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.

β-Arrestins as Important Regulators of Glucose and Energy Homeostasis

2021 ◽  
Vol 84 (1) ◽  
Author(s):  
Sai P. Pydi ◽  
Luiz F. Barella ◽  
Lu Zhu ◽  
Jaroslawna Meister ◽  
Mario Rossi ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Cell Types ◽  
Mutant Mice ◽  
Whole Body ◽  
Annual Review ◽  
Publication Date ◽  
Cytoplasmic Proteins ◽  
New Findings ◽  
Novel Drugs ◽  
G Protein Coupled

β-Arrestin-1 and -2 (also known as arrestin-2 and -3, respectively) are ubiquitously expressed cytoplasmic proteins that dampen signaling through G protein–coupled receptors. However, β-arrestins can also act as signaling molecules in their own right. To investigate the potential metabolic roles of the two β-arrestins in modulating glucose and energy homeostasis, recent studies analyzed mutant mice that lacked or overexpressed β-arrestin-1 and/or -2 in distinct, metabolically important cell types. Metabolic analysis of these mutant mice clearly demonstrated that both β-arrestins play key roles in regulating the function of most of these cell types, resulting in striking changes in whole-body glucose and/or energy homeostasis. These studies also revealed that β-arrestin-1 and -2, though structurally closely related, clearly differ in their metabolic roles under physiological and pathophysiological conditions. These new findings should guide the development of novel drugs for the treatment of various metabolic disorders, including type 2 diabetes and obesity. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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.

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.

scholarly journals Neuromediators and neuropeptides: the biomarkers for metabolic disturbances in obesity

2018 ◽  
Vol 64 (4) ◽  
pp. 258-269 ◽  
Author(s):  
Ivan V. Gmoshinski ◽  
Sergey A. Apryatin ◽  
Vladimir A. Shipelin ◽  
Dmitriy B. Nikitjuk
Keyword(s):  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Cannabinoid Receptors ◽  
Diet Therapy ◽  
Experimental Models ◽  
The Body ◽  
Metabolic Disturbances ◽  
Clinical Observations ◽  
The Central Nervous System ◽  
G Protein Coupled

The role of biogenic amines (serotonin, dopamine) and neuropeptides in regulation of energy homeostasis of the organism and their role as markers of metabolic disorders in obesity (Ob) in animal experimental models and in clinical observations is reviewed. The energy homeostasis of the body is controlled via competition of alternative regulatory mechanisms that are mainly localized in the hypothalamus (HT). At the level of aminergic regulation, these are the serotonin and dopamine systems; at the level of the peptidergic system, these are NPY/AgRP and POMC/CART-related peptides. Opioid and cannabinoid receptors and their endogenous ligands closely linked to peptidergic and aminergic regulatory subsystems of the central nervous system ensure the connection between the «metabolic» regulation loop responding to a deficit or excess of energy substrates the «hedonistic» one associated with the body’s perception of pleasure from food consumption. The response of peptidergic and aminergic HT neurons to food and hormonal signals originating from the outside is based on the interaction between the corresponding ligands and G-protein-coupled receptors specific to them. Disruption or breakdown of the central mechanisms is considered to be one of the main pathogenetic factors of obesity and, simultaneously, the reason why reducing diet therapy proves inefficient or unstable. Partial permeability of the blood—brain barrier for neuropeptides makes them an attractive biomarker in the diagnosis of metabolic abnormalities in obese patients.

TGFβ: Signaling Blockade for Cancer Immunotherapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Szu-Ying Chen ◽  
Ons Mamäi ◽  
Rosemary J. Akhurst
Keyword(s):  
Cancer Biology ◽  
Transforming Growth Factor ◽  
Biological Activities ◽  
Tumor Stroma ◽  
Transforming Growth Factor Β ◽  
Therapeutic Window ◽  
Annual Review ◽  
Publication Date ◽  
Tgfβ Signaling ◽  
Mesenchymal Transformation

