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Luan K, Fan Y, Yang Q, Yang H, Zhou Z, Huang J, She Z, Zou T, Xiong H, Mei Z. Acetyl- 11-keto-β-boswellic acid alleviates hepatic metabolic dysfunction by inhibiting MGLL activity. J Lipid Res 2025:100812. [PMID: 40245985 DOI: 10.1016/j.jlr.2025.100812] [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: 11/11/2024] [Revised: 03/29/2025] [Accepted: 04/14/2025] [Indexed: 04/19/2025] Open
Abstract
Metabolic abnormalities have emerged as a central pathogenesis in various metabolic diseases, particularly nonalcoholic fatty liver disease (NAFLD) and its associated complications of obesity and insulin resistance. Despite this, effective pharmaceutical treatments for NAFLD-related metabolic disorders remain limited. In this study, we identified Acetyl-11-keto-beta-boswellic acid (AKBA), a natural compound isolated from the gum resin of Boswellia carterii, showing robust capacity against NAFLD as well as its related body weight gain and insulin resistance. Our findings demonstrate that the beneficial effects of AKBA on metabolic disorders are largely dependent on its direct interaction with monoacylglycerol lipase (MGLL) in hepatocytes. In vivo experiments using a high-fat and high-cholesterol (HFHC) diet -induced NAFLD mouse model revealed that AKBA effectively mitigated both the progression of NAFLD and associated metabolic dysfunctions. Proteomic and RNA sequencing analyses further elucidated that AKBA attenuates key pathways related to lipid accumulation, inflammation, and fibrosis. Mechanistically, AKBA was found to directly target MGLL in hepatocytes, inhibiting its activity in hydrolyzing monoacylglycerols. Structural analyses revealed that AKBA binds specifically to the GLU60, MET64, THR279, and PHE283 residues of MGLL. Importantly, AKBA showed no additional therapeutic effect in MGLL-deficient models, underscoring the crucial role of MGLL in mediating AKBA's therapeutic action. In conclusion, our study identifies AKBA as a novel and potent MGLL inhibitor and suggests that it holds promise as a therapeutic candidate for NAFLD and related metabolic diseases. This research highlights the potential of natural compounds in the development of targeted treatments for metabolic disorders.
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Affiliation(s)
- Kai Luan
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, China
| | - Yuhong Fan
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Qin Yang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Hailong Yang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Zelin Zhou
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, China
| | - Ju Huang
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, China
| | - Zhigang She
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Toujun Zou
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hui Xiong
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, China.
| | - Zhinan Mei
- School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, China; College of Plant Science and Technology of Huazhong Agriculture University, Wuhan, China.
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2
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Saeed S, la Cour Poulsen L, Visnovska T, Hoffmann A, Ghosh A, Wolfrum C, Rønningen T, Dahl MB, Wang J, Cayir A, Mala T, Kristinsson JA, Svanevik M, Hjelmesæth J, Hertel JK, Blüher M, Valderhaug TG, Böttcher Y. Chromatin landscape in paired human visceral and subcutaneous adipose tissue and its impact on clinical variables in obesity. EBioMedicine 2025; 114:105653. [PMID: 40118008 PMCID: PMC11976249 DOI: 10.1016/j.ebiom.2025.105653] [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: 09/27/2024] [Revised: 02/24/2025] [Accepted: 03/04/2025] [Indexed: 03/23/2025] Open
Abstract
BACKGROUND Obesity is a global health challenge and adipose tissue exhibits distinct depot-specific characteristics impacting differentially on the risk of metabolic comorbidities. METHODS Here, we integrate chromatin accessibility (ATAC-seq) and gene expression (RNA-seq) data from intra-individually paired human subcutaneous (SAT) and omental visceral adipose tissue (OVAT) samples to unveil depot-specific regulatory mechanisms. FINDINGS We identified twice as many depot-specific differentially accessible regions (DARs) in OVAT compared to SAT. SAT-specific regions showed enrichment for adipose tissue enhancers involving genes controlling extracellular matrix organization and metabolic processes. In contrast, OVAT-specific regions showed enrichment in promoters linked to genes associated with cardiomyopathies. Moreover, OVAT-specific regions were enriched for bivalent transcription start site and repressive chromatin states, suggesting a "lingering" regulatory state. Motif analysis identified CTCF and BACH1 as most significantly enriched motifs in SAT and OVAT-specific DARs, respectively. Distinct gene sets correlated with important clinical variables of obesity, fat distribution measures, as well as insulin, glucose, and lipid metabolism. INTERPRETATION We provide an integrated analysis of chromatin accessibility and transcriptional profiles in paired human SAT and OVAT samples, offering new insights into the regulatory landscape of adipose tissue and highlighting depot-specific mechanisms in obesity pathogenesis. FUNDING SS received EU-Scientia postdoctoral Fellowship and project funding from the European Union's Horizon 2020 Research and Innovation program under the Marie Skłodowska-Curie Grant, (agreement No. 801133). LlCP and TR were supported by Helse Sør-Øst grants to Y.B (ID 2017079, ID 278908). MB received funding from grants from the DFG (German Research Foundation)-Projekt number 209933838-SFB 1052 (project B1) and by Deutsches Zentrum für Diabetesforschung (DZD, Grant: 82DZD00601).
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Affiliation(s)
- Sadia Saeed
- Department of Clinical Molecular Biology, EpiGen, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | | | - Tina Visnovska
- EpiGen, Medical Division, Akershus University Hospital, Lørenskog, Norway.
| | - Anne Hoffmann
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital, Leipzig, Germany.
| | - Adhideb Ghosh
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland.
| | - Christian Wolfrum
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, ETH Zürich, Schwerzenbach, Switzerland.
| | - Torunn Rønningen
- Department of Clinical Molecular Biology, EpiGen, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; EpiGen, Medical Division, Akershus University Hospital, Lørenskog, Norway.
| | - Mai Britt Dahl
- Department of Clinical Molecular Biology, EpiGen, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Junbai Wang
- Department of Clinical Molecular Biology, EpiGen, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Akin Cayir
- EpiGen, Medical Division, Akershus University Hospital, Lørenskog, Norway.
| | - Tom Mala
- Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway.
| | - Jon A Kristinsson
- Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway.
| | - Marius Svanevik
- Department of Endocrinology, Obesity and Nutrition, Vestfold Hospital Trust, Tønsberg, Norway.
| | - Jøran Hjelmesæth
- Department of Endocrinology, Obesity and Nutrition, Vestfold Hospital Trust, Tønsberg, Norway.
| | - Jens Kristoffer Hertel
- Department of Endocrinology, Obesity and Nutrition, Vestfold Hospital Trust, Tønsberg, Norway.
