The effect of omega-3 fish oil supplementation on cognition and neuroinflammation in a mouse model of Western diet induced obesity.

Abstract

The Western diet (WD) is generally characterized by high sugar and saturated fat content, which result in caloric excess and obesity. However, it includes suboptimal intake of some nutrients including omega-3 fatty acids. Omega-3s are critical for cardiovascular, immune, and nervous system function, and poor omega-3 status may be one reason the WD causes impairment in these systems. The chronic inflammation and reduced omega-3 intake in Western diet-induced obesity (DIO) ultimately induce cognitive impairment. The hippocampus is the primary brain region responsible for learning and memory, and it is particularly susceptible to WD disruption. The WD causes cognitive impairment largely due to neuroinflammation and altered neuronal lipid profile. The omega-3s docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are highly incorporated into neuronal membranes where they are essential for synaptic function and provide a source for specialized pro-resolving mediators (SPMs) like neuroprotectins and resolvins which resolve neuroinflammation. SPMs are also produced peripherally, where they can improve DIO induced inflammation. It follows that improving the omega-3 deficit seen in the WD could improve DIO induced cognitive impairment through increasing SPM production and resolving neuroinflammation. To test this hypothesis we fed 24 mice a WD for 16 weeks with half receiving fish oil supplementation and half receiving the control soybean oil for the last 8 weeks. Twenty-four mice on a chow diet were likewise split randomly into fish oil and soybean oil groups to serve as the controls. Cognition was assessed with novel object recognition and Y-maze tests, and the hippocampus was collected for analysis. Red blood cell fatty acid analysis determined that the omega-3 index, the determinant of omega-3 status, was improved in the supplemented animals above the level of the chow diet control (p<0.001). Liver weight was also improved in the high fat diet with fish oil group over the high fat diet with soybean oil group. However, no significant difference was seen in cognition between any of the groups. While this indicates our supplement was sufficient to improve peripheral EPA and DHA, it may not have increased brain levels given our supplement was in triglyceride rather than phospholipid form, which decreases passage across the blood brain barrier (BBB). Oxylipin analysis, a measure of omega-3 anti-inflammatory activity and omega-6 pro-inflammatory activity in the brain was not able to measure omega-3 metabolites, and the supplement did not alleviate the WD induced changes in pro-inflammatory omega-6 metabolites. However, our WD did induce a change in the oxylipin profile of the brain. Levels of 12-HETE, 12(13)-DiHOME, and 9(10)-DiHOME were significantly altered by WD. Our results indicate that while a triglyceride form fish oil supplement was able to improve peripheral measures of omega-3 status in a WD model, it did not confer an observable benefit on the cognitive function or neuroinflammation of the hippocampus.