Abstract
Fatty acids play a crucial role in the brain as specific receptor ligands and as precursors of bioactive metabolites. Conjugated linoleic acid (CLA), a group of positional and geometric isomers of linoleic acid (LA, 18:2 n-6) present in meat and dairy products of ruminants and synthesized endogenously in non-ruminants and humans, has been shown to possess different nutritional properties associated with health benefits. Its ability to bind to peroxisome proliferator-activated receptor (PPAR) α, a nuclear receptor key regulator of fatty acid metabolism and inflammatory responses, partly mediates these beneficial effects. CLA is incorporated and metabolized into brain tissue where induces the biosynthesis of endogenous PPARα ligands palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), likely through a positive feedback mechanism where PPARα activation sustains its own cellular effects through ligand biosynthesis. In addition to PPARα, PEA and OEA may as well bind to other receptors such as TRPV1, further extending CLA own anti-neuroinflammatory actions. Future studies are needed to investigate whether dietary CLA may exert anti-inflammatory activity, particularly in the setting of neurodegenerative diseases and neuropsychiatric disorders with a neuroinflammatory basis.
Highlights
Fatty acids (FAs) are ubiquitous biological molecules that are used as metabolic fuels, essential components of cellular membranes and regulators of signaling molecules
Such PPARα-acetylcholine interaction takes place in other brain areas receiving strong impact of cholinergic inputs such as the sensorimotor cortex (Puligheddu et al, 2013; Puligheddu et al, 2017). These findings provided the rationale for using PPARα ligands, i.e., the clinically approved fibrates, as add-on therapy in neurological disorders caused by a gain of function of nicotinic acetylcholine receptors (nAChRs), such as in sleep-related hypermotor epilepsy (SHE, previously named nocturnal frontal lobe epilepsy, NFLE)
Our findings that Conjugated linoleic acid (CLA) increases PEA and OEA levels in peripheral tissues (Piras et al, 2015) and in mouse brain (Figure 2), and that this increase occurs in situ in the brain, to PPARα agonists [Figure 1 and (Melis et al, 2013a)], supports the hypothesis that PPARα activation induces PEA and OEA biosynthesis thereby sustaining PPARα activation with a positive feedback mechanism
Summary
Fatty acids (FAs) are ubiquitous biological molecules that are used as metabolic fuels, essential components of cellular membranes and regulators of signaling molecules. Cerebellar astrocytes were isolated from 7 days-old Sprague–Dawley rats and treated with 100 μM of CLA mixture, were shown to produce relevant concentration of CLA metabolites These results suggest that activation of PPAR-mediated differentiation pathways could be a mechanism by which CLA could exert beneficial effects on the brain, especially in disorders characterized by an impairment of peroxisomal β-oxidation inducing demyelination of nerve fibers. Treatment with the mixture LO + CLA significantly increased CLA levels to 50 nmol and 1,2 nmol/ml (around five and two folds vs the baseline levels) in plasma and CSF respectively This approach was based on the hypothesis that CLA may act synergistically with LO, as CLA is a high-affinity ligand of PPARα (Moya-Camarena et al, 1999), and might thereby induce the key enzymes for peroxisomal β-oxidation (Reddy and Hashimoto, 2001). Because there was a correlation between changes of CLA concentrations in CSF and plasma, this may suggest that the linear dose-response found in plasma of experimental animals (Banni et al, 1999) and more recently in humans (Murru et al, 2018) may occur in CSF
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