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital, Leipzig, Germany; Department of Medicine, University of Leipzig, Leipzig, Germany.
| | | | - Yvonne Böttcher
- Department of Clinical Molecular Biology, EpiGen, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; EpiGen, Medical Division, Akershus University Hospital, Lørenskog, Norway.
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3
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Bourdy R, Befort K. The Role of the Endocannabinoid System in Binge Eating Disorder. Int J Mol Sci 2023; 24:ijms24119574. [PMID: 37298525 DOI: 10.3390/ijms24119574] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/23/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
Eating disorders are multifactorial disorders that involve maladaptive feeding behaviors. Binge eating disorder (BED), the most prevalent of these in both men and women, is characterized by recurrent episodes of eating large amounts of food in a short period of time, with a subjective loss of control over eating behavior. BED modulates the brain reward circuit in humans and animal models, which involves the dynamic regulation of the dopamine circuitry. The endocannabinoid system plays a major role in the regulation of food intake, both centrally and in the periphery. Pharmacological approaches together with research using genetically modified animals have strongly highlighted a predominant role of the endocannabinoid system in feeding behaviors, with the specific modulation of addictive-like eating behaviors. The purpose of the present review is to summarize our current knowledge on the neurobiology of BED in humans and animal models and to highlight the specific role of the endocannabinoid system in the development and maintenance of BED. A proposed model for a better understanding of the underlying mechanisms involving the endocannabinoid system is discussed. Future research will be necessary to develop more specific treatment strategies to reduce BED symptoms.
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Affiliation(s)
- Romain Bourdy
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), Université de Strasbourg, UMR7364, CNRS, 12 Rue Goethe, 67000 Strasbourg, France
| | - Katia Befort
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), Université de Strasbourg, UMR7364, CNRS, 12 Rue Goethe, 67000 Strasbourg, France
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4
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Li X, Liu Q, Pan Y, Chen S, Zhao Y, Hu Y. New insights into the role of dietary triglyceride absorption in obesity and metabolic diseases. Front Pharmacol 2023; 14:1097835. [PMID: 36817150 PMCID: PMC9932209 DOI: 10.3389/fphar.2023.1097835] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/20/2023] [Indexed: 02/05/2023] Open
Abstract
The incidence of obesity and associated metabolic diseases is increasing globally, adversely affecting human health. Dietary fats, especially triglycerides, are an important source of energy for the body, and the intestine absorbs lipids through a series of orderly and complex steps. A long-term high-fat diet leads to intestinal dysfunction, inducing obesity and metabolic disorders. Therefore, regulating dietary triglycerides absorption is a promising therapeutic strategy. In this review, we will discuss diverse aspects of the dietary triglycerides hydrolysis, fatty acid uptake, triglycerides resynthesis, chylomicron assembly, trafficking, and secretion processes in intestinal epithelial cells, as well as potential targets in this process that may influence dietary fat-induced obesity and metabolic diseases. We also mention the possible shortcomings and deficiencies in modulating dietary lipid absorption targets to provide a better understanding of their administrability as drugs in obesity and related metabolic disorders.
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Affiliation(s)
- Xiaojing Li
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qiaohong Liu
- Institute of Clinical Pharmacology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuqing Pan
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Si Chen
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu Zhao
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China,*Correspondence: Yu Zhao, ; Yiyang Hu,
| | - Yiyang Hu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China,Institute of Clinical Pharmacology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China,*Correspondence: Yu Zhao, ; Yiyang Hu,
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5
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Role of the Endocannabinoid System in Metabolic Control Processes and in the Pathogenesis of Metabolic Syndrome: An Update. Biomedicines 2023; 11:biomedicines11020306. [PMID: 36830844 PMCID: PMC9952954 DOI: 10.3390/biomedicines11020306] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/14/2023] [Accepted: 01/18/2023] [Indexed: 01/24/2023] Open
Abstract
Metabolic syndrome is a complex disease state, which appears mostly as a consequence of an unhealthy, sedentary lifestyle. Metabolic complications include insulin resistance (IR), diabetes, dyslipidemia, hypertension, and atherosclerosis, impairing life standards and reducing life expectancy. The endocannabinoid system (ECS) has an important role in signalization processes, not only in the central nervous system, but also in the peripheral tissues. Several physiological functions are affected, and overexpression or downregulation contributes to several diseases. A better understanding of the functions of cannabinoid (CB) receptors may propose potential therapeutic effects by influencing receptor signaling and enzymes involved in downstream pathways. In this review, we summarize recent information regarding the roles of the ECS and the CB1 receptor signaling in the physiology and pathophysiology of energy and metabolic homeostasis, in the development of obesity by enhancing food intake, upregulating energy balance and fat accumulation, increasing lipogenesis and glucose production, and impairing insulin sensitivity and secretion. By analyzing the roles of the ECS in physiological and pathophysiological mechanisms, we introduce some recently identified signaling pathways in the mechanism of the pathogenesis of metabolic syndrome. Our review emphasizes that the presence of such recently identified ECS signaling steps raises new therapeutic potential in the treatment of complex metabolic diseases such as diabetes, insulin resistance, obesity, and hypertension.
