title: Dietary DHA reduces downstream endocannabinoid and inflammatory gene expression and epididymal fat mass while improving aspects of glucose use in muscle in C57BL/6J mice.
abstract: OBJECTIVE
  Endocannabinoid system (ECS) overactivation is associated with increased adiposity and likely contributes to type 2 diabetes risk. Elevated tissue cannabinoid receptor 1 (CB1) and circulating endocannabinoids (ECs) derived from the n-6 polyunsaturated acid (PUFA) arachidonic acid (AA) occur in obese and diabetic patients. Here we investigate whether the n-3 PUFA docosahexaenoic acid (DHA) in the diet can reduce ECS overactivation (that is, 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 end point.
  
  
  METHODS
  Male C57BL/6J mice were fed a semipurified diet containing DHA or the control lipid. Serum, skeletal muscle, epididymal fat pads and liver were collected after 62 and 118 days 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, whereas it reduced 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-derived and reductions in AA-derived EC and EC-like compounds. 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. Furthermore, 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.
authors.affiliation: Lipid Chemistry and Molecular Biology Laboratory, Center on Aging, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.affiliation: Lipid Chemistry and Molecular Biology Laboratory, Center on Aging, University of Connecticut Health Center, Farmington, CT, USA.|Genomics Institute of the Novartis Research Foundation, La Jolla, CA, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Carlson
authors.affiliation: Lipid Chemistry and Molecular Biology Laboratory, Center on Aging, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Kuchel
authors.affiliation: Obesity and Metabolism Research Unit, USDA-ARS Western Human Nutrition Research Center, Davis, CA, USA.|Department of Nutrition, University of California, Davis, Davis, CA, USA.|West Coast Metabolomics Center, University of California, Davis, Davis, CA, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Newman
authors.affiliation: Lipid Chemistry and Molecular Biology Laboratory, Center on Aging, University of Connecticut Health Center, Farmington, CT, USA.|Department of Nutrition, University of California, Davis, Davis, CA, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Watkins
mesh_terms: D000273:Adipose Tissue / Q000473:pathology*; D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D059305:Diet, High-Fat; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D063388:Endocannabinoids / Q000494:pharmacology*; D015525:Fatty Acids, Omega-3 / Q000378:metabolism / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000473:pathology*
chemical_list: D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D015525:Fatty Acids, Omega-3; D004281:Docosahexaenoic Acids; D005947:Glucose