Cannabinoid Receptors in Metabolic Regulation and Diabetes

Physiology ◽  
2021 ◽  
Vol 36 (2) ◽  
pp. 102-113
Author(s):  
Elisabeth Rohbeck ◽  
Juergen Eckel ◽  
Tania Romacho
Keyword(s):  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Cannabinoid Receptors ◽  
Metabolic Diseases ◽  
Therapeutic Targets ◽  
Endocannabinoid System ◽  
Wide Distribution ◽  
Therapeutic Interventions ◽  
Pharmacological Intervention ◽  
The Impact

There is an urgent need for developing effective drugs to combat the obesity and Type 2 diabetes mellitus epidemics. The endocannabinoid system plays a major role in energy homeostasis. It comprises the cannabinoid receptors 1 and 2 (CB1 and CB2), endogenous ligands called endocannabinoids and their metabolizing enzymes. Because the CB1 receptor is overactivated in metabolic alterations, pharmacological blockade of the CB1 receptor arose as a promising candidate to treat obesity. However, because of the wide distribution of CB1 receptors in the central nervous system, their negative central effects halted further therapeutic use. Although the CB2 receptor is mostly peripherally expressed, its role in metabolic homeostasis remains unclear. This review discusses the potential of CB1 and CB2 receptors at the peripheral level to be therapeutic targets in metabolic diseases. We focus on the impact of pharmacological intervention and/or silencing on peripheral cannabinoid receptors in organs/tissues relevant for energy homeostasis. Moreover, we provide a perspective on novel therapeutic strategies modulating these receptors. Targeting CB1 with peripherally restricted antagonists, neutral antagonists, inverse agonists, or monoclonal antibodies could represent successful strategies. CB2 agonism has shown promising results at preclinical level. Beyond classic antagonism and agonism targeting orthosteric sites, the recently described crystal structures of CB1 and CB2 open new possibilities for therapeutic interventions with negative and positive allosteric modulators. The challenge of simultaneously targeting CB1 and CB2 might be possible by developing dual-steric ligands. The future will tell whether these promising strategies result in a renaissance of the cannabinoid receptors as therapeutic targets in metabolic diseases.

Roles of Endocannabinoids and Endocannabinoid-like Molecules in Energy Homeostasis and Metabolic Regulation: A Nutritional Perspective

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
S.M. Khaledur Rahman ◽  
Toru Uyama ◽  
Zahir Hussain ◽  
Natsuo Ueda
Keyword(s):  
Arachidonic Acid ◽  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Cannabinoid Receptors ◽  
Biological Activities ◽  
Endocannabinoid System ◽  
Annual Review ◽  
Publication Date ◽  
Treatment And Prevention ◽  
G Protein Coupled

The endocannabinoid system is involved in signal transduction in mammals. It comprises principally G protein-coupled cannabinoid receptors and their endogenous agonists, called endocannabinoids, as well as the enzymes and transporters responsible for the metabolism of endocannabinoids. Two arachidonic acid–containing lipid molecules, arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol, function as endocannabinoids. N-acylethanolamines and monoacylglycerols, in which the arachidonic acid chain is replaced with a saturated or monounsaturated fatty acid, are not directly involved in the endocannabinoid system but exhibit agonistic activities for other receptors. These endocannabinoid-like molecules include palmitoylethanolamide, oleoylethanolamide (OEA), and 2-oleoylglycerol. Endocannabinoids stimulate feeding behavior and the anabolism of lipids and glucose, while OEA suppresses appetite. Both central and peripheral systems are included in these nutritional and metabolic contexts. Therefore, they have potential in the treatment and prevention of obesity. We outline the structure, metabolism, and biological activities of endocannabinoids and related molecules, and focus on their involvement in energy homeostasis and metabolic regulation. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Current Landscape: The Mechanism and Therapeutic Impact of Obesity for Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Chongru Zhao ◽  
Weijie Hu ◽  
Yi Xu ◽  
Dawei Wang ◽  
Yichen Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Energy Homeostasis ◽  
Treatment Strategies ◽  
Therapeutic Interventions ◽  
Novel Treatment ◽  
Common Cancer ◽  
Prevalence Of Obesity ◽  
Novel Treatment Strategies ◽  
Underlying Mechanisms ◽  
The Impact