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Lucero MY, Gardner SH, Yadav AK, Borri A, Zhao Z, Chan J. Activity-based Photoacoustic Probes Reveal Elevated Intestinal MGL and FAAH Activity in a Murine Model of Obesity. Angew Chem Int Ed Engl 2022; 61:e202211774. [PMID: 36083191 PMCID: PMC9613605 DOI: 10.1002/anie.202211774] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Indexed: 01/12/2023]
Abstract
Obesity is a chronic health condition characterized by the accumulation of excessive body fat which can lead to and exacerbate cardiovascular disease, type-II diabetes, high blood pressure, and cancer through systemic inflammation. Unfortunately, visualizing key mediators of the inflammatory response, such as monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH), in a selective manner is a profound challenge owing to an overlapping substrate scope that involves arachidonic acid (AA). Specifically, these enzymes work in concert to generate AA, which in the context of obesity, has been implicated to control appetite and energy metabolism. In this study, we developed the first selective activity-based sensing probes to detect MGL (PA-HD-MGL) and FAAH (PA-HD-FAAH) activity via photoacoustic imaging. Activation of PA-HD-MGL and PA-HD-FAAH by their target enzymes resulted in 1.74-fold and 1.59-fold signal enhancements, respectively. Due to their exceptional selectivity profiles and deep-tissue photoacoustic imaging capabilities, these probes were employed to measure MGL and FAAH activity in a murine model of obesity. Contrary to conflicting reports suggesting levels of MGL can be attenuated or elevated, our results support the latter. Indeed, we discovered a marked increase of both targets in the gastrointestinal tract. These key findings set the stage to uncover the role of the endocannabinoid pathway in obesity-mediated inflammation.
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Affiliation(s)
- Melissa Y. Lucero
- Department of ChemistryUniversity of Illinois at Urbana-ChampaignUrbanaIL61801USA
- Beckman Institute for Advanced Science and TechnologyUrbanaIL61801USA
| | - Sarah H. Gardner
- Department of BiochemistryUniversity of Illinois at Urbana-ChampaignUrbanaIL61801USA
- Beckman Institute for Advanced Science and TechnologyUrbanaIL61801USA
| | - Anuj K. Yadav
- Department of ChemistryUniversity of Illinois at Urbana-ChampaignUrbanaIL61801USA
- Beckman Institute for Advanced Science and TechnologyUrbanaIL61801USA
| | - Austin Borri
- Department of BiochemistryUniversity of Illinois at Urbana-ChampaignUrbanaIL61801USA
- Beckman Institute for Advanced Science and TechnologyUrbanaIL61801USA
| | - Zhenxiang Zhao
- Department of ChemistryUniversity of Illinois at Urbana-ChampaignUrbanaIL61801USA
- Beckman Institute for Advanced Science and TechnologyUrbanaIL61801USA
| | - Jefferson Chan
- Department of ChemistryUniversity of Illinois at Urbana-ChampaignUrbanaIL61801USA
- Department of BiochemistryUniversity of Illinois at Urbana-ChampaignUrbanaIL61801USA
- Beckman Institute for Advanced Science and TechnologyUrbanaIL61801USA
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7
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Srivastava RK, Lutz B, Ruiz de Azua I. The Microbiome and Gut Endocannabinoid System in the Regulation of Stress Responses and Metabolism. Front Cell Neurosci 2022; 16:867267. [PMID: 35634468 PMCID: PMC9130962 DOI: 10.3389/fncel.2022.867267] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/14/2022] [Indexed: 11/26/2022] Open
Abstract
The endocannabinoid system, with its receptors and ligands, is present in the gut epithelium and enteroendocrine cells, and is able to modulate brain functions, both indirectly through circulating gut-derived factors and directly through the vagus nerve, finally acting on the brain’s mechanisms regarding metabolism and behavior. The gut endocannabinoid system also regulates gut motility, permeability, and inflammatory responses. Furthermore, microbiota composition has been shown to influence the activity of the endocannabinoid system. This review examines the interaction between microbiota, intestinal endocannabinoid system, metabolism, and stress responses. We hypothesize that the crosstalk between microbiota and intestinal endocannabinoid system has a prominent role in stress-induced changes in the gut-brain axis affecting metabolic and mental health. Inter-individual differences are commonly observed in stress responses, but mechanisms underlying resilience and vulnerability to stress are far from understood. Both gut microbiota and the endocannabinoid system have been implicated in stress resilience. We also discuss interventions targeting the microbiota and the endocannabinoid system to mitigate metabolic and stress-related disorders.
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Affiliation(s)
- Raj Kamal Srivastava
- Department of Zoology, Indira Gandhi National Tribal University, Anuppur, India
- *Correspondence: Raj Kamal Srivastava,
| | - Beat Lutz
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
- Leibniz Institute for Resilience Research (LIR), Mainz, Germany
| | - Inigo Ruiz de Azua
- Leibniz Institute for Resilience Research (LIR), Mainz, Germany
- Inigo Ruiz de Azua,
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8
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Schiano Moriello A, Di Marzo V, Petrosino S. Mutual Links between the Endocannabinoidome and the Gut Microbiome, with Special Reference to Companion Animals: A Nutritional Viewpoint. Animals (Basel) 2022; 12:ani12030348. [PMID: 35158670 PMCID: PMC8833664 DOI: 10.3390/ani12030348] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/21/2022] [Accepted: 01/30/2022] [Indexed: 12/07/2022] Open
Abstract
There is growing evidence that perturbation of the gut microbiome, known as “dysbiosis”, is associated with the pathogenesis of human and veterinary diseases that are not restricted to the gastrointestinal tract. In this regard, recent studies have demonstrated that dysbiosis is linked to the pathogenesis of central neuroinflammatory disorders, supporting the existence of the so-called microbiome-gut-brain axis. The endocannabinoid system is a recently recognized lipid signaling system and termed endocannabinoidome monitoring a variety of body responses. Accumulating evidence demonstrates that a profound link exists between the gut microbiome and the endocannabinoidome, with mutual interactions controlling intestinal homeostasis, energy metabolism and neuroinflammatory responses during physiological conditions. In the present review, we summarize the latest data on the microbiome-endocannabinoidome mutual link in health and disease, focalizing the attention on gut dysbiosis and/or altered endocannabinoidome tone that may distort the bidirectional crosstalk between these two complex systems, thus leading to gastrointestinal and metabolic diseases (e.g., idiopathic inflammation, chronic enteropathies and obesity) as well as neuroinflammatory disorders (e.g., neuropathic pain and depression). We also briefly discuss the novel possible dietary interventions based not only on probiotics and/or prebiotics, but also, and most importantly, on endocannabinoid-like modulators (e.g., palmitoylethanolamide) for intestinal health and beyond.
