Resumen de la sesiĆ³n |
Tuesday, July 23 |
11:00 |
Modulation of Immunometabolism Via NLRX1 Or PLXDC2: Novel Bimodal Mechanisms for the Treatment of Inflammatory Bowel Diseases
* Silvio Danese, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Gastroenterology and Gastrointestinal Endoscopy Unit, Italy Jean-Frederic Colombel, Icahn School of Medicine at Mount Sinai, The Dr. Henry D. Janowitz Division of Gastroenterology, United States of America Florian Rieder, Department of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, United States of America Laurent Peyrin-Biroulet, Department of Gastroenterology, Nancy University Hospital, F-54500 Vanduvre-lès-Nancy, France; INSERM, NGERE, University of Lorraine, F-54000 Nancy, , France Britta Siegmund, Division of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Hu, Germany Severine Vermeire, Department of Gastroenterology and Hepatology, Department of Chronic Diseases and Metabolism, University Hospitals Leuven, KU Leuven, Belgium Marla Dubinsky, Division of Pediatric Gastroenterology and Nutrition, Mount Sinai Kravis Children's Hospital, Icahn School of Medicine Mount Sinai, United States of America Stefan Schreiber, Institute of Clinical Molecular Biology, Department of Internal Medicine,Christian-Albrechts-University and University Hospital Schleswig-Holstein, Ca, United States of America Andres Yarur, Division of Gastroenterology and Hepatology, Center for Inflammatory Bowel Diseases. Cedars Sinai Medical Center, United States of America Remo Panaccione, Division of Gastroenterology & Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Canada Brian Feagan, Department of Medicine, Division of Gastroenterology, University of Western Ontario, London, Ontario, Canada; Alimentiv Inc, London, Ontario, Canada; , Canada Rebecca Mosig, Landos Biopharma, United States of America Fabio Cataldi, Landos Biopharma, United States of America Bram Verstockt, University Hospitals Leuven- KU Leuven, Department of Gastroenterology and Hepatology- Department of Chronic Diseases and Metabolism, Belgium Immunometabolism exerts a bimodal action at the interface of extracellular immune response and intracellular metabolism (Chi. Cell Mol Immunol (19)). Hence, immunometabolic pathways represent an worthy target as a dual checkpoint for the inflammatory cycle. NLRX1 & PLXDC2 have been identified in immunometabolic pathways in multiple cell types in inflammatory bowel disease (IBD, Leber, et al. J Immunol 203(12); Tubau-Juni, et al. J Immunol 206(Supp)). This analysis compares these two key immunometabolic pathways. For both programs, in vitro murine T cell & macrophage differentiation & in vivo mouse dextran sodium sulfate (DSS) colitis models, gene expression, metabolic profiles & cytokine expression were assessed. NX-13, a novel NLRX1 agonist, resulted in regulation of cellular metabolism: activation of mitochondrial genes such as mt-nd3 & odgh and down-regulation of glucose uptake by murine T cells. NLRX1 stabilization by NX-13 increased antioxidant enzyme expression & reduced ROS in T cells. NX-13 specifically reduced effector T cells. These bimodal effects converge to dampened acute DSS colitis (Fig1A). PLXDC2 activation by LABP-69 directly reduced glycolysis, reflected by decreased extracellular acidification in bone marrow-derived macrophages (BMDM) stimulated with lipopolysaccharide as well as reduced superoxide levels in BMDM. PLXDC2 activation downregulated inflammatory cytokines TNFα & IFNγ in T cells. The PLXDC2 agonist PX-04 decreased inflammation in acute DSS colitis in mice (Fig1B). Agents targeting immunometabolism demonstrate innovative potential therapeutic MOAs applicable in IBD. NLRX1 & PLXDC2 represent distinct pathways that modulate the metabolic state simultaneously with inflammation and hence can be targeted to stop chronic inflammation. |
11:15 |
Suppression of Adipocyte ABHD6 in Mice Promotes Healthy Expansion of Adipose Tissue in Obesity
* Pegah Poursharifi, CRCHUM, Canada Camille Attané, CRCHUM Laura-Lee Klein, CRCHUM Sara-Ivana Calce, CRCHUM Covida Mootoosamy, CRCHUM Jonathan Shea, CRCHUM Isabelle Chenier, CRCHUM Anindya Ghosh, CRCHUM Clemence Schmitt, CRCHUM Roxane Lussier, CRCHUM Anfal Al-Mass, CRCHUM Yat Hei Leung, CRCHUM Abel Oppong, CRCHUM Mohamed Abu-Farha, Dasman Diabetes Institute Jehad Abubaker, Dasman Diabetes Institute Fahd Al-Mulla, Dasman Diabetes Institute Ying Bai, CRCHUM and Beijing University of Chinese Medicine Dongwei Zhang, Beijing University of Chinese Medicine Marie-Soleil Gauthier, IRCM Benoit Coulombe, IRCM Marie-Line Peyot, CRCHUM André Tchernof, IUCPQ, Université Laval S. R. Murthy Madiraju, CRCHUM Marc Prentki, CRCHUM Excessive accumulation of visceral fat in obesity often leads to insulin resistance, inflammation, type 2 diabetes