Obesity is defined as a chronic disease induced by an imbalance of energy homeostasis. Obesity is a widespread health problem with increasing prevalence worldwide. Breast cancer (BC) has already been the most common cancer and one of the leading causes of cancer death in women worldwide. Nowadays, the impact of the rising prevalence of obesity has been recognized as a nonnegligible issue for BC development, outcome, and management. Adipokines, insulin and insulin-like growth factor, sex hormone and the chronic inflammation state play critical roles in the vicious crosstalk between obesity and BC. Furthermore, obesity can affect the efficacy and side effects of multiple therapies such as surgery, radiotherapy, chemotherapy, endocrine therapy, immunotherapy and weight management of BC. In this review, we focus on the current landscape of the mechanisms of obesity in fueling BC and the impact of obesity on diverse therapeutic interventions. An in-depth exploration of the underlying mechanisms linking obesity and BC will improve the efficiency of the existing treatments and even provide novel treatment strategies for BC treatment.

scholarly journals Neurobiology of cannabinoid receptor signaling

2020 ◽  
Vol 22 (3) ◽  
pp. 207-222
Keyword(s):  
Intracellular Signaling ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Therapeutic Interventions ◽  
Pharmacological Intervention ◽  
Receptor Signaling ◽  
Specific Expression ◽  
Cannabinoid Type 1 Receptor ◽  
Promising Therapeutic Approach ◽  
As Stress

The endocannabinoid system (ECS) is a highly versatile signaling system within the nervous system. Despite its widespread localization, its functions within the context of distinct neural processes are very well discernable and specific. This is remarkable, and the question remains as to how such specificity is achieved. One key player in the ECS is the cannabinoid type 1 receptor (CB1), a G protein–coupled receptor characterized by the complexity of its cell-specific expression, cellular and subcellular localization, and its adaptable regulation of intracellular signaling cascades. CB1 receptors are involved in different synaptic and cellular plasticity processes and in the brain’s bioenergetics in a context-specific manner. CB2 receptors are also important in several processes in neurons, glial cells, and immune cells of the brain. As polymorphisms in ECS components, as well as external impacts such as stress and metabolic challenges, can both lead to dysregulated ECS activity and subsequently to possible neuropsychiatric disorders, pharmacological intervention targeting the ECS is a promising therapeutic approach. Understanding the neurobiology of cannabinoid receptor signaling in depth will aid optimal design of therapeutic interventions, minimizing unwanted side effects.

scholarly journals Human GPR17 Nonsynonymous Variants Identified in Individuals with Metabolic Diseases Have Distinct Functional Signaling Profiles

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A656-A656
Author(s):  
Jason M Conley ◽  
Hongxia Ren
Keyword(s):  
Protein Expression ◽  
Cellular Localization ◽  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Molecular Signaling ◽  
Expression Levels ◽  
Severe Insulin Resistance ◽  
Signaling Function ◽  
Functional Profiling

