 54090, Tlalnepantla, Mexico
| | - Toyokazu Uchida-Fuentes
- Unidad de Biomedicina, FES Iztacala, Universidad Nacional Autónoma de México. Av. de Los Barrios 1, Los Reyes Iztacala, C.P., 54090, Tlalnepantla, Mexico
| | - Héctor Ramos-Tovar
- Unidad de Biomedicina, FES Iztacala, Universidad Nacional Autónoma de México. Av. de Los Barrios 1, Los Reyes Iztacala, C.P., 54090, Tlalnepantla, Mexico
| | - Martha Fregoso-Padilla
- Unidad de Biomedicina, FES Iztacala, Universidad Nacional Autónoma de México. Av. de Los Barrios 1, Los Reyes Iztacala, C.P., 54090, Tlalnepantla, Mexico
| | - Marco Aurelio Rodríguez-Monroy
- Unidad de Biomedicina, FES Iztacala, Universidad Nacional Autónoma de México. Av. de Los Barrios 1, Los Reyes Iztacala, C.P., 54090, Tlalnepantla, Mexico
| | - Ana V Vega
- Unidad de Biomedicina, FES Iztacala, Universidad Nacional Autónoma de México. Av. de Los Barrios 1, Los Reyes Iztacala, C.P., 54090, Tlalnepantla, Mexico
| | - Gabriel Navarrete-Vázquez
- Facultad de Farmacia, Universidad Autónoma del Estado de Morelos. Av. Universidad 1001, Chamilpa, C.P., 62209, Cuernavaca, Morelos, Mexico
| | - Erik Andrade-Jorge
- Unidad de Biomedicina, FES Iztacala, Universidad Nacional Autónoma de México. Av. de Los Barrios 1, Los Reyes Iztacala, C.P., 54090, Tlalnepantla, Mexico
| | - Rafael Villalobos-Molina
- Unidad de Biomedicina, FES Iztacala, Universidad Nacional Autónoma de México. Av. de Los Barrios 1, Los Reyes Iztacala, C.P., 54090, Tlalnepantla, Mexico
| | - Ricardo Ortiz-Ortega
- Unidad de Biomedicina, FES Iztacala, Universidad Nacional Autónoma de México. Av. de Los Barrios 1, Los Reyes Iztacala, C.P., 54090, Tlalnepantla, Mexico
| | - Alonso Vilches-Flores
- Unidad de Biomedicina, FES Iztacala, Universidad Nacional Autónoma de México. Av. de Los Barrios 1, Los Reyes Iztacala, C.P., 54090, Tlalnepantla, Mexico.
| |
Collapse
|
|
40
|
Hanlon EC, Leproult R, Stuhr KL, Doncheck EM, Hillard CJ, Van Cauter E. Circadian Misalignment of the 24-hour Profile of Endocannabinoid 2-Arachidonoylglycerol (2-AG) in Obese Adults. J Clin Endocrinol Metab 2020; 105:5714353. [PMID: 31970413 PMCID: PMC7015463 DOI: 10.1210/clinem/dgaa028] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 01/20/2020] [Indexed: 01/18/2023]
Abstract
CONTEXT The endocannabinoid (eCB) system partly controls hedonic eating, a major cause of obesity. While some studies suggested an overactivation of the eCB system in obesity, peripheral levels of eCBs across the 24-hour cycle have not been characterized in obese individuals despite the fact that in lean adults, levels of the eCB 2-arachidonoylglycerol (2-AG) vary across the day. OBJECTIVE We sought to examine 24-hour profiles of serum concentrations of 2-AG in healthy obese and nonobese adults, under well-controlled laboratory conditions. We also simultaneously assessed 24-hour profiles of 2-oleoylglycerol (2-OG), leptin, and cortisol in each participant. DESIGN With fixed light-dark and sleep-wake cycles, blood sampling was performed over an entire 24-hour period, including identical meals at 0900, 1400, and 1900. PARTICIPANTS Twelve obese (8 women, mean body mass index [BMI]: 39.1 kg/m2) and 15 nonobese (6 women; mean BMI: 23.6 kg/m2) healthy adults were studied. RESULTS We observed a 24-hour variation of 2-AG levels in obese individuals but, relative to nonobese adults, the amplitude was dampened and the timings of the nadir and peak were delayed by 4 to 5 hours. The profile of 2-OG was similarly misaligned. In contrast, when expressed relative to the 24-hour mean level, the 24-hour rhythm of cortisol and leptin were similar in obese and nonobese participants. CONCLUSIONS Obesity appears to be associated with a dampening and delay of the 24-hour variation of eCB activity relative to the central circadian signal as well as to the daily leptin rhythm. This misalignment may play a role in the pathophysiology of obesity.
