Regulation of obesity-related insulin resistance with gut anti-inflammatory agents

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 DunnDana J. Philpott, David S. Guttman, Minna Woo, Shawn Winer, Daniel A. Winer

Research output: Contribution to journalArticlepeer-review

137 Scopus citations

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 (Beta7null), 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.

Original languageEnglish (US)
Pages (from-to)527-542
Number of pages16
JournalCell Metabolism
Volume21
Issue number4
DOIs
StatePublished - Apr 7 2015
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by CIHR grant 119414 (D.A.W.), CDA grants OG-3-12-3844 (D.A.W.) and CS-5-12-3886 (D.A.W.), and the University of Toronto BBDC SunLife New Investigator Award (D.A.W.). S.T. received a CIHR Banting Fellowship. H. Luck and M.G. received Canada Graduate Scholarships. X.S.R. received a BBDC Fellowship in Diabetes Care (Eli Lilly Canada). We thank Charlotte Dong and Patricia Brubaker for FD4 assay protocols and Denis Reynaud at AFBM (The Hospital for Sick Children) in performing HPLC. We acknowledge the NIH Tetramer Core Facility for provision of tetramers.

Publisher Copyright:
© 2015 Elsevier Inc.

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