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Affiliation(s)
- Aniello Schiano Moriello
- Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Napoli, Italy; (A.S.M.); (V.D.M.)
- Epitech Group SpA, Via Einaudi 13, 35030 Padova, Italy
| | - Vincenzo Di Marzo
- Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Napoli, Italy; (A.S.M.); (V.D.M.)
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, CRIUCPQ and INAF, Centre NUTRISS, Faculties of Medicine and Agriculture and Food Sciences, Université Laval, Quebéc City, QC G1V 4G5, Canada
| | - Stefania Petrosino
- Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Napoli, Italy; (A.S.M.); (V.D.M.)
- Epitech Group SpA, Via Einaudi 13, 35030 Padova, Italy
- Correspondence:
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Takahata K, Seki C, Kimura Y, Kubota M, Ichise M, Sano Y, Yamamoto Y, Tagai K, Shimada H, Kitamura S, Matsuoka K, Endo H, Shinotoh H, Kawamura K, Zhang MR, Takado Y, Higuchi M. First-in-human in vivo undefined imaging and quantification of monoacylglycerol lipase in the brain: a PET study with 18F-T-401. Eur J Nucl Med Mol Imaging 2022; 49:3150-3161. [PMID: 35022846 DOI: 10.1007/s00259-021-05671-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/26/2021] [Indexed: 11/04/2022]
Abstract
PURPOSE Monoacylglycerol lipase (MAGL) regulates cannabinoid neurotransmission and the pro-inflammatory arachidonic acid pathway by degrading endocannabinoids. MAGL inhibitors may accordingly act as cannabinoid-potentiating and anti-inflammatory agents. Although MAGL dysfunction has been implicated in neuropsychiatric disorders, it has never been visualized in vivo in human brain. The primary objective of the current study was to visualize MAGL in the human brain using the novel PET ligand 18F-T-401. METHODS Seven healthy males underwent 120-min dynamic 18F-T-401-PET scans with arterial blood sampling. Six subjects also underwent a second PET scan with 18F-T-401 within 2 weeks of the first scan. For quantification of MAGL in the human brain, kinetic analyses using one- and two-tissue compartment models (1TCM and 2TCM, respectively), along with multilinear analysis (MA1) and Logan graphical analysis, were performed. Time-stability and test-retest reproducibility of 18F-T-401-PET were also evaluated. RESULTS 18F-T-401 showed rapid uptake and gradual washout from the brain. Logan graphical analysis showed linearity in all subjects, indicating reversible radioligand kinetics. Using a metabolite-corrected arterial input function, MA1 estimated regional total distribution volume (VT) values by best identifiability. VT values were highest in the cerebral cortex, moderate in the thalamus and putamen, and lowest in white matter and the brainstem, which was in agreement with regional MAGL expression in the human brain. Time-stability analysis showed that MA1 estimated VT values with a minimal bias even using truncated 60-min scan data. Test-retest reliability was also excellent with the use of MA1. CONCLUSIONS Here, we provide the first demonstration of in vivo visualization of MAGL in the human brain. 18F-T-401 showed excellent test-retest reliability, reversible kinetics, and stable estimation of VT values consistent with known regional MAGL expressions. PET with 18F-T-401-PET is promising tool for measurement of central MAGL.
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Affiliation(s)
- Keisuke Takahata
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan. .,Department of Neuro-Psychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, Japan.
| | - Chie Seki
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan
| | - Yasuyuki Kimura
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.,Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, 7-430 Morioka, Obu, Aichi, Japan
| | - Manabu Kubota
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.,Department of Psychiatry, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawara-cho, Sakyo-ku, Kyoto, Japan
| | - Masanori Ichise
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.,Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, 7-430 Morioka, Obu, Aichi, Japan
| | - Yasunori Sano
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan
| | - Yasuharu Yamamoto
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan
| | - Kenji Tagai
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan
| | - Hitoshi Shimada
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.,Department of Functional Neurology & Neurosurgery, Center for Integrated Human Brain Science, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuo, Niigata, Niigata, Japan
| | - Soichiro Kitamura
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan
| | - Kiwamu Matsuoka
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan
| | - Hironobu Endo
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan
| | - Hitoshi Shinotoh
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan
| | - Kazunori Kawamura
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage, Chiba, Chiba, Japan
| | - Ming-Rong Zhang
- Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage, Chiba, Chiba, Japan
| | - Yuhei Takado
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan
| | - Makoto Higuchi
- Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan
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10
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Matheson J, Zhou XMM, Bourgault Z, Le Foll B. Potential of Fatty Acid Amide Hydrolase (FAAH), Monoacylglycerol Lipase (MAGL), and Diacylglycerol Lipase (DAGL) Enzymes as Targets for Obesity Treatment: A Narrative Review. Pharmaceuticals (Basel) 2021; 14:ph14121316. [PMID: 34959715 PMCID: PMC8703892 DOI: 10.3390/ph14121316] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/06/2021] [Accepted: 12/14/2021] [Indexed: 12/23/2022] Open
Abstract
The endocannabinoid system (ECS) plays an integral role in maintaining metabolic homeostasis and may affect hunger, caloric intake, and nutrient absorption. Obesity has been associated with higher levels of the endogenous cannabinoid transmitters (endocannabinoids). Therefore, the ECS is an important target in obesity treatment. Modulating the enzymes that synthesize and degrade endocannabinoids, namely fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), and diacylglycerol lipase (DAGL), may be a promising strategy to treat obesity. This review aims to synthesize all studies investigating pharmacological or genetic manipulation of FAAH, MAGL, or DAGL enzymes in association with obesity-related measures. Pharmacological inhibition or genetic deletion of FAAH tended to promote an obesogenic state in animal models, though the relationships between human FAAH polymorphisms and obesity-related outcomes were heterogeneous, which could be due to FAAH having both pro-appetitive and anti-appetitive substrates. Genetic deletion of Mgll and Dagla as well as pharmacological inhibition of DAGL tended to reduce body weight and improve metabolic state in animal studies, though the effects of Mgll manipulation were tissue-dependent. Monitoring changes in body weight in ongoing clinical trials of FAAH inhibitors may clarify whether FAAH inhibition is a potential therapeutic strategy for treatment obesity. More preclinical work is needed to characterize the role of MAGL and DAGL modulation in obesity-related outcomes.