Collapse
Affiliation(s)
- Erin C Hanlon
- Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, Illinois
- Correspondence and Reprint Requests: Erin C. Hanlon, PhD, University of Chicago. Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, 5841 S. Maryland Ave, MC 1027, Chicago, Illinois 60637, Tel 773 834 5849. E-mail:
| | - Rachel Leproult
- Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, Illinois
| | - Kara L Stuhr
- Department of Pharmacology and Toxicology, Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Elizabeth M Doncheck
- Department of Pharmacology and Toxicology, Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Cecilia J Hillard
- Department of Pharmacology and Toxicology, Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Eve Van Cauter
- Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, Illinois
| |
Collapse
|
|
41
|
Hanlon EC. Impact of circadian rhythmicity and sleep restriction on circulating endocannabinoid (eCB) N-arachidonoylethanolamine (anandamide). Psychoneuroendocrinology 2020; 111:104471. [PMID: 31610409 PMCID: PMC7001881 DOI: 10.1016/j.psyneuen.2019.104471] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 09/26/2019] [Accepted: 10/01/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The endocannabinoid (eCB) system is involved in diverse aspects of human physiology and behavior but little is known about the impact of circadian rhythmicity on the system. The two most studied endocannabinoids, AEA (ananamide) and 2-AG (2-arachidonoylglycerol), can be measured in peripheral blood however the functional relevance of peripheral eCB levels is not clear. Having previously detailed the 24-h profile of serum 2-AG, here we report the 24-h serum profile of AEA to determine if these two endocannabinoids vary in parallel across the biological day including a nocturnal 8.5-h sleep period. Further, we assessed and compared the effect of a physiological challenge, in the form of sleep restriction to 4.5-h, on these two profiles. METHODS In this randomized crossover study, we examined serum concentrations of AEA across a 24-h period in fourteen young adults. Congeners of AEA, the structural analogs oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were simultaneously assayed. Prior to 24-h blood sampling, each participant was exposed to two nights of normal (8.5 h) or restricted sleep (4.5 h). The two sleep conditions were separated by at least one month. In both sleep conditions, during the period of blood sampling, each individual ate the same high-carbohydrate meal at 0900, 1400, and 1900. RESULTS Mean 24-h concentrations of AEA were 0.697 ± 0.11 pmol/ml. A reproducible biphasic 24-h profile of AEA was observed with a first peak occurring during early sleep (0200) and a second peak in the mid-afternoon (1500) while a nadir was detected in the mid-morning (1000). The 24-h profiles for both OEA and PEA followed a similar pattern to that observed for AEA. AEA, OEA, and PEA levels were not affected by sleep restriction at any time of day, contrasting with the elevation of early afternoon levels previously observed for 2-AG. CONCLUSIONS The 24-h rhythm of AEA is markedly different from that of 2-AG, being of lesser amplitude and biphasic, rather than monophasic. These observations suggest distinct regulatory pathways of the two eCB and indicate that time of day needs to be carefully controlled in studies attempting to delineate their relative roles. Moreover, unlike 2-AG, AEA is not altered by sleep restriction, suggesting that physiological perturbations may affect AEA and 2-AG differently. Similar 24-h profiles were observed for OEA and PEA following normal and restricted sleep, further corroborating the validity of the wave-shape and lack of response to sleep loss observed for the AEA profile. Therapeutic approaches involving agonism or antagonism of peripheral eCB signaling will likely need to be tailored according to time of day.
Collapse
Affiliation(s)
- Erin C Hanlon
- University of Chicago, Department of Medicine, MC 1027, Section of Endocrinology, Diabetes, and Metabolism, 5841 S Maryland Ave, Chicago, IL 60637, United States.
| |
Collapse
|
|
42
|
Wnt signaling mediates TLR pathway and promote unrestrained adipogenesis and metaflammation: Therapeutic targets for obesity and type 2 diabetes. Pharmacol Res 2019; 152:104602. [PMID: 31846761 DOI: 10.1016/j.phrs.2019.104602] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 11/17/2019] [Accepted: 12/13/2019] [Indexed: 12/11/2022]
Abstract
Diabesity is the combination of type 2 diabetes and obesity characterized by chronic low-grade inflammation. The Wnt signaling act as an evolutionary pathway playing crucial role in regulating cellular homeostasis and energy balance from hypothalamus to metabolic organs. Aberrant activity of certain appendages in the canonical and non-canonical Wnt system deregulates metabolism and leads to adipose tissue expansion, this key event initiates metabolic stress causing metaflammation and obesity. Metaflammation induced obesity initiates abnormal development of adipocytes mediating through the non-canonical Wnt signaling inhibition of canonical Wnt pathway to fan the flames of adipogenesis. Moreover, activation of toll like receptor (TLR)-4 signaling in metabolic stress invites immune cells to release pro-inflammatory cytokines for recruitment of macrophages in adipose tissues, further causes polarization of macrophages into M1(classically activated) and M2 (alternatively activated) subtypes. These events end with chronic low-grade inflammation which interferes with insulin signaling in metabolic tissues to develop type 2 diabetes. However, there is a dearth in understanding the exact mechanism of Wnt-TLR axis during diabesity. This review dissects the molecular facets of Wnt and TLRs that modulates cellular components during diabesity and provides current progress, challenges and alternative therapeutic strategies at preclinical and clinical level.
