To the Editor: Thanks to Dr. Penland for bringing up these thought-provoking and challenging topics. I appreciate his contemplation and valiancy.
The role of lipids in brain function is significant. Thirty years ago, lipids were described in a great textbook of biochemistry as being unlike nucleic acids and proteins—that they “do not have information-carrying function” (1). With the series of convergent discoveries in the fields of neural development, synaptic physiology, and receptor pharmacology, the roles played by lipids and their receptors in brain function are being addressed in neuroscience.
Lipids comprise 50%–60% of the dry weight of the adult brain, of which approximately 35% are in the form of long-chain polyunsaturated fatty acids. These polyunsaturated fatty acids are derived through biosynthesis from their respective dietary essential fatty acid precursors, linoleic acid and α-linolenic acid or directly from dietary sources such as eggs, fish, and meat or from single-cell oils.
Dietary fat profoundly affects gene expression through binding directly with transcription factors or through eicosanoid regulation of intracellular signaling cascades, which results in alterations in metabolism, growth, and cell differentiation (2). Chronic N-3 fatty acid deficiency has been found to reduce dopamine receptor binding and increase serotonin receptor density in the frontal cortex of both young and aged rats as well as to alter dopamine metabolism (3–5). A formula low in linoleic acid and α-linolenic acid has been reported to result in low serotonin and dopamine levels in the frontal cortex of adult pigs (6).
The dynamic function of lipids, lipid signaling, was well described by Piomelli (7) as having four defining features: 1) the generation of informational diversity through permutation of simple structural units; 2) the “pervasive use of serial signaling”—that is, the application of a single biochemical pathway to multiple signaling needs; 3) the adoption of a signaling modality defined by the rapid on-demand response to primary signaling events, such as receptor activation; and 4) the localized nature of lipid-mediated signaling. Piomelli stated that in no other mammalian tissue do such features emerge more clearly than in the brain, where the roles of lipid messengers extend from the development of the neocortex to the processing of behavior. He further emphasized the diversity, the heterogeneity, and the complexity of the roles of lipids in the brain, as reflected by the discussion of the varieties of lipids classes “not only among different cell types, but also among different organelles of the same cell.” In fact, heterogeneities exist even within individual cell membranes between the inner and outer leaflet of the plasma membrane (8) and between “lipid rafts” and their surrounding membrane environment (9).
I have little doubt that disturbed lipids metabolization played a role in the psychiatric manifestation of the patient we presented (10). However, because of minimal research on human behavior in rapid weight reduction or starvation, it remains speculative.
I hope recent research in lipidomics that has been used to assess the brain function of lipids, with greater complexity, will bring definitive answers soon.
1. Lehninger AL: Biochemistry. New York, Worth Publishers, 1975
2.Jump DB, Clarke SD: Regulation of gene expression by dietary fat. Annu Rev Nutr 1999; 19:63–90
3.Delion S, Chalon S, Herault J, Guilloteau D, Besnard JC, Durand G: Chronic dietary alpha-linolenic acid deficiency alters dopaminergic and serotonergic neurotransmission in rats. J Nutr 1994; 124:2466–2476
4.Delion S, Chalon S, Guilloteau D, Besnard JC, Durand G: alpha-Liolenic acid dietary deficiency alters age-related changes of dopaminergic and serotonergic neurotransmission on the rat frontal cortex. J Neurochem 1996; 66:1582–1591
5.Zimmer I, Hembert S, Dward G, Breton P, Guilloteau D, Besnard JC, Chalon S: Chronic n-3 polyunsaturated fatty acid diet-deficiency acts on dopamine metabolism in the rat frontal cortex: a microdialysis study. Neuroscience Letters 1998; 240:177–181
6.Innis SM, de la Presa Owens S: Docosahexenoic and arachidonic acid prevent a decrease in dopaminergic and serotonergic neurotransmitters in frontal cortex caused by a linoleic and alpha-linolenic deficient diet in formula-fed piglets. J Nutr 1999; 129:2088–2093
7.Piomelli D: Review: the challenge of brain lipidomics. Prostaglandins Other Lipid Mediat 2005; 77:23–24
8.Pike LJ: Lipid rafts: heterogeneity on the high seas. Biochem J 2004; 378:281
9.Thompson GA Jr: The Regulation of Membrane Lipid Metabolism. Ann Arbor, Mich, CRC Press, 1992
10.Jiang W, Gagliardi JP, Raj YP, Silvertooth EJ, Christopher EJ, Krishnan KRR: Acute psychotic disorder after gastric bypass surgery: differential diagnosis and treatment. Am J Psychiatry 2006; 163:15–19