In comparison to SFAs, PUFAs have been shown to improve VMH dysfunction in rodent models of metabolic syndrome (Pella et al., 2011) through the normalising of appetite by restoration of neuropeptide concentrations (Das, 2008) and reducing hedonistic effects through the alteration of the dopaminergic and endocannabinoid systems (Golub et al., 2011). These alterations result in a reduction of appetite, enhancing satiety and reducing weight gain. Nonetheless, findings are generally inconsistent and in the human literature, only the addition of PUFAs as a supplement in the short-term has been examined (Lawton et al., 2000; Buckley & Howe, 2010). In general, the metabolic effects of long-term consumption of PUFAs incorporated into foodstuffs on the CNS needs to be clarified by utilising rodent models, specifically rat, under controlled conditions employing isoenergetic, purified and low-fat control diets (see Chapter 2).
As mentioned previously, the neuroprotection provided by omega-3 PUFAs is linked with membrane fluidity, neurotransmission, enzyme modulation and gene expression (Mazza et al., 2007). The benefits of dietary consumption of omega-3 PUFAs have been demonstrated in both humans and rodent studies in the form of improved cognition in healthy individuals and those with neurodegenerative conditions such as Alzheimer’s (Wu et al., 2004; Dyall, 2010; Su, 2010). It has been
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proposed that these improvements occur through the stimulation of neurogenesis (Dauncey, 2009; Venna et al., 2009; Matsuoka, 2011).
The omega-3 fatty acid, eicosapentaenoic acid (EPA), was the first to be associated with up-regulation of neurogenesis (Beltz et al., 2007). This was shown in the lobster which has innately elevated levels of neurogenesis, making it easier to see neurogenic changes following an intervention. Increased cell proliferation was seen within the brain of lobsters consuming a diet enriched with PUFAs from brine
shrimp or the microalgae Spirulina, which is often consumed by humans as a
nutritional supplement (Beltz et al., 2007). This increase manifested as an overall rise in baseline levels of neurogenesis, leading the author to conclude that the nervous system benefits from this nutritional addition. However, as no metabolic parameters were measured it is not known whether the improvement was directly stimulated by PUFAs or mediators of energy metabolism.
The patented LMN diet, rich in polyphenols and PUFAs, has been shown to enhance neurogenesis in the SGZ and SVZ in mice, but also to prevent cognitive
decline seen with ageing and Alzheimer’s disease (Valente et al., 2009; Fernández-
Fernández et al., 2012). Unfortunately, no metabolic factors were measured in either
of these studies and therefore, it is impossible to make a connection between the PUFA consumption, metabolic factors and any potential influence they may have had on the enhancement of neurogenesis. Additional studies have explored the mechanisms behind the protective role of omega-3 FAs in learning and memory with
ageing (Dyall et al., 2010). Supplementation with EPA and DHA reversed some of
the decrease observed in hippocampal neurogenesis in elderly rats and prevented the reduction in hippocampal nuclear receptors (RARs/RXRs) involved in cell proliferation (Goncalves et al., 2009). Since the effects of the PUFA-enriched diet on energy metabolism were not investigated, no direct relationship was suggested for the mediation in neurogenesis. Instead the authors suggest that BDNF was the most likely candidate for controlling the observed changes, as its expression is known to be enhanced by omega-3 PUFA consumption and the nuclear receptor agonists, tamibarotene (Am80) and imipramine (Katsuki et al., 2009; Venna et al., 2009).
A study has established the link between adult neurogenesis and the consumption of the omega-3 PUFA, DHA, by showing that it stimulates
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hippocampal neurogenesis in the dentate gyrus of adult rats (Kawakita et al., 2006).
DHA is one of the main structural lipids in the mammalian brain, and plays a crucial role in the development and function of brain neurons (Barasi, 2007). The authors
validated this finding through an in vitro study. By using primary culture of neural
stem cells from 15-day-old rat embryos, and culturing these cells under different conditions with or without DHA, the study demonstrated that DHA is an essential molecule for cell differentiation by promoting cell cycle exit and preventing cell
death (Kawakita et al., 2006). One study suggests that DHA enhances neuronal
differentiation of NSCs, in part, by controlling the expression level of basic helix- loop-helix (bHLH) transcription factors and promoting cell cycle exit (Katakura et al., 2009).
Furthermore, PUFAs have also been shown to activate the fat-sensing G- protein-coupled receptors (GPRs) present in tissues involved in the control of
inflammation and energy metabolism (Oh & Lagakos, 2011; Talukdar et al., 2011).
These include the receptors GPR40 and GPR120, which have been investigated for their role in PUFA-mediated reversal of SFA-induced hypothalamic inflammation associated with obesity (Cintra et al., 2012). The GPR40 receptor is involved in the upregulation of hippocampal neurogenesis required for improved memory function, and DHA has been shown to directly activate this receptor thereby suggesting
another potential mechanism by which it may stimulate neurogenesis (Ma et al.,
2008; 2010; Yamashima, 2008).
In summary, evidence continues to surface that the chronic consumption of PUFA-enriched diets stimulates adult neurogenesis in brain regions associated with cognition and this may involve the GPRs. However, further work is required to determine fully the role of PUFA-induced changes in energy metabolism on neurogenesis itself, and within the hypothalamus, as the evidence for its role so far comes from non-dietary studies. There is evidence that omega-3 PUFAs exert their effects on cognition by affecting molecular events implicated in both synaptic plasticity and energy metabolism. BDNF is one proposed mediator between these two processes (Gomez-Pinilla, 2011), as PUFAs are known to enhance synthesis, secretion and intracellular signalling of this molecule, and therefore, may restore
neurogenesis by this means (Wu et al., 2004; Balanzá-Martínez et al., 2011). As of
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homeostasis through changes in hypothalamic neurogenesis and whether these changes are mediated by BDNF. The slow turnover of hypothalamic neurons
(Kokoeva et al., 2007) alongside the technical limitations of labelling methods
involving BrdU (Taupin et al., 2007; Cifuentes et al., 2011), as discussed further in
Chapter 2, may explain why this relationship has not been explored further. If a relationship could be established, it would provide a neurobiological basis for the positive health benefits of dietary PUFAs, further supporting their role as a nutraceutical.