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Title:   Author  item
                                            FJAERE, EVEN - University Of Copenhagenitem
                                            AUNE, ULRIKE - University Of Copenhagenitem
                                            KEENAN, ALISON - University Of Copenhagenitem
                                            MA, TAO - University Of Copenhagenitem
                                            LILLEFOSSE, HALDIS - National Institute Of Nutrition And Seafood Research, Nifesitem
                                            XI, YANNAN - University Of Californiaitem
                                            Newman, Johnitem
                                            HAJ, FAWAZ - University Of Californiaitem
                                            LIASET, BJORN - National Institute Of Nutrition And Seafood Research, Nifesitem
                                            KRISTIANSEN, KARSTEN - University Of Copenhagenitem
                                            MADSEN, LISE - University Of Copenhagen
  Submitted to: Journal of Biological Chemistry
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 11/1/2013
                                    Publication  Date: 4/17/2014
                                    Citation: Fjaere, E., Aune, U., Keenan, A., Ma, T., Lillefosse, H., Xi, Y., Newman, J.W., Haj, F., Liaset, B., Kristiansen, K., Madsen, L. 2014. Indomethacin treatment prevents diet-induced obesity and insulin resistance, but not glucose intolerance in C57BL/6J mice. Journal of Biological Chemistry. DOI: 10.1074/jbc.M113525220.Interpretive Summary: Cyclooxygenase (COX) is an enzyme which produces an activated lipid substrate for a variety of enzymes which in turn yield an array of products with important roles in the regulation of cell growth and inflammation.  In this study, the metabolic consequences of cyclooxygenase inhibition were assessed in obesity-prone mice an obesogenic fed a high fat/high sucrose diet.  Mice were housed under thermoneutral conditions, i.e. temperatures were maintained at body temperature, and fed these diets for 7wks with or without the COX inhibitor indomethacin.   After 6 weeks, mice were subjected to an intraperitoneal glucose tolerance test, insulin tolerance test, pyruvate tolerance test, and indirect calorimetry measurements.  Indomethacin treatment prevented diet-induced obesity and maintained insulin sensitivity and pancreatic beta-cell function.  However, indomethacin-treated mice exhibited increased hepatic glucose production and reduced glucose clearance.  Considering the worldwide use of COX inhibitors and intake of fat and carbohydrates, the relevance of these findings to humans warrants further investigation.
                                Technical Abstract: OBJECTIVE: We performed experiments to examine the metabolic consequences of inhibition of cyclooxygenase (COX) activity in obesity-prone C57BL/6J mice fed a high fat/high sucrose (HF/HS) diet.

RESEARCH DESIGN AND METHODS: C57BL/6J mice were fed a HF/HS diet for 7 weeks under thermoneutral conditions with or without indomethacin added to the feed (16 mg/kg). After 6 weeks, mice were subjected to an intraperitoneal glucose tolerance test, insulin tolerance test, pyruvate tolerance test, and indirect calorimetry measurements. 

RESULTS: Treatment with indomethacin prevented HF/HS diet-induced obesity. Whole body insulin sensitivity, first phase insulin secretion, and beta cell islet mass in mice fed HF/HS plus indomethacin were similar to those of mice fed a low fat (LF) diet. However, mice treated with indomethacin in combination with a HF/HS, but not a LF diet, exhibited pronounced glucose intolerance, and hepatic glucose output was significantly increased. 

CONCLUSION: Mice fed an indomethacin supplemented HF/HS diet exhibited impaired systemic glucose clearance during a glucose challenge suggesting that inability to compensate for a constitutive high hepatic glucose output may in part contribute to the observed glucose intolerance. Considering the worldwide use of COX inhibitors and intake of fat and carbohydrates, the relevance of these findings to humans warrants further investigation.


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