(P16-040-23) Dietary DHA Supports Glucose Use by Muscle in Association With Improved Endocannabinoid System Gene Expression in C57bl/6 Mice

Objectives: Elevated levels of endocannabinoid system (ECS) ligands (eCB) have been associated with increased adiposity and obesity and are likely contributors to type II diabetes pathogenesis. High CB1 receptor expression and circulating AA-derived eCB are found in obese and diabetic patients.  Our objective was to determine if docosahexaenoic acid (DHA) is a modifier of tissue AA content and eCB tone, which includes the actions of ligands (AEA/2-AG and DHA-derived DHEA), their receptors, and eCB synthesis and degradation to prevent an overactive ECS whilst improving aspects of glycemia.

Methods: Male C57bl/6 mice were fed ad-libitum semi-purified diets containing DHA or control lipid in a final formulation of equal lipid and protein contents for 118d. Mouse serum, gastrocnemius, epididymal fat, and liver were collected after 62 and 118d of feeding. Metabolites and eCB were measured by GC-MS.

Results: Mice fed the DHA diet had lower epididymal fat pad mass compared to the control diet group. A compensatory response resulted in DHA fed mice with higher eCB receptors and synthesis/degradation enzyme mRNA expression. AA-derived eCB (2-AG and AEA), and downstream ECS activation markers were lower in the DHA group at 62 and 118d. Mice fed the DHA diet had higher glucose-related (GLUT 4 & and insulin-R) mRNAs and proteins, and lower 12-HETE consistent with lower precursor AA. Linoleic acid peroxidation products, 9-HODE and 13-HODE, were higher in liver in the DHA-fed mice. Lower 1-AG and 2-AG were found in muscle at 62 and 118d in the DHA group. The integration of metabolite levels in muscle and liver suggests less dependence for glucose in mice fed the DHA diet compared to controls. Metabolites associated with glycolysis (pyruvate, 3-phosphoglycerate, and phosphoenolpyruvate) were lower in mice given the DHA diet.  This change in glucose usage was observed in both muscle and liver.

Conclusions: Collectively our findings demonstrate that a DHA diet fed to mice resulted in a lower glucose uptake and greater glucose use and higher lipolysis compared to controls.  The metabolite changes support the finding of lower fat pad mass in DHA-fed mice and restored eCB tone.

Funding Sources: This research was supported by metabolomics collaborations at the University of Connecticut, Center on Aging, UConn Health Sciences Center (BAW), and USDA Intramural Projects 2031-51530-052-00D (JWN).