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Title:   Author  item
                                            KIM, JEFFREY - University Of Connecticutitem
                                            CARLSON, MORGAN - University Of Connecticutitem
                                            KUCHEL, GEORGE - University Of Connecticutitem
                                            Newman, Johnitem
                                            WATKINS, BRUCE - University Of Connecticut
  Submitted to: International Journal of Obesity
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 7/3/2015
                                    Publication  Date: 7/3/2015
                                    Citation: Kim, J., Carlson, M.E., Kuchel, G.A., Newman, J.W., Watkins, B.A. 2015. Dietary DHA reduced downstream endocannabinoid and inflammatory gene expression, epididymal fat mass, and improved aspects of glucose use in muscle in C57BL/6J mice. International Journal of Obesity. 40:129–37; doi: 10.1038/ijo.2015.135.Interpretive Summary: The endocannabinoid system (ECS) is a neurometabolic system consisting of cell surface receptors, unique lipid mediators, and enzymes responsible for the synthesis and degradation of these lipids.  The ECS system directly impacts energy balance and immune function in mammals, and its over-activation is associated with increased adiposity and likely contributes to type II diabetes risk, and levels of both cannabinoid receptors and circulating n-6 polyunsaturated acid (PUFA)-derived EC mediators are elevated in obese and diabetic patients. Here we investigate whether the n-3 PUFA docosahexaenoic acid (DHA) in the diet can reduce ECS over-activation to influence glycemic control. To this end, male C57BL/6J mice were fed a semi-purified diet containing DHA or a control lipid. Serum, skeletal muscle, epididymal fat pads, and liver were collected after 62 and 118 d of feeding.  Metabolites, genes and gene-products associated with the ECS, glucose uptake and metabolism, and inflammatory status were measured.  Dietary DHA enrichment reduced epididymal fat pad mass and increased ECS-related genes, while reducing downstream ECS activation markers, indicating that ECS activation was diminished.  The mRNA of glucose-related genes and proteins were elevated in mice fed the DHA diet with increases in DHA  and reductions in AA-derived ECs.  In addition, DHA feeding reduced plasma levels of various inflammatory cytokines, 5-lipoxygenase-dependent inflammatory mediators, and the vasoconstrictive 20-HETE.  In conclusion, this study provides evidence that DHA feeding altered ECS gene expression to reduce CB receptor activation and reduce fat accretion.  Further, the DHA diet led to higher expression of genes associated with glucose use by muscle in mice, and reduced those associated with systemic inflammation.
                                Technical Abstract: Objective: Endocannabinoid system (ECS) overactivation is associated with increased adiposity and likely contributes to type II diabetes risk. Elevated tissue cannabinoid receptor 1 (CB1) and circulating endocannabinoids derived from the n-6 polyunsaturated acid (PUFA) arachidonic acid occur in obese and diabetic patients. Here we investigate whether the n-3 PUFA docosahexaenoic acid (DHA) in the diet can reduce ECS overactivation (i.e. action of ligands, receptors, and enzymes of EC synthesis and degradation) to influence glycemic control. This study targets the ECS tonal regulation of circulating glucose uptake by skeletal muscle as its primary endpoint.
Design: Male C57BL/6J mice were fed a semi-purified diet containing DHA or the control lipid. Serum, skeletal muscle, epididymal fat pads, and liver were collected after 62 and 118 d of feeding.  Metabolites, genes and gene-products associated with the ECS, glucose uptake and metabolism, and inflammatory status were measured.
Results: Dietary DHA enrichment reduced epididymal fat pad mass and increased ECS-related genes, while reducing downstream ECS activation markers, indicating that ECS activation was diminished.  The mRNA of glucose-related genes and proteins elevated in mice fed the DHA diet with increases in DHA  and reductions in AA-derived ECs.  In addition, DHA feeding reduced plasma levels of various inflammatory cytokines, 5-lipoxygenase-dependent inflammatory mediators, and the vasoconstrictive 20-HETE.
Conclusions: This study provides evidence that DHA feeding altered ECS gene expression to reduce CB1 activation and reduce fat accretion.  Further, the DHA diet led to higher expression of genes associated with glucose use by muscle in mice, and reduced those associated with systemic inflammatory status.


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