Collapse
|
|
43
|
Veilleux A, Di Marzo V, Silvestri C. The Expanded Endocannabinoid System/Endocannabinoidome as a Potential Target for Treating Diabetes Mellitus. Curr Diab Rep 2019; 19:117. [PMID: 31686231 DOI: 10.1007/s11892-019-1248-9] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE OF REVIEW The endocannabinoid (eCB) system, i.e. the receptors that respond to the psychoactive component of cannabis, their endogenous ligands and the ligand metabolic enzymes, is part of a larger family of lipid signals termed the endocannabinoidome (eCBome). We summarize recent discoveries of the roles that the eCBome plays within peripheral tissues in diabetes, and how it is being targeted, in an effort to develop novel therapeutics for the treatment of this increasingly prevalent disease. RECENT FINDINGS As with the eCB system, many eCBome members regulate several physiological processes, including energy intake and storage, glucose and lipid metabolism and pancreatic health, which contribute to the development of type 2 diabetes (T2D). Preclinical studies increasingly support the notion that targeting the eCBome may beneficially affect T2D. The eCBome is implicated in T2D at several levels and in a variety of tissues, making this complex lipid signaling system a potential source of many potential therapeutics for the treatments for T2D.
Collapse
Affiliation(s)
- Alain Veilleux
- École de nutrition, Université Laval, Québec, QC, Canada
- Institut sur la nutrition et les aliments fonctionnels, Université Laval, Québec, QC, Canada
- Canadian Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Québec, Canada
| | - Vincenzo Di Marzo
- École de nutrition, Université Laval, Québec, QC, Canada
- Institut sur la nutrition et les aliments fonctionnels, Université Laval, Québec, QC, Canada
- Canadian Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Québec, Canada
- Institut de cardiologie et de pneumologie de Québec, Université Laval, Québec, QC, Canada
- Department de médecine, Université Laval, Québec, QC, Canada
| | - Cristoforo Silvestri
- Canadian Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Québec, Canada.
- Institut de cardiologie et de pneumologie de Québec, Université Laval, Québec, QC, Canada.
- Department de médecine, Université Laval, Québec, QC, Canada.
| |
Collapse
|
|
44
|
Nguyen T, Thomas BF, Zhang Y. Overcoming the Psychiatric Side Effects of the Cannabinoid CB1 Receptor Antagonists: Current Approaches for Therapeutics Development. Curr Top Med Chem 2019; 19:1418-1435. [PMID: 31284863 DOI: 10.2174/1568026619666190708164841] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 11/08/2018] [Accepted: 11/15/2018] [Indexed: 12/11/2022]
Abstract
The Cannabinoid CB1 Receptor (CB1R) is involved in a variety of physiological pathways and has long been considered a golden target for therapeutic manipulation. A large body of evidence in both animal and human studies suggests that CB1R antagonism is highly effective for the treatment of obesity, metabolic disorders and drug addiction. However, the first-in-class CB1R antagonist/inverse agonist, rimonabant, though demonstrating effectiveness for obesity treatment and smoking cessation, displays serious psychiatric side effects, including anxiety, depression and even suicidal ideation, resulting in its eventual withdrawal from the European market. Several strategies are currently being pursued to circumvent the mechanisms leading to these side effects by developing neutral antagonists, peripherally restricted ligands, and allosteric modulators. In this review, we describe the progress in the development of therapeutics targeting the CB1R in the last two decades.
