Resistin-Like Molecule α Decreases Glucose Tolerance during Intestinal Inflammation

Abstract

Resistin-like molecule α (Relm-α) is a secreted cysteine-rich protein belonging to a newly defined family of proteins, including resistin, Relm-β, and Relm-γ. 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-α at baseline and following an experimental model of colitis. Relm-α 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-α was uncovered as Retnla−/− mice were markedly protected from DSS-induced disease activity and histopathological features. Relm-α 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-κB, ERK1/2, and p38 in macrophages and eosinophils. Following DSS exposure, serum level of Relm-α 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-α in the regulation of colonic inflammation and a novel link between colonic injury, glucose tolerance, and energy intake.

Paradoxical effects of constitutive human IL-32γ in transgenic mice during experimental colitis

“…Male mice of 10-12 wk were used. DSS (MP Biomedicals) was supplied in the drinking water as a 3.5% solution for 5 d. At regular time intervals, the mice were evaluated as described previously (33). Mice were anesthetized, killed, and large intestines (from cecum to anus) were quickly removed.…”

The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice

“…Given that Retnla is an alternatively activated macrophage-inducible gene 15,16 that modulates immune responses in inflammatory diseases 13,18,36,37 , and that atherosclerosis can be considered both a lipid metabolism disorder and a chronic inflammatory disease 23 , we examined whether Retnla deficiency also influences inflammatory plaque phenotypes. Consistent with the increased en face plaque area, aortic root lesions were also increased in Ldlr À / À Retnla À / À mice compared with Ldlr À / À mice (Fig.…”

“…Faecal bile acid excretion (μmol per day per 100 g body weight) ARTICLE family members, Retnlb and resistin are implicated as mediators of inflammation 46,56,57 and abundantly expressed in macrophages of atheroma involved in atherosclerosis development 45,58 13,18 , while in a model of chronic inflammation by Schistosoma mansoni infection, both the lung inflammation and liver fibrosis were increased by Retnla deficiency via an enhanced Th2 immune responses 36,37 . These results suggest that the beneficial and detrimental roles of Retnla in inflammatory diseases are likely influenced by the type of immune stimulus, the duration of the stimulus exposure and the tissue type.…”

“…Recent evidence has revealed possible roles of Retnla in metabolic regulation. For example, Retnla inhibited differentiation of adipocytes 17 and was downregulated in food-restricted mice 18,19 , lactating mice 20 and leptin receptor À / À (db/db) mice, a model of obesity and type 2 diabetes 21 . Nevertheless, the function of Retnla in metabolic regulation is yet to be defined.…”

Polarizing the T helper 17 response inCitrobacter rodentiuminfection via expression of resistin-like molecule α

“…[7][8][9] In contrast, studies by Rothenberg and colleagues uncovered a pro-inflammatory function for RELMα in mouse models of inflammatory bowel disease. 10,11 Our recent study focused on examining the role of RELMα in bacterial infection-induced inflammation. …”