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: Helen Luck, Sue Tsai, Jason Chung, Xavier Clemente-Casares, Magar Ghazarian, Xavier S Revelo, Helena Lei, Cynthia T Luk, Sally Yu Shi, Anuradha Surendra, Julia K Copeland, Jennifer Ahn, David Prescott, Brittany A Rasmussen, Melissa Hui Yen Chng, Edgar G Engleman, Stephen E Girardin, Tony K T Lam, Kenneth Croitoru, Shannon Dunn, Dana J Philpott, David S Guttman, Minna Woo, Shawn Winer, Daniel A Winer
• Journal: Cell metabolism (Cell Metab) Vol. 21 Issue 4 Pg. 527-42 (Apr 07 2015) ISSN: 1932-7420 [Electronic] United States
• PMID: 25863246 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• Integrin beta Chains
• integrin beta7
• Mesalamine

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Blotting, Western
• Cytokines (blood)
• Diet, High-Fat (adverse effects)
• Flow Cytometry
• Gastrointestinal Tract (drug effects, immunology)
• Histological Techniques
• Immunity, Mucosal (immunology)
• Immunohistochemistry
• Insulin Resistance (immunology)
• Integrin beta Chains (metabolism)
• Mesalamine (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mucous Membrane (cytology, immunology)
• Obesity (immunology)