Abstract GPR17 is a G protein-coupled receptor (GPCR) implicated in the regulation of glucose metabolism and energy homeostasis. Our genetic knockout studies in rodents suggest that GPR17 is a potential therapeutic target for the treatment of metabolic diseases. However, the contributions of GPR17 to human metabolism and metabolic deficits are not well understood. Here, we analyzed the human GPR17 coding sequences of individuals from control and metabolic disease cohorts that were comprised of patients with clinical phenotypes including severe insulin resistance, hypercholesterolemia, and obesity. Across cohorts, 18 nonsynonymous GPR17 variants were identified, including eight variants that were exclusive to the disease cohort. We characterized the protein expression levels, cellular localization, and downstream functional signaling profiles of nine human GPR17 variants (F43L, V96M, V103M, D105N, A131T, G136S, R248Q, R301H, and G354V). We found that the protein expression levels and subcellular localization for each of the nine GPR17 variants were similar to that of the wild type GPR17. As the endogenous GPR17 ligand is still elusive, we used a synthetic GPR17 agonist to quantitatively measure the functional signaling profiles of GPR17 variants. We found some of the variants had distinctly altered signaling profiles. GPR17-G136S lost agonist-mediated cAMP, Ca2+, and beta-arrestin signaling. GPR17-V96M retained cAMP inhibition similar to GPR17-WT but had impaired Ca2+ and beta-arrestin signaling. GPR17-D105N displayed impaired cAMP and Ca2+ signaling but enhanced agonist-stimulated beta-arrestin recruitment. Also, GPR17-G354V retained cAMP and Ca2+ signaling function but had attenuated beta-arrestin recruitment. The identification and functional profiling of naturally occurring human GPR17 variants from individuals with metabolic diseases revealed receptor variants with distinct signaling profiles, including differential signaling perturbations that resulted in receptor signaling bias. These results are expected to contribute to our understanding of the molecular signaling mechanisms underlying GPR17 in metabolic regulation.

scholarly journals Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1903
Author(s):  
Tae Hyun Kim ◽  
Dong-Gyun Hong ◽  
Yoon Mee Yang
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Metabolic Regulation ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Therapeutic Targets ◽  
Signaling Crosstalk ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

The liver plays a key role in maintaining energy homeostasis by sensing and responding to changes in nutrient status under various metabolic conditions. Recently highlighted as a major endocrine organ, the contribution of the liver to systemic glucose and lipid metabolism is primarily attributed to signaling crosstalk between multiple organs via hepatic hormones, cytokines, and hepatokines. Hepatokines are hormone-like proteins secreted by hepatocytes, and a number of these have been associated with extra-hepatic metabolic regulation. Mounting evidence has revealed that the secretory profiles of hepatokines are significantly altered in non-alcoholic fatty liver disease (NAFLD), the most common hepatic manifestation, which frequently precedes other metabolic disorders, including insulin resistance and type 2 diabetes. Therefore, deciphering the mechanism of hepatokine-mediated inter-organ communication is essential for understanding the complex metabolic network between tissues, as well as for the identification of novel diagnostic and/or therapeutic targets in metabolic disease. In this review, we describe the hepatokine-driven inter-organ crosstalk in the context of liver pathophysiology, with a particular focus on NAFLD progression. Moreover, we summarize key hepatokines and their molecular mechanisms of metabolic control in non-hepatic tissues, discussing their potential as novel biomarkers and therapeutic targets in the treatment of metabolic diseases.

scholarly journals Expression and Function of the Endocannabinoid System in the Retina and the Visual Brain

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Jean-François Bouchard ◽  
Christian Casanova ◽  
Bruno Cécyre ◽  
William John Redmond
Keyword(s):  
Visual Processing ◽  
Metabolic Regulation ◽  
Cannabinoid Receptors ◽  
Endocannabinoid System ◽  
G Protein Coupled Receptors ◽  
Retinal Diseases ◽  
Pain Anxiety ◽  
Pharmacological Targets ◽  
And Function ◽  
G Protein Coupled

Endocannabinoids are important retrograde modulators of synaptic transmission throughout the nervous system. Cannabinoid receptors are seven transmembrane G-protein coupled receptors favoringGi/oprotein. They are known to play an important role in various processes, including metabolic regulation, craving, pain, anxiety, and immune function. In the last decade, there has been a growing interest for endocannabinoids in the retina and their role in visual processing. The purpose of this review is to characterize the expression and physiological functions of the endocannabinoid system in the visual system, from the retina to the primary visual cortex, with a main interest regarding the retina, which is the best-described area in this system so far. It will show that the endocannabinoid system is widely present in the retina, mostly in the through pathway where it can modulate neurotransmitter release and ion channel activity, although some evidence also indicates possible mechanisms via amacrine, horizontal, and Müller cells. The presence of multiple endocannabinoid ligands, synthesizing and catabolizing enzymes, and receptors highlights various pharmacological targets for novel therapeutic application to retinal diseases.

