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Decreases Glucose Tolerance during Intestinal Inflammation1Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229
Resistin-like molecule 
(Relm-) is a secreted cysteine-rich protein belonging to a newly defined family of proteins, including resistin, Relm-β, and Relm-
. Resistin was initially defined based on its insulin resistance activity, but the family members are highly up-regulated in various inflammatory states, especially those involving intestinal inflammation. In this study, we report the role of Relm- at baseline and following an experimental model of colitis. Relm- was readily detected in the serum at baseline (4–5 ng/ml), and its level was regulated by energy uptake. Retnla–/– mice had decreased baseline circulating leptin levels, but displayed normal glucose, glucose clearance, and insulin levels. Following exposure to the oral innate trigger dextran sodium sulfate (DSS), a nonredundant proinflammatory role for Relm- was uncovered as Retnla–/– mice were markedly protected from DSS-induced disease activity and histopathological features. Relm- regulated eosinophil-directed cytokines (e.g., IL-5, CCL11/eotaxin-1, and CCL5/RANTES) and IL-17 ex vivo. Consistently, DSS-treated Retnla–/– mice displayed substantially decreased eosinophil accumulation and decreased phosphorylation of NF-
B, ERK1/2, and p38 in macrophages and eosinophils. Following DSS exposure, serum level of Relm- was up-regulated, and DSS-treated Retnla–/– mice were markedly protected from hyperglycemia induced by glucose injection independent of changes in insulin levels. Retnla–/– mice were protected from increases in gut hormone serum levels of gastric inhibitory polypeptide and peptide YY that were induced following DSS treatment. These findings demonstrate a central proinflammatory role for Relm- in the regulation of colonic inflammation and a novel link between colonic injury, glucose tolerance, and energy intake.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants P01 HL-076383 (to M.E.R.) and R01 AI057803 (to M.E.R.); Crohn’s and Colitis Foundation of America Career Development Award 2007 (to S.P.H.); Digestive Disease Health Center Pilot and Feasibility Research Grant of the National Institutes of Health-supported Cincinnati Children’s Hospital Research Foundation Digestive Health Center (1P30DK078392) (to S.P.H.); National Institutes of Health Grant R01 AI073553 (to S.P.H.); a fellowship award (to A.M.) from the Machiah Foundation; a supporting foundation of the Jewish Community Endowment Fund; and the generous support of the Alexander M. and June L. Maisin Foundation and the Kanbar Charitable Trust, the Campaign Urging Research for Eosinophilic Disorders, the Food Allergy Project, and the Buckeye Foundation.
2 Address correspondence and reprint requests to Dr. Marc E. Rothenberg, Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229. E-mail address: Rothenberg{at}cchmc.org
3 Abbreviations used in this paper: Relm, resistin-like molecule; DAPI, 4',6-diamidino-2-phenylindole dihydrochloride; DSS, dextran sodium sulfate; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide-1; IBD, inflammatory bowel disease; MBP, major basic protein; PYY, peptide YY.
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