Lipid signalling in the mesolimbic dopamine pathway

Nutrient-sensing mechanisms provide a means whereby information about the metabolic state of the organism can be relayed to brain circuits controlling motivation. Mesolimbic dopamine (DA) neurons play a key role in mobilizing behaviour and are targeted by peripheral hormones controlling appetite and energy expenditure, such as leptin, ghrelin and GLP-1. Emerging findings suggest that neurons responding to endocrine signals can also detect fatty acids (FA). FA are essential building blocks for nerve cells but they can also have important signalling, metabolic and neuroimmune actions. Several lines of evidence implicate FA metabolism and partitioning in the brain as a nutrient sensor regulating energy homeostasis.

The type and quantity of fat consumed can be highly variable, leading to changes in the composition and amount of circulating and central FA. Dietary lipids can also affect the generation of FA synthesized and released by neural cells [1]. The biological impact of FA depends on their chemical structure. The monounsaturated FA oleate and the saturated FA palmitate are the most abundant long-chain FA in circulation and can exert different actions in the brain. Independent of changes in body weight, prolonged intake of saturated dietary fat (palm oil; enriched in palmitate) dampens mesolimbic DA function in rats while a monounsaturated high-fat diet (olive oil; containing mostly oleate) is protective [2]. Furthermore, excessive intake of saturated fat leading to obesity elicits anxiodepressive behaviour in a manner relying on neuroinflammatory responses in the nucleus accumbens (NAc) [3].

Oleate has central actions to supress feeding and neurotransmission, actions that may be mediated by cellular FA transport and metabolism. In turn, blocking FA hydrolysis from circulating triacylglycerol in the NAc has been shown to increase feeding and weight gain [4]. FA intracellular metabolism is mediated by carrier proteins including FA transporters (brain isoforms CD36, FATP1 and 4). Inside the cell FA are bound to FA binding proteins (brain isoforms FABP3, 5 and 7) that control uptake and transport of FA to different organelles. FA are activated into Acyl CoA which can be either esterified into complex lipids or oxidized by the mitochondria. DA neurons were found to express FATP1, FATP4 and FABP3, to incorporate long-chain FA and esterify FA into lipid droplets localized to the soma and processes [5]. Administration of oleate, but not palmitate, into the VTA inhibited food intake. Intra-VTA oleate also supressed the rewarding effects of sucrose and DA neuronal firing, effects prevented by blocking intracellular FA transport [5]. Therefore, DA neurons not only have the machinery for FA handling, but can alter their activity in response to FA and metabolize and store fat. A critical goal of  future research is to determine how dietary lifestyle, overconsumption and obesity development alters the DA neuron lipidome, intracellular FA metabolism and neuronal function. Indeed, human obesity is linked to increased brain FA uptake [6], a consequence which may underlie the psychiatric and neurodegenerative risks  associated with obesity.

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Acknowledgements

SF and TA are both supported by FRQS scholar awards. Research was supported by a CIHR operating grant to SF (#275314). Many thanks to the Cecile Hryhorczuk, Léa Décarie-Spain and Sandeep Sharma for their hard work.

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Correspondence to Stephanie Fulton.

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Fulton, S., Alquier, T. Lipid signalling in the mesolimbic dopamine pathway. Neuropsychopharmacol 44, 221–222 (2019). https://doi.org/10.1038/s41386-018-0188-4

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