An inhibitor of phospholipase A2 group IIA modulates adipocyte signaling and protects against diet-induced metabolic syndrome in rats

Iyer, Abishek and Lim, Junxian and Poudyal, Hemant and Reid, Robert C. and Suen, Jacky Y. and Webster, Julie and Prins, Johannes B. and Whitehead, Jonathan P. and Fairlie, David P. and Brown, Lindsay (2012) An inhibitor of phospholipase A2 group IIA modulates adipocyte signaling and protects against diet-induced metabolic syndrome in rats. Diabetes, 61 (9). pp. 2320-2329. ISSN 0012-1797

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Abstract

Obesity, type 2 diabetes, and cardiovascular disease correlate with infiltration to adipose tissue of different immune cells, with uncertain influences on metabolism. Rats were fed a diet high in carbohydrates and saturated fats to develop diet-induced obesity over 16 weeks. This nutritional overload caused overexpression and secretion of phospholipase A2 group IIA (pla2g2a) from immune cells in adipose tissue rather than adipocytes, whereas expression of adipose-specific phospholipase A2 (pla2g16) was unchanged. These immune cells produce prostaglandin E2 (PGE2), which influences adipocyte signaling. We found that a selective inhibitor of human pla2g2a (5-(4-benzyloxyphenyl)-(4S)-(phenyl-heptanoylamino)-pentanoic acid [KH064]) attenuated secretion of PGE2 from human immune cells stimulated with the fatty acid, palmitic acid, or with lipopolysaccharide. Oral administration of KH064 (5 mg/kg/day) to rats fed the high-carbohydrate, high-fat diet prevented the overexpression of pla2g2a and the increased macrophage infiltration and elevated PGE2 concentrations in adipose tissue. The treatment also attenuated visceral adiposity and reversed most characteristics of metabolic syndrome, producing marked improvements in insulin sensitivity, glucose intolerance, and cardiovascular abnormalities. We suggest that pla2g2a may have a causal relationship with chronic adiposity and metabolic syndrome and that its inhibition in vivo may be a valuable new approach to treat obesity, type 2 diabetes, and metabolic dysfunction in humans.


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Item Type: Article (Commonwealth Reporting Category C)
Refereed: Yes
Item Status: Live Archive
Additional Information: This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1179/-/DC1. The article is covered by a Creative Commons licence. Copyright 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
Faculty / Department / School: Historic - Faculty of Sciences - Department of Biological and Physical Sciences
Date Deposited: 06 Jan 2013 05:03
Last Modified: 22 Jul 2014 02:54
Uncontrolled Keywords: fatty tissue; high-fat diet; rats; obese
Fields of Research : 11 Medical and Health Sciences > 1101 Medical Biochemistry and Metabolomics > 110102 Medical Biochemistry: Carbohydrates
11 Medical and Health Sciences > 1101 Medical Biochemistry and Metabolomics > 110107 Metabolic Medicine
10 Technology > 1004 Medical Biotechnology > 100499 Medical Biotechnology not elsewhere classified
Socio-Economic Objective: C Society > 92 Health > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920104 Diabetes
Identification Number or DOI: 10.2337/db11-1179
URI: http://eprints.usq.edu.au/id/eprint/21871

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