Discovered over four decades ago, transforming growth factor β (TGFβ) is a potent pleiotropic cytokine that has context-dependent effects on most cell types. It acts as a tumor suppressor in some cancers and/or supports tumor progression and metastasis through its effects on the tumor stroma and immune microenvironment. In TGFβ-responsive tumors it can promote invasion and metastasis through epithelial-mesenchymal transformation, the appearance of cancer stem cell features, and resistance to many drug classes, including checkpoint blockade immunotherapies. Here we consider the biological activities of TGFβ action on different cells of relevance toward improving immunotherapy outcomes for patients, with a focus on the adaptive immune system. We discuss recent advances in the development of drugs that target the TGFβ signaling pathway in a tumor-specific or cell type–specific manner to improve the therapeutic window between response rates and adverse effects. Expected final online publication date for the Annual Review of Cancer Biology, Volume 6 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Regulatory Themes and Variations by the Stress-Signaling Nucleotide Alarmones (p)ppGpp in Bacteria

2021 ◽  
Vol 55 (1) ◽  
Author(s):  
Brent W. Anderson ◽  
Danny K. Fung ◽  
Jue D. Wang
Keyword(s):  
Metabolic Regulation ◽  
Protein Translation ◽  
Annual Review ◽  
Publication Date ◽  
Stress Signaling ◽  
Nucleotide Synthesis ◽  
Evolutionary Diversification ◽  
Metabolic Remodeling ◽  
Emerging Themes ◽  
Metabolic Interconversion

Bacterial stress-signaling alarmones are important components of a protective network against diverse stresses such as nutrient starvation and antibiotic assault. pppGpp and ppGpp, collectively (p)ppGpp, have well-documented regulatory roles in gene expression and protein translation. Recent work has highlighted another key function of (p)ppGpp: inducing rapid and coordinated changes in cellular metabolism by regulating enzymatic activities, especially those involved in purine nucleotide synthesis. Failure of metabolic regulation by (p)ppGpp results in the loss of coordination between metabolic and macromolecular processes, leading to cellular toxicity. In this review, we document how (p)ppGpp and newly characterized nucleotides pGpp and (p)ppApp directly regulate these enzymatic targets for metabolic remodeling. We examine targets’ common determinants for alarmone interaction as well as their evolutionary diversification. We highlight classical and emerging themes in nucleotide signaling, including oligomerization and allostery along with metabolic interconversion and crosstalk, illustrating how they allow optimized bacterial adaptation to their environmental niches. Expected final online publication date for the Annual Review of Genetics, Volume 55 is November 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The Molecular targets of Cannabinoids in the treatment of Cancer and Inflammation

2021 ◽  
Vol 27 ◽  
Author(s):  
Alenabi Aylar ◽  
Malekinejad Hassan
Keyword(s):  
Cannabinoid Receptors ◽  
Inflammatory Diseases ◽  
Biological Effects ◽  
Synthetic Cannabinoids ◽  
Endocannabinoid System ◽  
Anticancer Effects ◽  
Anti Cancer ◽  
Culture Models ◽  
Cancer And Inflammation ◽  
G Protein Coupled

Objective: In this review we discuss the emerging evidence for the effectiveness of cannabinoids in the treatment of cancer and inflammation. The remarkable effects complete the traditional evidence for their successful application in the treatment of pain and cancer-related side effects. Methods: we searched Pub Med (132 articles) and Google scholar (9 articles) databases and gathered the clinical (4 articles), preclinical (28 articles) studies, reports on cell culture models (30 articles) and other original and review articles (78 articles) related to inflammation, cancer and cannabinoids. Results: Cannabinoids are described in three different forms, comprising endo- phyto- and synthetic compounds that exert biological effects. The molecular and cellular pathways of endogenous cannabinoids in the maintenance of homeostasis are well documented. In addition to classical cannabinoid receptors type 1 and 2, Vanilloid receptors and G protein-coupled receptor 55 were identified as common receptors. Subsequently, the effectiveness of phyto- and synthetic cannabinoids mediated by cannabinoid receptors has been demonstrated in the treatment of inflammatory diseases including neurodegenerative diseases as well as gastrointestinal and respiratory inflammations. Another accepted property of cannabinoids is their anti-cancer effects. Cannabinoids were found to be effective in the treatment of lung, colorectal, prostate, breast, pancreas and hepatic cancers. The anticancer effects of cannabinoids were characterized by their anti-proliferative property, inhibition of cancer cells migration, suppression of vascularization and induction of apoptosis. Conclusion: The current review provides and overview the role of endocannabinoid system in the mediation of physiological functions, the type and expression of cannabinoids receptors under physiological and pathological conditions. In additions, the molecular pathways involved in the effects of cannabinoids and the effectiveness of cannabinoids in the treatment of inflammations and cancers are highlighted.

