Abstract
Objectives: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.Design: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.
Highlights
Stimulation of the endocannabinoid system (ECS) has been known for some time to influence several physiological activities, including hunger, pain modulation, mood and inflammation, with the primary function appearing to affect energy homeostasis that is evident in the shift toward energy storage upon ECS activation.[1,2,3] The receptors of the ECS, cannabinoid receptors 1 and 2 (CB1 and cannabinoid receptor 2 (CB2)), belong to the Gi/o protein-coupled receptor superfamily that can be activated by cannabinoid agonists or inhibited by antagonists with varying outcomes.[4]
Few studies have directly investigated the interactions of n-3 fatty acid feeding and changes in the ECS as they relate to fat accretion and glucose metabolism
We examined how dietary docosahexaenoic acid (DHA) affects the ECS and subsequent metabolic functions associated with obesity and type 2 diabetes in muscle and adipose tissues
Summary
Stimulation of the endocannabinoid system (ECS) has been known for some time to influence several physiological activities, including hunger, pain modulation, mood and inflammation, with the primary function appearing to affect energy homeostasis that is evident in the shift toward energy storage upon ECS activation.[1,2,3] The receptors of the ECS, cannabinoid receptors 1 and 2 (CB1 and CB2), belong to the Gi/o protein-coupled receptor superfamily that can be activated by cannabinoid agonists or inhibited by antagonists with varying outcomes.[4]. The ECS role in energy homeostasis is supported by multiple studies. Models using either pharmacological blockade of CB1- or CB1-null mice have shown reduced food intake.[8,9] lower energy intake did not account for the total body weight reduction.[10,11] In both obese subjects and leptin-deficient mice, an attenuated glucose uptake and fatty acid oxidation were reversed by CB1 antagonism.[12,13] Anandamide (AEA) and
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