Exploration of Body Weight Regulation: By Polyunsaturated Fatty Acids in Rat: Potential Association with Hypothalamic Neurogenesis

Of the environmental factors which influence body weight, nutrients have the most impact. Saturated fatty acids (SFAs) are a macronutrient, which induce obesity, characterised by metabolic dysfunction and altered feeding behaviour. Currently, there are no effective pharmaceutical treatments for obesity. Nutraceutical intervention, including consumption of polyunsaturated fatty acids (PUFAs), represents a promising alternative. PUFAs oppose the effects of SFAs, attenuating weight gain by enhancing satiety. However, in studies using human and rodent models findings are difficult to interpret, due to variation in protocols. The primary aim of this project was to create a rational model of chronic PUFA consumption. Obesity is underpinned by alterations in hypothalamic neuronal plasticity including impairment of neurogenesis. These changes occur in response to nutrients or by regulation of appetite-related hormones. In contrast, dietary restriction stimulates neurogenesis, and evidence has suggested that PUFAs enhance hypothalamic neurogenesis. The secondary aim of this project was to pilot methods for stimulating and observing neurogenesis in hypothalamus of rat. These two lines of enquiry were pursued to begin addressing the complex research question of whether PUFAs exert beneficial effects on body weight by stimulating hypothalamic neurogenesis. Wistar rats fed commercially formulated diets equally enriched with high concentrations of SFAs and PUFAs, from lard and fish oil, respectively, for two months showed no difference in energy intake or body weight. Both diets induced leptin and insulin resistance, but PUFAs reduced triglyceride concentrations. Hence, PUFAs improved lipid metabolism independently of induced obese phenotype. The meal pattern signatures associated with each diet were also similar; however, PUFA-fed animals demonstrated enhanced diurnal satiety. Closer examination of the diet compositions revealed the overlap of results was likely due to the presence of SFAs in the PUFA diet. This led to reformulation, using fatty acids of greater purity. The chosen sources were coconut oil (SFAs), and a commercial preparation of omega-3 PUFAs. A shorter-term, preliminary investigation involving three weeks’ dietary exposure was conducted. Energy intake was again similar between SFA- and omega-3-fed animals but weight gain was attenuated and adiposity reduced by omega-3 feeding. However, the enhanced satiety previously observed was not borne out. A rise in concentration of brain-derived neurotrophic factor, known to be associated with beneficial effects of PUFA intake, in the final study week suggests that studies of longer duration may be required to fully assess the effects of dietary PUFAs. Concurrent pilot work showed that hypothalamic cell proliferation could be stimulated in response to simple enrichment (play tube) introduced to the cage. However, a full study failed to repeat these findings, supporting the notion that neurogenesis is subject to many influences, including age, species, strain and stress, the degrees of influence of which would have to be determined in a series of systematically controlled studies. Failure to stimulate cell proliferation in PUFA-fed rats suggested further that change in dietary fatty acid composition is not a powerful enough intervention to stimulate neurogenesis, when used alone in Wistar rats. In conclusion, application of appropriate controls for dietary energy content and composition show that benefits to body weight metabolism of long-term consumption of diets highly enriched with PUFAs, and, in particular, omega-3 fatty acids can be successfully modelled in rat. However, further work is required to determine the precise timeline of their emergence and underlying mechanisms.