Phospholipid Scrambling by G Protein–Coupled Receptors

2021 ◽  
Vol 51 (1) ◽  
Author(s):  
George Khelashvili ◽  
Anant K. Menon
Keyword(s):  
G Protein ◽  
Conformational Changes ◽  
Credit Card ◽  
Lipid Membrane ◽  
G Protein Coupled Receptors ◽  
Annual Review ◽  
Publication Date ◽  
Flip Flop ◽  
G Protein Coupled

Rapid flip-flop of phospholipids across the two leaflets of biological membranes is crucial for many aspects of cellular life. The transport proteins that facilitate this process are classified as pump-like flippases and floppases and channel-like scramblases. Unexpectedly, Class A G protein–coupled receptors (GPCRs), a large class of signaling proteins exemplified by the visual receptor rhodopsin and its apoprotein opsin, are constitutively active as scramblases in vitro. In liposomes, opsin scrambles lipids at a unitary rate of >100,000 per second. Atomistic molecular dynamics simulations of opsin in a lipid membrane reveal conformational transitions that expose a polar groove between transmembrane helices 6 and 7. This groove enables transbilayer lipid movement, conceptualized as the swiping of a credit card (lipid) through a card reader (GPCR). Conformational changes that facilitate scrambling are distinct from those associated with GPCR signaling. In this review, we discuss the physiological significance of GPCR scramblase activity and the modes of its regulation in cells. Expected final online publication date for the Annual Review of Biophysics, Volume 51 is May 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Glucosinolates in Brassica Vegetables: Characterization and Factors That Influence Distribution, Content, and Intake

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xianli Wu ◽  
Hui Huang ◽  
Holly Childs ◽  
Yanbei Wu ◽  
Liangli Yu ◽  
...  
Keyword(s):  
Biological Activities ◽  
Chemical Degradation ◽  
Cooking Methods ◽  
Annual Review ◽  
Publication Date ◽  
Inverse Association ◽  
Brassica Spp ◽  
Brassica Vegetables ◽  
Health Promoting ◽  
Genetic And Environmental Factors

Glucosinolates (GSLs) are a class of sulfur-containing compounds found predominantly in the genus Brassica of the Brassicaceae family. Certain edible plants in Brassica, known as Brassica vegetables, are among the most commonly consumed vegetables in the world. Over the last three decades, mounting evidence has suggested an inverse association between consumption of Brassica vegetables and the risk of various types of cancer. The biological activities of Brassica vegetables have been largely attributed to the hydrolytic products of GSLs. GSLs can be hydrolyzed by enzymes; thermal or chemical degradation also breaks down GSLs. There is considerable variation of GSLs in Brassica spp., which are caused by genetic and environmental factors. Most Brassica vegetables are consumed after cooking; common cooking methods have a complex influence on the levels of GSLs. The variation of GSLs in Brassica vegetables and the influence of cooking and processing methods ultimately affect their intake and health-promoting properties. Expected final online publication date for the Annual Review of Food Science and Technology, Volume 12 is March 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Central 5-HTR2C in the Control of Metabolic Homeostasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Ting Yao ◽  
Jiehui He ◽  
Zhicheng Cui ◽  
Ruwen Wang ◽  
Kaixuan Bao ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Metabolic Regulation ◽  
Metabolic Disorders ◽  
Energy Homeostasis ◽  
Molecular Pathways ◽  
Metabolic Hormones ◽  
Obesity Drugs ◽  
G Protein Coupled ◽  
The Brain

The 5-hydroxytryptamine 2C receptor (5-HTR2C) is a class G protein-coupled receptor (GPCR) enriched in the hypothalamus and the brain stem, where it has been shown to regulate energy homeostasis, including feeding and glucose metabolism. Accordingly, 5-HTR2C has been the target of several anti-obesity drugs, though the associated side effects greatly curbed their clinical applications. Dissecting the specific neural circuits of 5-HTR2C-expressing neurons and the detailed molecular pathways of 5-HTR2C signaling in metabolic regulation will help to develop better therapeutic strategies towards metabolic disorders. In this review, we introduced the regulatory role of 5-HTR2C in feeding behavior and glucose metabolism, with particular focus on the molecular pathways, neural network, and its interaction with other metabolic hormones, such as leptin, ghrelin, insulin, and estrogens. Moreover, the latest progress in the clinical research on 5-HTR2C agonists was also discussed.

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