scholarly journals The Endocannabinoid System in the Retina: From Physiology to Practical and Therapeutic Applications

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Thomas Schwitzer ◽  
Raymund Schwan ◽  
Karine Angioi-Duprez ◽  
Anne Giersch ◽  
Vincent Laprevote
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cannabinoid Receptors ◽  
Synthetic Cannabinoids ◽  
Endocannabinoid System ◽  
Main Role ◽  
Cannabinoid System ◽  
Retinal Processing ◽  
The Central Nervous System ◽  
The Impact

Cannabisis one of the most prevalent drugs used in industrialized countries. The main effects ofCannabisare mediated by two major exogenous cannabinoids: ∆9-tetrahydroxycannabinol and cannabidiol. They act on specific endocannabinoid receptors, especially types 1 and 2. Mammals are endowed with a functional cannabinoid system including cannabinoid receptors, ligands, and enzymes. This endocannabinoid signaling pathway is involved in both physiological and pathophysiological conditions with a main role in the biology of the central nervous system. As the retina is a part of the central nervous system due to its embryonic origin, we aim at providing the relevance of studying the endocannabinoid system in the retina. Here, we review the distribution of the cannabinoid receptors, ligands, and enzymes in the retina and focus on the role of the cannabinoid system in retinal neurobiology. This review describes the presence of the cannabinoid system in critical stages of retinal processing and its broad involvement in retinal neurotransmission, neuroplasticity, and neuroprotection. Accordingly, we support the use of synthetic cannabinoids as new neuroprotective drugs to prevent and treat retinal diseases. Finally, we argue for the relevance of functional retinal measures in cannabis users to evaluate the impact of cannabis use on human retinal processing.

scholarly journals Dietary fructose aggravates the pathobiology of traumatic brain injury by influencing energy homeostasis and plasticity

2015 ◽  
Vol 36 (5) ◽  
pp. 941-953 ◽  
Author(s):  
Rahul Agrawal ◽  
Emily Noble ◽  
Laurent Vergnes ◽  
Zhe Ying ◽  
Karen Reue ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Brain Plasticity ◽  
Phenotypic Expression ◽  
Membrane Lipid ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
The Impact

Fructose consumption has been on the rise for the last two decades and is starting to be recognized as being responsible for metabolic diseases. Metabolic disorders pose a particular threat for brain conditions characterized by energy dysfunction, such as traumatic brain injury. Traumatic brain injury patients experience sudden abnormalities in the control of brain metabolism and cognitive function, which may worsen the prospect of brain plasticity and function. The mechanisms involved are poorly understood. Here we report that fructose consumption disrupts hippocampal energy homeostasis as evidenced by a decline in functional mitochondria bioenergetics (oxygen consumption rate and cytochrome C oxidase activity) and an aggravation of the effects of traumatic brain injury on molecular systems engaged in cell energy homeostasis (sirtuin 1, peroxisome proliferator-activated receptor gamma coactivator-1alpha) and synaptic plasticity (brain-derived neurotrophic factor, tropomyosin receptor kinase B, cyclic adenosine monophosphate response element binding, synaptophysin signaling). Fructose also worsened the effects of traumatic brain injury on spatial memory, which disruption was associated with a decrease in hippocampal insulin receptor signaling. Additionally, fructose consumption and traumatic brain injury promoted plasma membrane lipid peroxidation, measured by elevated protein and phenotypic expression of 4-hydroxynonenal. These data imply that high fructose consumption exacerbates the pathology of brain trauma by further disrupting energy metabolism and brain plasticity, highlighting the impact of diet on the resilience to neurological disorders.

scholarly journals The Role of Endocannabinoid System in Menopause and Its Related-Diseases

