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Title:   Author  item
                                            CAMPBELL, CAITLIN - University Of Californiaitem
                                            GRAPOV, DMITRY - University Of Californiaitem
                                            FIEHN, OLIVER - University Of Californiaitem
                                            CHANDLER, CAROL - University Of Californiaitem
                                            BURNETT, DUSTIN - University Of Californiaitem
                                            SOUZA, ELAINE - University Of Californiaitem
                                            CASAZZA, GRETCHEN - University Of Californiaitem
                                            GUSTAFSON, MARY - University Of Californiaitem
                                            Keim, Nancyitem
                                            Newman, Johnitem
                                            HUNTER, GARY - University Of Alabamaitem
                                            FERNANDEZ, JOSE - University Of Alabamaitem
                                            W. TIMOTHY, GARVEY - University Of Alabamaitem
                                            HARPER, MARY-ELLEN - University Of Ottawaitem
                                            HOPPEL, CHARLES - Case Western Reserve University (CWRU)item
                                            MEISSEN, JOHN - University Of Californiaitem
                                            TAKEUCHI, KOHEI - University Of Californiaitem
                                            Adams, Sean
  Submitted to: PLOS ONE
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 12/30/2014
                                    Publication  Date: 1/8/2014
                                    Citation: Campbell, C., Grapov, D., Fiehn, O., Chandler, C.J., Burnett, D.J., Souza, E.C., Casazza, G.A., Gustafson, M.B., Keim, N.L., Newman, J.W., Hunter, G.R., Fernandez, J.R., W. Timothy, G., Harper, M., Hoppel, C.L., Meissen, J.K., Takeuchi, K., Adams, S.H. 2014. Improved metabolic health alters host metabolism in parallel with changes in systemic xeno-metabolites of gut origin. PLoS One. 9(1):e84260. DOI: 10.1371/journal.pone.0084260.Interpretive Summary: Novel plasma metabolite patterns reflective of improved metabolic health (insulin sensitivity, fitness, reduced body weight) were identified before and after a 14-17 wk weight loss and exercise intervention in sedentary, obese insulin-resistant women.  To control for potential confounding effects of diet- or microbiome-derived molecules on the systemic metabolome, sampling was during a tightly-controlled feeding test week paradigm.  Pairwise and multivariate analysis revealed intervention- and insulin-sensitivity associated: (1) Changes in plasma xeno-metabolites (“non-self” metabolites of dietary or gut microbial origin) following an oral glucose tolerance test (e.g. higher post-OGTT propane-1,2,3-tricarboxylate [tricarballylic acid]) or in the overnight-fasted state (e.g., lower '-tocopherol); (2) Increased indices of saturated very long chain fatty acid elongation capacity; (3) Increased post-OGTT alpha-ketoglutaric acid (alpha-KG), fasting alpha-KG inversely correlated with Matsuda index, and altered patterns of malate, pyruvate and glutamine hypothesized to stem from improved mitochondrial efficiency and more robust oxidation of glucose.  The results support a working model in which improved metabolic health modifies host metabolism in parallel with altering systemic exposure to xeno-metabolites.  This highlights that interpretations regarding the origins of peripheral blood or urinary “signatures” of insulin resistance and metabolic health must consider the potentially important contribution of gut-derived metabolites toward the host’s metabolome.
                                Technical Abstract: Novel plasma metabolite patterns reflective of improved metabolic health (insulin sensitivity, fitness, reduced body weight) were identified before and after a 14-17 wk weight loss and exercise intervention in sedentary, obese insulin-resistant women.  To control for potential confounding effects of diet- or microbiome-derived molecules on the systemic metabolome, sampling was during a tightly-controlled feeding test week paradigm.  Pairwise and multivariate analysis revealed intervention- and insulin-sensitivity associated: (1) Changes in plasma xeno-metabolites (“non-self” metabolites of dietary or gut microbial origin) following an oral glucose tolerance test (e.g. higher post-OGTT propane-1,2,3-tricarboxylate [tricarballylic acid]) or in the overnight-fasted state (e.g., lower '-tocopherol); (2) Increased indices of saturated very long chain fatty acid elongation capacity; (3) Increased post-OGTT alpha-ketoglutaric acid (alpha-KG), fasting alpha-KG inversely correlated with Matsuda index, and altered patterns of malate, pyruvate and glutamine hypothesized to stem from improved mitochondrial efficiency and more robust oxidation of glucose.  The results support a working model in which improved metabolic health modifies host metabolism in parallel with altering systemic exposure to xeno-metabolites.  This highlights that interpretations regarding the origins of peripheral blood or urinary “signatures” of insulin resistance and metabolic health must consider the potentially important contribution of gut-derived metabolites toward the host’s metabolome.


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