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Affiliation(s)
- Justin Matheson
- Translational Addiction Research Laboratory, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, 33 Ursula Franklin Street, Toronto, ON M5S 2S1, Canada; (X.M.M.Z.); (Z.B.); (B.L.F.)
- Correspondence:
| | - Xin Ming Matthew Zhou
- Translational Addiction Research Laboratory, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, 33 Ursula Franklin Street, Toronto, ON M5S 2S1, Canada; (X.M.M.Z.); (Z.B.); (B.L.F.)
- Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, 27 King’s College Circle, Toronto, ON M5S 3H7, Canada
| | - Zoe Bourgault
- Translational Addiction Research Laboratory, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, 33 Ursula Franklin Street, Toronto, ON M5S 2S1, Canada; (X.M.M.Z.); (Z.B.); (B.L.F.)
- Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, 27 King’s College Circle, Toronto, ON M5S 3H7, Canada
| | - Bernard Le Foll
- Translational Addiction Research Laboratory, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, 33 Ursula Franklin Street, Toronto, ON M5S 2S1, Canada; (X.M.M.Z.); (Z.B.); (B.L.F.)
- Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, 27 King’s College Circle, Toronto, ON M5S 3H7, Canada
- Addictions Division, Centre for Addiction and Mental Health, 100 Stokes Street, Toronto, ON M6J 1H4, Canada
- Department of Psychiatry, Faculty of Medicine, University of Toronto, 250 College Street, Toronto, ON M5T 1R8, Canada
- Institute of Medical Sciences, University of Toronto, 1 King’s College Circle, Room 2374, Toronto, ON M5S 1A8, Canada
- Department of Family and Community Medicine, University of Toronto, 500 University Avenue, 5th Floor, Toronto, ON M5G 1V7, Canada
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11
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Miralpeix C, Reguera AC, Fosch A, Zagmutt S, Casals N, Cota D, Rodríguez-Rodríguez R. Hypothalamic endocannabinoids in obesity: an old story with new challenges. Cell Mol Life Sci 2021; 78:7469-7490. [PMID: 34718828 PMCID: PMC8557709 DOI: 10.1007/s00018-021-04002-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/28/2021] [Accepted: 10/19/2021] [Indexed: 11/20/2022]
Abstract
The crucial role of the hypothalamus in the pathogenesis of obesity is widely recognized, while the precise molecular and cellular mechanisms involved are the focus of intense research. A disrupted endocannabinoid system, which critically modulates feeding and metabolic functions, through central and peripheral mechanisms, is a landmark indicator of obesity, as corroborated by investigations centered on the cannabinoid receptor CB1, considered to offer promise in terms of pharmacologically targeted treatment for obesity. In recent years, novel insights have been obtained, not only into relation to the mode of action of CB receptors, but also CB ligands, non-CB receptors, and metabolizing enzymes considered to be part of the endocannabinoid system (particularly the hypothalamus). The outcome has been a substantial expansion in knowledge of this complex signaling system and in drug development. Here we review recent literature, providing further evidence on the role of hypothalamic endocannabinoids in regulating energy balance and the implication for the pathophysiology of obesity. We discuss how these lipids are dynamically regulated in obesity onset, by diet and metabolic hormones in specific hypothalamic neurons, the impact of gender, and the role of endocannabinoid metabolizing enzymes as promising targets for tackling obesity and related diseases.
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Affiliation(s)
- Cristina Miralpeix
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, 3300, Bordeaux, France.
| | - Ana Cristina Reguera
- Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Josep Trueta S/N, 08195, Sant Cugat del Vallès, Spain
| | - Anna Fosch
- Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Josep Trueta S/N, 08195, Sant Cugat del Vallès, Spain
| | - Sebastian Zagmutt
- Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Josep Trueta S/N, 08195, Sant Cugat del Vallès, Spain
| | - Núria Casals
- Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Josep Trueta S/N, 08195, Sant Cugat del Vallès, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de La Obesidad Y La Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Daniela Cota
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, 3300, Bordeaux, France
| | - Rosalía Rodríguez-Rodríguez
- Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Josep Trueta S/N, 08195, Sant Cugat del Vallès, Spain.
