title: Resistin-like molecule alpha decreases glucose tolerance during intestinal inflammation.
abstract: Resistin-like molecule alpha (Relm-alpha) is a secreted cysteine-rich protein belonging to a newly defined family of proteins, including resistin, Relm-beta, and Relm-gamma. 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-alpha at baseline and following an experimental model of colitis. Relm-alpha 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-alpha was uncovered as Retnla(-/-) mice were markedly protected from DSS-induced disease activity and histopathological features. Relm-alpha 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-kappaB, ERK1/2, and p38 in macrophages and eosinophils. Following DSS exposure, serum level of Relm-alpha 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-alpha in the regulation of colonic inflammation and a novel link between colonic injury, glucose tolerance, and energy intake.
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Munitz
authors.forename: Luqman
authors.initials: L
authors.lastname: Seidu
authors.forename: Eric T
authors.initials: ET
authors.lastname: Cole
authors.forename: Richard
authors.initials: R
authors.lastname: Ahrens
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hogan
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016207:Cytokines; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; C413576:Retnla protein, mouse; D016264:Dextran Sulfate; D005947:Glucose