Date of Completion

8-21-2013

Embargo Period

8-21-2016

Keywords

Endocannabinoid Signaling, n-3 PUFA, Diabetes, Metabolomics, Oxylipin, DHEA

Major Advisor

Bruce A. Watkins, Ph.D.

Associate Advisor

Bradley W. Bolling, Ph.D.

Associate Advisor

Morgan E. Carlson, Ph.D.

Associate Advisor

Karl L. Insogna, M.D.

Associate Advisor

Jeff S. Volek, Ph.D., R.D.

Field of Study

Nutritional Science

Degree

Doctor of Philosophy

Open Access

Campus Access

Abstract

The overall research hypothesis is that dietary long chain n-3 PUFA (docosahexaenoic acid, DHA and eicosapentaenoic acid, EPA) enrichment of membrane and tissue lipids restores endocannabinoid tone (actions of ligands, receptors, and enzymes of endocannabinoid synthesis and degradation) and signaling of this system to improve health and reduce obesity and diabetes. Overactivation of the endocannabinoid system (ECS) has been previously associated with obesity and type 2 diabetes in rodents and humans. The cell culture experiments presented herein showed that C2C12 myoblasts treated with long chain n-3 PUFA resulted in dampening of ECS tone (mRNA and protein biomarkers) and increased cannabinoid receptor numbers as determined by flow cytometry. Improvements in glucose-related gene expression were observed in cell cultures with an increase in basal glucose uptake in the DHA-derived endocannabinoid, DHEA. In studies with C57/blk6 mice fed a semi-purified diet containing DHA, a robust increase in DHA while decrease in arachidonate was observed in brain, skeletal muscle, adipose tissue, liver, and bone, altering substrate levels of endocannabinoid precursors. ECS-related mRNA was characterized in skeletal muscle and adipose tissue, suggesting an increase in both basal and insulin-stimulated glucose uptake thus supporting the findings observed in the C2C12 myoblast cell cultures. Metabolomic analyses of serum, gastrocnemius, and liver from the C57/blk6 mice were also carried out to measure changes in endocannabinoids as well as macronutrient metabolite levels in vivo. From these studies the DHA semi-purified diet elevated DHA derived endocannabinoids and lowered arachidonate-containing glycerol lipids. Moreover, the mice fed the DHA diet showed higher levels of fatty acid oxidation products and lower levels of glycolytic intermediates suggesting changes in flux of metabolic pathways associated with energy expenditure. Lastly, global metabolomics analysis of serum from older adults revealed that blood levels of n-3 PUFA were associated with a decline of arachidonate-derived endocannabinoids and oxylipins. Together, these findings indicate that dietary n-3 PUFA dampen ECS tone, leading to an improvement in glucose homeostasis and ultimately influencing obesity status.

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