2021 ◽  
Vol 8 (4) ◽  
Author(s):  
Torella M ◽  
◽  
Tortora C ◽  
Argenziano M ◽  
Riemma G ◽  
...  
Keyword(s):  
Body Weight ◽  
Cardiovascular Diseases ◽  
Food Intake ◽  
Cancer Progression ◽  
Cannabinoid Receptors ◽  
Ovarian Function ◽  
Endocannabinoid System ◽  
Osteoclast Activity ◽  
Leading Role ◽  
The Impact

Menopause is a crucial event in women’s health, characterized by the cessation of ovarian function. The estrogens deficiency exposes women to several diseases, including obesity, osteoporosis, cardiovascular diseases and cancer. Menopause-related diseases deeply impact on women’s quality of life and represent a serious public and economic health burden. The Endocannabinoid System (ECS) includes Cannabinoid Type 1 (CB1) and Cannabinoid Type 2 (CB2) receptors, endocannabinoids and all the enzymes involved in their biosynthesis and degradation. It plays a significant role in energy balance, bone metabolism, muscular contractility, vascular tone and cancer progression. CB1 activation is responsible for increasing food intake and body weight, stimulating osteoclast activity, inhibiting oxidative stress and preventing cancer progression. Conversely, the stimulation of CB2 induces a reduction in food intake and in body weight, inhibits osteoclast activity, prevents vascular risk and reduces cancer cells proliferation. Moreover, several polymorphic variants of cannabinoid receptors genes are involved into obesity and osteoporosis. In menopause, the alteration of cannabinoid receptors expression and endocannabinoids levels as well as their role in hormone-related pathways could act a leading role in different pathologies (obesity, osteoporosis, cardiovascular diseases and cancer). Therefore, ECS could be considered a possible prognostic marker and a therapeutic target to oppose the harmful effects of these menopause-related diseases. In this review we aimed to summarize the current state-of-knowledge concerning the impact of ECS on major health issues of postmenopausal women.

scholarly journals Distinctive Evidence Involved in the Role of Endocannabinoid Signalling in Parkinson’s Disease: A Perspective on Associated Therapeutic Interventions

2020 ◽  
Vol 21 (17) ◽  
pp. 6235
Author(s):  
Tapan Behl ◽  
Gagandeep Kaur ◽  
Simona Bungau ◽  
Rishabh Jhanji ◽  
Arun Kumar ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cannabinoid Receptors ◽  
Life Quality ◽  
Endocannabinoid System ◽  
Therapeutic Interventions ◽  
Diseased State ◽  
Preclinical And Clinical Studies ◽  
Signalling Systems

Current pharmacotherapy of Parkinson’s disease (PD) is symptomatic and palliative, with levodopa/carbidopa therapy remaining the prime treatment, and nevertheless, being unable to modulate the progression of the neurodegeneration. No available treatment for PD can enhance the patient’s life-quality by regressing this diseased state. Various studies have encouraged the enrichment of treatment possibilities by discovering the association of the effects of the endocannabinoid system (ECS) in PD. These reviews delineate the reported evidence from the literature on the neuromodulatory role of the endocannabinoid system and expression of cannabinoid receptors in symptomatology, cause, and treatment of PD progression, wherein cannabinoid (CB) signalling experiences alterations of biphasic pattern during PD progression. Published papers to date were searched via MEDLINE, PubMed, etc., using specific key words in the topic of our manuscript. Endocannabinoids regulate the basal ganglia neuronal circuit pathways, synaptic plasticity, and motor functions via communication with dopaminergic, glutamatergic, and GABAergic signalling systems bidirectionally in PD. Further, gripping preclinical and clinical studies demonstrate the context regarding the cannabinoid compounds, which is supported by various evidence (neuroprotection, suppression of excitotoxicity, oxidative stress, glial activation, and additional benefits) provided by cannabinoid-like compounds (much research addresses the direct regulation of cannabinoids with dopamine transmission and other signalling pathways in PD). More data related to endocannabinoids efficacy, safety, and pharmacokinetic profiles need to be explored, providing better insights into their potential to ameliorate or even regress PD.

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