and cardiovascular diseases. However, some obese individuals with obesity show healthy expansion of white adipose tissue (WAT), without cardiometabolic complications, and such obese condition is named metabolically healthy obesity (MHO). Global deletion of the monoacylglycerol (MAG) hydrolase, α/β-hydrolase domain-containing 6 (ABHD6) has revealed the therapeutic potential of ABHD6 inhibitors against obesity, yet the immunometabolic role of adipocyte ABHD6 in WAT expansion and energy balance in obesity is not known. We now show that while inducible adipocyte-specific ABHD6-KO (AA-KO) mice become obese upon high-fat diet (HFD) feeding, they do not display insulin resistance, fatty liver, and inflammation. AA-KO HFD-fed mice, show healthy expansion of visceral fat with smaller adipocytes, curtailed inflammation, and elevated lipolysis and fatty acid oxidation. AA-KO adipocytes-conditioned medium but not that from control mice promotes preadipocyte differentiation and anti-inflammatory polarization of WAT macrophages. We provide evidence that the favorable properties of the AA-KO adipocytes secretome may be due in part to the increased adiponectin and decreased IL-6 levels, and to the enhanced MAG levels which activates PPARs. The ABHD6 interactome consists in part of proteins involved in insulin signaling and inflammatory pathways. ABHD6 suppression in preadipocytes inhibits their proliferation and promotes adipocyte differentiation, synergistically with insulin. In insulin resistant female subjects, ABHD6 expression is elevated in the visceral fat and positively correlates with obesity and altered metabolic indices. Overall, the results indicate that adipose ABHD6 suppression prevents the metabolic and inflammation complications of obesity, but not obesity per se, possibly via MAG/PPAR activation and enhanced insulin signaling, and that AA-KO mice show promise as a model for the study of MHO. |
11:30 |
Investigating the role of endocannabinoid and immune system in the small intestine of severe obese subjects with type-2 diabetes
* Volatiana Rakotoarivelo, Centre de recherche de lInstitut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Université Laval, Canada Bénedicte Allam-Ndoul, Centre de Nutrition, Santé et Société (NUTRISS), INAF, Canada, Canada Thomas Z. Mayer, Centre de Nutrition, Santé et Société (NUTRISS), INAF, Canada, Canada Laurent Biertho, Centre de recherche de lInstitut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Université Laval, Canada, Canada Nicolas Flamand, Centre de recherche de lInstitut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Université Laval, Canada, Canada Vincenzo Di Marzo, Centre de recherche de lInstitut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Université Laval, Canada, Canada Alain Veilleux, Centre de Nutrition, Santé et Société (NUTRISS), INAF, Canada, Canada Obesity is currently considered as a multifactorial chronic disease and is accompanied by health complications including type-2 diabetes (T2D). Growing evidence has shown that low-grade inflammation associated with obesity and subsequent loss of gut barrier function contributes to insulin resistance. The endocannabinoids (eCBs), 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA, anandamide), and their main targets, the cannabinoid CB1 and CB2 receptors, are all expressed in the intestine. CB1 is present in metabolic tissues and regulates their function, while CB2 is predominant in immune cells where it modulates inflammation. Deciphering gut eCB signaling, therefore, encompasses both energy metabolism and chronic low-grade inflammation associated with obesity. We aimed to characterize the inflammatory status of the gut in response to long-term adaptation to obesity and T2D as well as to define how the human eCB system acts at the interface between energy metabolism and immunity. We obtained human ileal samples from bariatric surgery in subject with and without T2D. We showed that intestinal and circulating levels of eCBs and eCB-like compounds are higher in subjects with T2D. Moreover, expression analysis of 200 genes involved in inflammatory processes revealed that the expression of TLR4 and of genes coding for pro-inflammatory cytokines (i.e. IL1, IL6 and IL15) was lower in subjects with T2D. This apparent reduced local inflammatory status in the gut is opposed to the presence of a low-grade systemic inflammatory status, which has been previously reported in subjects with T2D, and this might be due in part to the fact that the T2D subjects were under treatment. Our study highlights gut specific inflammation mechanisms possibly linked to the eCB system. Understanding this process could lead to the identification of new targets for the treatment of obesity and related metabolic disorders. |