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12
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UHPLC-MS-Based Serum and Urine Metabolomics Reveals the Anti-Diabetic Mechanism of Ginsenoside Re in Type 2 Diabetic Rats. Molecules 2021; 26:molecules26216657. [PMID: 34771066 PMCID: PMC8588396 DOI: 10.3390/molecules26216657] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 11/17/2022] Open
Abstract
Panax ginseng was employed in the treatment of “Xiao-Ke” symptom, which nowadays known as diabetes mellitus, in traditional Chinese medicine for more than a thousand years. Ginsenoside Re was the major pharmacologic ingredient found abundantly in ginseng. However, the anti-diabetic of Ginsenoside Re and its underlying mechanism in metabolic level are still unclear. Serum and urine metabolomic method was carried out to investigate the anti-diabetic pharmacological effects and the potential mechanism of Ginsenoside Re on high-fat diet combined streptozotocin-induced type 2 diabetes mellitus (T2DM) rats based on ultra-high-performance liquid chromatography coupled with quadrupole exactive orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap/MS). Serum and urine samples were collected from the control group (CON), T2DM group, metformin (MET) treatment group, and ginsenoside Re treatment group after intervention. The biochemical parameters of serum were firstly analyzed. The endogenous metabolites in serum and urine were detected by UHPLC-MS. The potential metabolites were screened by multivariate statistical analysis and identified by accurate mass measurement, MS/MS, and metabolite databases. The anti-diabetic-related metabolites were analyzed by KEGG metabolic pathway, and its potential mechanism was discussed. The treatment of ginsenoside Re significantly reduced the blood glucose and serum lipid level improved the oxidative stress caused by T2DM. Biochemical parameters (urea nitrogen, uric acid) showed that ginsenoside Re could improve renal function in T2DM rats. Respective 2 and 6 differential metabolites were found and identified in serum and urine of ginsenoside Re compared with T2DM group and enriched in KEGG pathway. Metabolic pathways analysis indicated that the differential metabolites related to T2DM were mainly involved in arachidonic acid metabolism, Vitamin B6, steroid hormone biosynthesis, and bile secretion metabolic pathways. This study verified the anti-diabetic and anti-oxidation effects of ginsenoside Re, elaborated that ginsenoside Re has a good regulation of the metabolic disorder in T2DM rats, which could promote insulin secretion, stimulated cannabinoid type 1 receptor (CB1), and CaMKK β to activate AMPK signaling pathway, inhibited insulin resistance, and improved blood glucose uptake and diabetic nephropathy, so as to play the role of anti-diabetic.
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13
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Bisogno T, Lauritano A, Piscitelli F. The Endocannabinoid System: A Bridge between Alzheimer's Disease and Gut Microbiota. Life (Basel) 2021; 11:934. [PMID: 34575083 PMCID: PMC8470731 DOI: 10.3390/life11090934] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/03/2021] [Accepted: 09/04/2021] [Indexed: 12/12/2022] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease that progresses from mild cognitive impairment to severe dementia over time. The main clinical hallmarks of the disease (e.g., beta-amyloid plaques and neurofibrillary tangles) begin during preclinical AD when cognitive deficits are not yet apparent. Hence, a more profound understanding of AD pathogenesis is needed to develop new therapeutic strategies. In this context, the endocannabinoid (eCB) system and the gut microbiome are increasingly emerging as important players in maintaining the general homeostasis and the health status of the host. However, their interaction has come to light just recently with gut microbiota regulating the eCB tone at both receptor and enzyme levels in intestinal and adipose tissues. Importantly, eCB system and gut microbiome, have been suggested to play a role in AD in both animal and human studies. Therefore, the microbiome gut-brain axis and the eCB system are potential common denominators in the AD physiopathology. Hence, the aim of this review is to provide a general overview on the role of both the eCB system and the microbiome gut-brain axis in AD and to suggest possible mechanisms that underlie the potential interplay of these two systems.
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Affiliation(s)
- Tiziana Bisogno
- Endocannabinoid Research Group, Istituto di Farmacologia Traslazionale, Consiglio Nazionale Delle Ricerche, Area Della Ricerca di Roma 2 Via Fosso del Cavaliere 100, 00133 Roma, Italy
| | - Anna Lauritano
- Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Via Campi Flegrei 34, 80078 Pozzuoli, Italy;
| | - Fabiana Piscitelli
- Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Via Campi Flegrei 34, 80078 Pozzuoli, Italy;
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14
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Role of the Endocannabinoid System in the Adipose Tissue with Focus on Energy Metabolism. Cells 2021; 10:cells10061279. [PMID: 34064024 PMCID: PMC8224009 DOI: 10.3390/cells10061279] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/12/2021] [Accepted: 05/15/2021] [Indexed: 12/15/2022] Open
Abstract
The endocannabinoid system is involved in a wide range of processes including the control of energy acquisition and expenditure. Endocannabinoids and their receptors are present in the central nervous system but also in peripheral tissues, notably the adipose tissues. The endocannabinoid system interacts with two main hormones regulating appetite, namely leptin and ghrelin. The inhibitory effect of the cannabinoid receptor 1 (CB1) antagonist rimonabant on fat mass suggested that the endocannabinoid system can also have a peripheral action in addition to its effect on appetite reduction. Thus, several investigations have focused on the peripheral role of the endocannabinoid system in the regulation of metabolism. The white adipose tissue stores energy as triglycerides while the brown adipose tissue helps to dissipate energy as heat. The endocannabinoid system regulates several functions of the adipose tissues to favor energy accumulation. In this review we will describe the presence of the endocannabinoid system in the adipose tissue. We will survey the role of the endocannabinoid system in the regulation of white and brown adipose tissue metabolism and how the eCB system participates in obesity and metabolic diseases.
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15
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Dione N, Lacroix S, Taschler U, Deschênes T, Abolghasemi A, Leblanc N, Di Marzo V, Silvestri C. Mgll Knockout Mouse Resistance to Diet-Induced Dysmetabolism Is Associated with Altered Gut Microbiota. Cells 2020; 9:E2705. [PMID: 33348740 PMCID: PMC7765900 DOI: 10.3390/cells9122705] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/10/2020] [Accepted: 12/10/2020] [Indexed: 12/13/2022] Open
Abstract
Monoglyceride lipase (MGLL) regulates metabolism by catabolizing monoacylglycerols (MAGs), including the endocannabinoid 2-arachidonoyl glycerol (2-AG) and some of its bioactive congeners, to the corresponding free fatty acids. Mgll knockout mice (Mgll-/-) exhibit elevated tissue levels of MAGs in association with resistance to the metabolic and cardiovascular perturbations induced by a high fat diet (HFD). The gut microbiome and its metabolic function are disrupted in obesity in a manner modulated by 2-arachidonoyl glycerol (2-AG's) main receptors, the cannabinoid CB1 receptors. We therefore hypothesized that Mgll-/- mice have an altered microbiome, that responds differently to diet-induced obesity from that of wild-type (WT) mice. We subjected mice to HFD and assessed changes in the microbiomes after 8 and 22 weeks. As expected, Mgll-/- mice showed decreased adiposity, improved insulin sensitivity, and altered circulating incretin/adipokine levels in response to HFD. Mgll-/- mice on a chow diet exhibited significantly higher levels of Hydrogenoanaerobacterium, Roseburia, and Ruminococcus than WT mice. The relative abundance of the Lactobacillaceae and Coriobacteriaceae and of the Lactobacillus, Enterorhabdus, Clostridium_XlVa, and Falsiporphyromonas genera was significantly altered by HFD in WT but not Mgll-/- mice. Differently abundant families were also associated with changes in circulating adipokine and incretin levels in HFD-fed mice. Some gut microbiota family alterations could be reproduced by supplementing 2-AG or MAGs in culturomics experiments carried out with WT mouse fecal samples. We suggest that the altered microbiome of Mgll-/- mice contributes to their obesity resistant phenotype, and results in part from increased levels of 2-AG and MAGs.
