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

Iyer, Abishek, Lim, Junxian, Poudyal, Hemant, Reid, Robert C., Suen, Jacky Y., Webster, Julie, Prins, Johannes B., Whitehead, Jonathan P., 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: 2320-2329.

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Author Iyer, Abishek
Lim, Junxian
Poudyal, Hemant
Reid, Robert C.
Suen, Jacky Y.
Webster, Julie
Prins, Johannes B.
Whitehead, Jonathan P.
Fairlie, David P.
Brown, Lindsay
Title An inhibitor of phospholipase A2 group IIA modulates adipocyte signaling and protects against diet-induced metabolic syndrome in rats
Formatted title An inhibitor of phospholipase A2 group IIA modulates adipocyte signaling and protects against diet-induced metabolic syndrome in rats
Journal name Diabetes  (ERA 2012 Listed)    (ERA 2010 Rank A*)   Check publisher's open access policy
Publication date 2012-09
Sub-type Article
DOI 10.2337/db11-1179
Volume number 61
Issue number 9
ISSN 0012-1797; 1939-327X
Start page 2320
End page 2329
Total pages 10
Place of publication Alexandria, VA, United States
Publisher American Diabetes Association
Collection year 2013
Language eng
Formatted 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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Created: Wed, 12 Sep 2012, 11:31:16 EST by Susan Allen on behalf of Institute for Molecular Bioscience