Collapse
Affiliation(s)
- Thuy Nguyen
- Research Triangle Institute, Research Triangle Park, NC 27709, United States
| | - Brian F Thomas
- Research Triangle Institute, Research Triangle Park, NC 27709, United States
| | - Yanan Zhang
- Research Triangle Institute, Research Triangle Park, NC 27709, United States
| |
Collapse
|
|
45
|
Nguyen T, Gamage TF, Decker AM, Barrus D, Langston TL, Li JX, Thomas BF, Zhang Y. Synthesis and Pharmacological Evaluation of 1-Phenyl-3-Thiophenylurea Derivatives as Cannabinoid Type-1 Receptor Allosteric Modulators. J Med Chem 2019; 62:9806-9823. [PMID: 31596583 DOI: 10.1021/acs.jmedchem.9b01161] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
We previously reported diarylurea derivatives as cannabinoid type-1 receptor (CB1) allosteric modulators, which were effective in attenuating cocaine-seeking behavior. Herein, we extended the structure-activity relationships of PSNCBAM-1 (2) at the central phenyl ring directly connected to the urea moiety. Replacement with a thiophene ring led to 11 with improved or comparable potencies in calcium mobilization, [35S]GTPγS binding, and cAMP assays, whereas substitution with nonaromatic rings led to significant attenuation of the modulatory activity. These compounds had no inverse agonism in [35S]GTPγS binding, a characteristic that is often thought to contribute to adverse psychiatric effects. While 11 had good metabolic stability in rat liver microsomes, it showed modest solubility and blood-brain barrier permeability. Compound 11 showed an insignificant attenuation of cocaine seeking behavior in rats, most likely due to its limited CNS penetration, suggesting that pharmacokinetics and distribution play a role in translating the in vitro efficacy to in vivo behavior.
Collapse
Affiliation(s)
- Thuy Nguyen
- Research Triangle Institute , Research Triangle Park , North Carolina 27709 , United States
| | - Thomas F Gamage
- Research Triangle Institute , Research Triangle Park , North Carolina 27709 , United States
| | - Ann M Decker
- Research Triangle Institute , Research Triangle Park , North Carolina 27709 , United States
| | - Daniel Barrus
- Research Triangle Institute , Research Triangle Park , North Carolina 27709 , United States
| | - Tiffany L Langston
- Research Triangle Institute , Research Triangle Park , North Carolina 27709 , United States
| | - Jun-Xu Li
- Department of Pharmacology and Toxicology , University of Buffalo, the State University of New York , Buffalo , New York 14214 , United States
| | - Brian F Thomas
- Research Triangle Institute , Research Triangle Park , North Carolina 27709 , United States
| | - Yanan Zhang
- Research Triangle Institute , Research Triangle Park , North Carolina 27709 , United States
| |
Collapse
|
|
46
|
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.
Collapse
|
|
47
|
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.
Collapse
|
|
48
|
Vasanth Rao VRB, Candasamy M, Bhattamisra SK. Obesity an overview: Genetic conditions and recent developments in therapeutic interventions. Diabetes Metab Syndr 2019; 13:2112-2120. [PMID: 31235145 DOI: 10.1016/j.dsx.2019.05.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 05/06/2019] [Indexed: 01/22/2023]
Abstract
Obesity is a complex disorder that is linked to many coexisting disorders. Recent epidemiological data have suggested that the prevalence of obesity is at an all-time high, growing to be one of the world's biggest problems. There are several mechanisms on how individuals develop obesity which includes genetic and environmental factors. Not only does obesity contribute to other health issues but it also greatly affects the quality of life, physical ability, mental strength and imposes a huge burden in terms of healthcare costs. Along with that, obesity is associated with the risk of mortality and has been shown to reduce the median survival rate. Obesity is basically when the body is not able to balance energy intake and output. When energy intake exceeds energy expenditure, excess calories will be stored as fat leading to weight gain and eventually obesity. The therapeutic market for treating obesity is composed of many different interventions from lifestyle intervention, surgical procedures to pharmacotherapeutic approaches. All of these interventions have their respective benefits and disadvantages and are specifically prescribed to a patient based on the severity of their obesity as well as the existence of other health conditions. This review discusses the genetic and environmental causes of obesity along with the recent developments in anti-obesity therapies.
Collapse
Affiliation(s)
- Vikram Rao B Vasanth Rao
- School of Postgraduate Studies, International Medical University, No 126, Jalan Jalil Perkasa 19, Jalan Jalil Perkasa 19, Bukit Jalil, 57000, Kuala Lumpur, Malaysia.
| | - Mayuren Candasamy
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Subrat Kumar Bhattamisra
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia.
