The role of peripheral metabolic signals in neural reward mechanisms

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ObjectivesDietary lipids are a critical source of 3 polyunsaturated fatty acids (FA) and not only provide essential building blocks and energy for the brain but also have important signalling actions. Dietary 3 FA can improve emotional, cognitive and behavioural functions, in part via supressing microglia activity and neuroimmune responses. In contrast, n-3 dietary deficiency leading to reduced 3 brain levels can promote depressive-like behaviour and stimulate palatable food seeking and weight gain. The 3 FA receptor GPR120 is important for mediating the anti-inflammatory actions 3 in the periphery, yet very little of known about the role of GPR120 in the brain. The objective of the proposed research program is to determine the contribution of brain GPR120 in the actions of 3 on energy balance, food reward, anxio-depressive behaviour and pro-inflammatory responses in brain reward circuitry.Background and progressA saturated high-fat diet stimulates anxio-depressive behaviours and sucrose reward in a manner tied to elevations in circulating immune markers and activation of microglia, increased nuclear factor kappa B (NFB) transcriptional activity and increased pro-inflammatory markers in the nucleus accumbens (NAc). Notably, behavioural impairments and NAc inflammatory signature, including microglia reactivity, by can be blocked by viral inhibition of NFB in the NAc. Diets enriched in saturated FA lower brain 3 levels, and thus reduced 3 signalling may be involved. The fatty acid membrane receptor GPR120 is a G-protein coupled receptor activated by 3 that mediates the anti-inflammatory effects of 3 in peripheral macrophages. We recently reported that GPR120 is expressed in limbic sites controlling motivation, emotion and cognition, and that central GPR120 agonism decreases food intake, food reward and anxiety-like behaviour. Our preliminary data reveal that GPR120 is highly enriched in microglia and show that GPR120 agonist application to primary microglia robustly suppresses cytokine gene expression. Excessive and/or prolonged microglial activation is associated with depressive states whereas inhibiting microglia proliferation has been to suppress body weight gain and prevents inflammation in responses to a high lipid diet. Accordingly, we will test the hypothesis that microglial GPR120 is involved in the catabolic and neuroprotective effects of 3 using targeted gene intervention, pharmacological and in vitro approaches.