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 Dunn; Dana J. Philpott; David S. Guttman; Minna Woo; Shawn Winer; Daniel A. Winer

doi:10.1016/j.cmet.2015.03.001

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

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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.

Original language	English (US)
Pages (from-to)	527-542
Number of pages	16
Journal	Cell Metabolism
Volume	21
Issue number	4
DOIs	https://doi.org/10.1016/j.cmet.2015.03.001
State	Published - Apr 7 2015
Externally published	Yes

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Publisher Copyright:
© 2015 Elsevier Inc.

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Luck, H., Tsai, S., Chung, J., Clemente-Casares, X., Ghazarian, M., Revelo, X. S., Lei, H., Luk, C. T., Shi, S. Y., Surendra, A., Copeland, J. K., Ahn, J., Prescott, D., Rasmussen, B. A., Chng, M. H. Y., Engleman, E. G., Girardin, S. E., Lam, T. K. T., Croitoru, K., ... Winer, D. A. (2015). Regulation of obesity-related insulin resistance with gut anti-inflammatory agents. Cell Metabolism, 21(4), 527-542. https://doi.org/10.1016/j.cmet.2015.03.001

Luck, H, Tsai, S, Chung, J, Clemente-Casares, X, Ghazarian, M, Revelo, XS, Lei, H, Luk, CT, Shi, SY, Surendra, A, Copeland, JK, Ahn, J, Prescott, D, Rasmussen, BA, Chng, MHY, Engleman, EG, Girardin, SE, Lam, TKT, Croitoru, K, Dunn, S, Philpott, DJ, Guttman, DS, Woo, M, Winer, S & Winer, DA 2015, 'Regulation of obesity-related insulin resistance with gut anti-inflammatory agents', Cell Metabolism, vol. 21, no. 4, pp. 527-542. https://doi.org/10.1016/j.cmet.2015.03.001

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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.",

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

Abstract

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