| |
Collapse
|
|
49
|
Ruiz de Azua I, Lutz B. Multiple endocannabinoid-mediated mechanisms in the regulation of energy homeostasis in brain and peripheral tissues. Cell Mol Life Sci 2019; 76:1341-1363. [PMID: 30599065 PMCID: PMC11105297 DOI: 10.1007/s00018-018-2994-6] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 11/22/2018] [Accepted: 12/10/2018] [Indexed: 02/06/2023]
Abstract
The endocannabinoid (eCB) system is widely expressed in many central and peripheral tissues, and is involved in a plethora of physiological processes. Among these, activity of the eCB system promotes energy intake and storage, which, however, under pathophysiological conditions, can favour the development of obesity and obesity-related disorders. It is proposed that eCB signalling is evolutionary beneficial for survival under periods of scarce food resources. Remarkably, eCB signalling is increased both in hunger and in overnutrition conditions, such as obesity and type-2 diabetes. This apparent paradox suggests a role of the eCB system both at initiation and at clinical endpoint of obesity. This review will focus on recent findings about the role of the eCB system controlling whole-body metabolism in mice that are genetically modified selectively in different cell types. The current data in fact support the notion that eCB signalling is not only engaged in the development but also in the maintenance of obesity, whereby specific cell types in central and peripheral tissues are key sites in regulating the entire body's energy homeostasis.
Collapse
MESH Headings
- Adipose Tissue/metabolism
- Animals
- Brain/metabolism
- Endocannabinoids/metabolism
- Energy Metabolism
- Muscle, Skeletal/metabolism
- Obesity/metabolism
- Obesity/pathology
- Receptor, Cannabinoid, CB1/antagonists & inhibitors
- Receptor, Cannabinoid, CB1/genetics
- Receptor, Cannabinoid, CB1/metabolism
- Receptor, Cannabinoid, CB2/antagonists & inhibitors
- Receptor, Cannabinoid, CB2/genetics
- Receptor, Cannabinoid, CB2/metabolism
Collapse
Affiliation(s)
- Inigo Ruiz de Azua
- German Resilience Center (DRZ) and Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 5, 55128, Mainz, Germany.
| | - Beat Lutz
- German Resilience Center (DRZ) and Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 5, 55128, Mainz, Germany
| |
Collapse
|
|
50
|
Sloan ME, Grant CW, Gowin JL, Ramchandani VA, Le Foll B. Endocannabinoid signaling in psychiatric disorders: a review of positron emission tomography studies. Acta Pharmacol Sin 2019; 40:342-350. [PMID: 30166624 PMCID: PMC6460371 DOI: 10.1038/s41401-018-0081-z] [Citation(s) in RCA: 28] [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: 02/19/2018] [Accepted: 06/18/2018] [Indexed: 12/28/2022]
Abstract
Endocannabinoid signaling is implicated in an array of psychopathologies ranging from anxiety to psychosis and addiction. In recent years, radiotracers targeting the endocannabinoid system have been used in positron emission tomography (PET) studies to determine whether individuals with psychiatric disorders display altered endocannabinoid signaling. We comprehensively reviewed PET studies examining differences in endocannabinoid signaling between individuals with psychiatric illness and healthy controls. Published studies evaluated individuals with five psychiatric disorders: cannabis use disorder, alcohol use disorder, schizophrenia, post-traumatic stress disorder, and eating disorders. Most studies employed radiotracers targeting cannabinoid receptor 1 (CB1). Cannabis users consistently demonstrated decreased CB1 binding compared to controls, with normalization following short periods of abstinence. Findings in those with alcohol use disorder and schizophrenia were less consistent, with some studies demonstrating increased CB1 binding and others demonstrating decreased CB1 binding. Evidence of aberrant CB1 binding was also found in individuals with anorexia nervosa and post-traumatic stress disorder, but limited data have been published to date. Thus, existing evidence suggests that alterations in endocannabinoid signaling are present in a range of psychiatric disorders. Although recent efforts have largely focused on evaluating CB1 binding, the synthesis of new radiotracers targeting enzymes involved in endocannabinoid degradation, such as fatty acid amide hydrolase, will allow for other facets of endocannabinoid signaling to be evaluated in future studies.
Collapse
Affiliation(s)
- Matthew E Sloan
- Section on Human Psychopharmacology, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, 20814, USA
| | - Caroline W Grant
- Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, 20814, USA
| | - Joshua L Gowin
- Section on Human Psychopharmacology, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, 20814, USA
| | - Vijay A Ramchandani
- Section on Human Psychopharmacology, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, 20814, USA
| | - Bernard Le Foll
- Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M5S 2S1, Canada.
- Addiction Medicine Service, Centre for Addiction and Mental Health, Toronto, ON, M6J 1H4, Canada.
- Departments of Family and Community Medicine, Pharmacology and Toxicology, Psychiatry, Institute of Medical Science, University of Toronto, Toronto, ON, M5S 2S1, Canada.
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M6J 1H4, Canada.
| |
Collapse
|