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Affiliation(s)
- Niokhor Dione
- Département de Médecine, Université Laval, Québec, QC G1V 0A6, Canada; (N.D.); (A.A.); (V.D.M.)
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in metabolic Health, Québec, QC G1V 4G5, Canada; (S.L.); (T.D.); (N.L.)
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, QC G1V 4G5, Canada
| | - Sébastien Lacroix
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in metabolic Health, Québec, QC G1V 4G5, Canada; (S.L.); (T.D.); (N.L.)
- Institut sur la Nutrition et les Aliments Fonctionnels, Université Laval, Québec, QC G1V 0A6, Canada
- Faculté des Sciences de L’agriculture et de L’alimentation, Université Laval, Québec, QC G1V 0A6, Canada
| | - Ulrike Taschler
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria;
| | - Thomas Deschênes
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in metabolic Health, Québec, QC G1V 4G5, Canada; (S.L.); (T.D.); (N.L.)
- Institut sur la Nutrition et les Aliments Fonctionnels, Université Laval, Québec, QC G1V 0A6, Canada
- Faculté des Sciences de L’agriculture et de L’alimentation, Université Laval, Québec, QC G1V 0A6, Canada
| | - Armita Abolghasemi
- Département de Médecine, Université Laval, Québec, QC G1V 0A6, Canada; (N.D.); (A.A.); (V.D.M.)
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in metabolic Health, Québec, QC G1V 4G5, Canada; (S.L.); (T.D.); (N.L.)
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, QC G1V 4G5, Canada
| | - Nadine Leblanc
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in metabolic Health, Québec, QC G1V 4G5, Canada; (S.L.); (T.D.); (N.L.)
- Institut sur la Nutrition et les Aliments Fonctionnels, Université Laval, Québec, QC G1V 0A6, Canada
- Faculté des Sciences de L’agriculture et de L’alimentation, Université Laval, Québec, QC G1V 0A6, Canada
| | - Vincenzo Di Marzo
- Département de Médecine, Université Laval, Québec, QC G1V 0A6, Canada; (N.D.); (A.A.); (V.D.M.)
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in metabolic Health, Québec, QC G1V 4G5, Canada; (S.L.); (T.D.); (N.L.)
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, QC G1V 4G5, Canada
- Institut sur la Nutrition et les Aliments Fonctionnels, Université Laval, Québec, QC G1V 0A6, Canada
- Faculté des Sciences de L’agriculture et de L’alimentation, Université Laval, Québec, QC G1V 0A6, Canada
- Institute of Biomolecular Chemistry, National Research Council, 80078 Pozzuoli, NA, Italy
| | - Cristoforo Silvestri
- Département de Médecine, Université Laval, Québec, QC G1V 0A6, Canada; (N.D.); (A.A.); (V.D.M.)
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in metabolic Health, Québec, QC G1V 4G5, Canada; (S.L.); (T.D.); (N.L.)
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, QC G1V 4G5, Canada
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16
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Maternal high-fat diet induces long-term obesity with sex-dependent metabolic programming of adipocyte differentiation, hypertrophy and dysfunction in the offspring. Clin Sci (Lond) 2020; 134:921-939. [PMID: 32239178 DOI: 10.1042/cs20191229] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 03/19/2020] [Accepted: 04/01/2020] [Indexed: 12/13/2022]
Abstract
Maternal obesity determines obesity and metabolic diseases in the offspring. The white adipose tissue (WAT) orchestrates metabolic pathways, and its dysfunction contributes to metabolic disorders in a sex-dependent manner. Here, we tested if sex differences influence the molecular mechanisms of metabolic programming of WAT in offspring of obese dams. To this end, maternal obesity was induced with high-fat diet (HFD) and the offspring were studied at an early phase [postnatal day 21 (P21)], a late phase (P70) and finally P120. In the early phase we found a sex-independent increase in WAT in offspring of obese dams using magnetic resonance imaging (MRI), which was more pronounced in females than males. While the adipocyte size increased in both sexes, the distribution of WAT differed in males and females. As mechanistic hints, we identified an inflammatory response in females and a senescence-associated reduction in the preadipocyte factor DLK in males. In the late phase, the obese body composition persisted in both sexes, with a partial reversal in females. Moreover, female offspring recovered completely from both the adipocyte hypertrophy and the inflammatory response. These findings were linked to a dysregulation of lipolytic, adipogenic and stemness-related markers as well as AMPKα and Akt signaling. Finally, the sex-dependent metabolic programming persisted with sex-specific differences in adipocyte size until P120. In conclusion, we do not only provide new insights into the molecular mechanisms of sex-dependent metabolic programming of WAT dysfunction, but also highlight the sex-dependent development of low- and high-grade pathogenic obesity.
