title: Regulation of obesity-related insulin resistance with gut anti-inflammatory agents.
abstract: Obesity has reached epidemic proportions, but little is known about its influence on the intestinal immune system. Here we show that the gut immune system is altered during high-fat diet (HFD) feeding and is a functional regulator of obesity-related insulin resistance (IR) that can be exploited therapeutically. Obesity induces a chronic phenotypic pro-inflammatory shift in bowel lamina propria immune cell populations. Reduction of the gut immune system, using beta7 integrin-deficient mice (Beta7(null)), decreases HFD-induced IR. Treatment of wild-type HFD C57BL/6 mice with the local gut anti-inflammatory, 5-aminosalicyclic acid (5-ASA), reverses bowel inflammation and improves metabolic parameters. These beneficial effects are dependent on adaptive and gut immunity and are associated with reduced gut permeability and endotoxemia, decreased visceral adipose tissue inflammation, and improved antigen-specific tolerance to luminal antigens. Thus, the mucosal immune system affects multiple pathways associated with systemic IR and represents a novel therapeutic target in this disease.
authors: Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Helen
authors: H
authors: Luck
authors: Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors: Sue
authors: S
authors: Tsai
authors: Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors: Jason
authors: J
authors: Chung
authors: Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors: Xavier
authors: X
authors: Clemente-Casares
authors: Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Magar
authors: M
authors: Ghazarian
authors: Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors: Xavier S
authors: XS
authors: Revelo
authors: Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors: Helena
authors: H
authors: Lei
authors: Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors: Cynthia T
authors: CT
authors: Luk
authors: Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors: Sally Yu
authors: SY
authors: Shi
authors: Centre for the Analysis of Genome Evolution & Function, University of Toronto, 33 Wilcocks Street, Toronto, ON M5S 3B3, Canada.
authors: Anuradha
authors: A
authors: Surendra
authors: Centre for the Analysis of Genome Evolution & Function, University of Toronto, 33 Wilcocks Street, Toronto, ON M5S 3B3, Canada.
authors: Julia K
authors: JK
authors: Copeland
authors: Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Jennifer
authors: J
authors: Ahn
authors: Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: David
authors: D
authors: Prescott
authors: Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors: Brittany A
authors: BA
authors: Rasmussen
authors: Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Palo Alto, CA 94305-5324, USA.
authors: Melissa Hui Yen
authors: MH
authors: Chng
authors: Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Palo Alto, CA 94305-5324, USA.
authors: Edgar G
authors: EG
authors: Engleman
authors: Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Stephen E
authors: SE
authors: Girardin
authors: Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors: Tony K T
authors: TK
authors: Lam
authors: Institute of Medical Science, Department of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Kenneth
authors: K
authors: Croitoru
authors: Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Shannon
authors: S
authors: Dunn
authors: Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Dana J
authors: DJ
authors: Philpott
authors: Centre for the Analysis of Genome Evolution & Function, University of Toronto, 33 Wilcocks Street, Toronto, ON M5S 3B3, Canada.
authors: David S
authors: DS
authors: Guttman
authors: Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada; Institute of Medical Science, Department of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Division of Endocrinology, Department of Medicine, University Health Network, University of Toronto, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada.
authors: Minna
authors: M
authors: Woo
authors: Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. Electronic address: shawn.winer@utoronto.ca.
authors: Shawn
authors: S
authors: Winer
authors: Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Pathology, University Health Network, 200 Elizabeth Street, Toronto, ON M5G 2C4, Canada. Electronic address: dan.winer@uhn.ca.
authors: Daniel A
authors: DA
authors: Winer
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015153:Blotting, Western; D016207:Cytokines / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects; D005434:Flow Cytometry; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000276:immunology*; D006652:Histological Techniques; D018928:Immunity, Mucosal / Q000276:immunology*; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000276:immunology*; D039641:Integrin beta Chains / Q000378:metabolism; D019804:Mesalamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009092:Mucous Membrane / Q000166:cytology / Q000276:immunology; D009765:Obesity / Q000276:immunology*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D039641:Integrin beta Chains; C091368:integrin beta7; D019804:Mesalamine