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17
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Tardelli M. Monoacylglycerol lipase reprograms lipid precursors signaling in liver disease. World J Gastroenterol 2020; 26:3577-3585. [PMID: 32742127 PMCID: PMC7366061 DOI: 10.3748/wjg.v26.i25.3577] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 06/18/2020] [Accepted: 06/23/2020] [Indexed: 02/06/2023] Open
Abstract
Dietary oversupply of triglycerides represent the hallmark of obesity and connected complications in the liver such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, which eventually progress to cirrhosis and hepatocellular carcinoma. Monoacylglycerol lipase is the last enzymatic step in the hydrolysis of triglycerides, generating glycerol and fatty acids (FAs), which are signaling precursors in physiology and disease. Notably, monoacylglycerol lipase (MGL) also hydrolyzes 2-arachidonoylglycerol, which is a potent ligand within the endocannabinoid system, into arachidonic acid - a precursor for prostaglandin synthesis; thus representing a pivotal substrates provider in multiple organs for several intersecting biological pathways ranging from FA metabolism to inflammation, pain and appetite. MGL inhibition has been shown protective in limiting several liver diseases as FAs may drive hepatocyte injury, fibrogenesis and de- activate immune cells, however the complexity of MGL network system still needs further and deeper understanding. The present review will focus on MGL function and FA partitioning in the horizons of liver disease.
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Affiliation(s)
- Matteo Tardelli
- Division of Gastroenterology and Hepatology, Joan and Sanford I Weill Cornell Department of Medicine, Weill Cornell Medical College, New York, NY 10021, United States
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Internal Medicine III, Medical University of Vienna, Vienna 1040, Austria
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18
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Hofer P, Taschler U, Schreiber R, Kotzbeck P, Schoiswohl G. The Lipolysome-A Highly Complex and Dynamic Protein Network Orchestrating Cytoplasmic Triacylglycerol Degradation. Metabolites 2020; 10:E147. [PMID: 32290093 PMCID: PMC7240967 DOI: 10.3390/metabo10040147] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 04/03/2020] [Accepted: 04/08/2020] [Indexed: 12/25/2022] Open
Abstract
The catabolism of intracellular triacylglycerols (TAGs) involves the activity of cytoplasmic and lysosomal enzymes. Cytoplasmic TAG hydrolysis, commonly termed lipolysis, is catalyzed by the sequential action of three major hydrolases, namely adipose triglyceride lipase, hormone-sensitive lipase, and monoacylglycerol lipase. All three enzymes interact with numerous protein binding partners that modulate their activity, cellular localization, or stability. Deficiencies of these auxiliary proteins can lead to derangements in neutral lipid metabolism and energy homeostasis. In this review, we summarize the composition and the dynamics of the complex lipolytic machinery we like to call "lipolysome".
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Affiliation(s)
- Peter Hofer
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; (P.H.); (U.T.); (R.S.)
| | - Ulrike Taschler
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; (P.H.); (U.T.); (R.S.)
| | - Renate Schreiber
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; (P.H.); (U.T.); (R.S.)
| | - Petra Kotzbeck
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria;
| | - Gabriele Schoiswohl
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; (P.H.); (U.T.); (R.S.)
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19
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Ran L, Wang X, Mi A, Liu Y, Wu J, Wang H, Guo M, Sun J, Liu B, Li Y, Wang D, Jiang R, Wang N, Gao W, Zeng L, Huang L, Chen X, LeRoith D, Liang B, Li X, Wu Y. Loss of Adipose Growth Hormone Receptor in Mice Enhances Local Fatty Acid Trapping and Impairs Brown Adipose Tissue Thermogenesis. iScience 2019; 16:106-121. [PMID: 31154207 PMCID: PMC6545351 DOI: 10.1016/j.isci.2019.05.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 04/10/2019] [Accepted: 05/13/2019] [Indexed: 01/06/2023] Open
Abstract
Growth hormone (GH) binds to its receptor (growth hormone receptor [GHR]) to exert its pleiotropic effects on growth and metabolism. Disrupted GH/GHR actions not only fail growth but also are involved in many metabolic disorders, as shown in murine models with global or tissue-specific Ghr deficiency and clinical observations. Here we constructed an adipose-specific Ghr knockout mouse model Ad-GHRKO and studied the metabolic adaptability of the mice when stressed by high-fat diet (HFD) or cold. We found that disruption of adipose Ghr accelerated dietary obesity but protected the liver from ectopic adiposity through free fatty acid trapping. The heat-producing brown adipose tissue burning and white adipose tissue browning induced by cold were slowed in the absence of adipose Ghr but were recovered after prolonged cold acclimation. We conclude that at the expense of excessive subcutaneous fat accumulation and lower emergent cold tolerance, down-tuning adipose GHR signaling emulates a healthy obesity situation which has metabolic advantages against HFD.
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Affiliation(s)
- Liyuan Ran
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian 116044, China
| | - Xiaoshuang Wang
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian 116044, China
| | - Ai Mi
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian 116044, China
| | - Yanshuang Liu
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China
| | - Jin Wu
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian 116044, China
| | - Haoan Wang
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian 116044, China
| | - Meihua Guo
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian 116044, China
| | - Jie Sun
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian 116044, China; College of Integrative Medicine, Dalian Medical University, Dalian 116044, China
| | - Bo Liu
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian 116044, China
| | - Youwei Li
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian 116044, China
| | - Dan Wang
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian 116044, China
| | - Rujiao Jiang
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian 116044, China
| | - Ning Wang
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian 116044, China
| | - Wenting Gao
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian 116044, China
| | - Li Zeng
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China
| | - Lin Huang
- Department of Pathophysiology, Dalian Medical University, Dalian 116044, China
| | - Xiaoli Chen
- Department of Food Science and Nutrition, University of Minnesota, Twin Cities, MN, USA
| | - Derek LeRoith
- Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn Mount Sinai School of Medicine, New York 10029, USA
| | - Bin Liang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China.
| | - Xin Li
- Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York 10010, USA; Department of Urology, New York University Langone Medical Center, New York 10016, USA; Perlmutter Cancer Institute, New York University Langone Medical Center, New York 10016, USA.
| | - Yingjie Wu
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116044, China; National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian 116044, China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian 116044, China; College of Integrative Medicine, Dalian Medical University, Dalian 116044, China; Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn Mount Sinai School of Medicine, New York 10029, USA; Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York 10010, USA.
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