The effects of distinct fatty acids on central leptin sensitivity, hypothalamic inflammation, and central-regulated hepatic metabolism

Consumption of a fat-rich diet is implicated in the development of central leptin resistance and obesity in modern societies. Epidemiological evidence suggests that saturated fatty acids (SFA) and n-6 polyunsaturated fatty acids (n-6 PUFA), highly consumed in Western diets, induce potent inflammation and impair leptin signalling in the hypothalamus, leading to the dysregulation of central leptin on body energy homeostasis and peripheral metabolism. However, n-3 PUFA and n-3 PUFA derivatives have well-known anti-inflammatory properties, and exert anti-obesity effects by improving central leptin sensitivity and its metabolic action in peripheral tissues. However, the role and mechanism of distinct fatty acids, especially directly act on central nervous system, regulate central leptin sensitivity, hypothalamic leptin signalling pathways, and hepatic energy homeostasis remain largely undiscovered. The present thesis aims to determine the effect of intracerebroventricular (icv) injection of distinct fatty acids on central leptin sensitivity in C57BL/6J male mice. Body energy homeostasis, hypothalamic leptin signalling, and centrally regulated hepatic glucose and lipid metabolism in response to distinct fatty acids will be characterised. The contribution of hypothalamic inflammatory effects induced by different fatty acids will also be investigated. The fatty acids to be examined are SFA palmitic acid (PA), n-6 PUFA arachidonic acid (ARA), n-3 PUFA docosahexaenoic acid (DHA), and n-3 PUFA derivative α-ethyl DHA ethyl ester. We demonstrate that the icv administration of PA and ARA induces central leptin resistance, evidenced by the inhibition of central leptin\u27s suppression on food intake and body weight gain. In addition to central leptin resistance, the hypothalamic leptin JAK2- STAT3 and PI3K-Akt signalling pathways were impaired, with the down-regulation of leptin signalling mediators pSTAT3, pJAK2, pAkt, and pFOXO1. Furthermore, the central administration of PA and ARA blunted the leptin-induced decrease of hepatic gluconeogenesis, glucose transportation, lipogenesis, cholesterol synthesis, and increase in hepatic β-oxidation. PA and ARA induced potent hypothalamic pro-inflammatory effects and increased pro-inflammatory cytokines and inflammatory mediators, as well as increased leptin signalling negative regulator SOCS3. On the other hand, central injection of DHA and DHA derivative exerted an anorexigenic effect by reducing energy intake and body weight gain in high-fat diet (HFD) mice. Both DHA and DHA derivative improved leptin JAK2-STAT3 and PI3K-Akt signalling in the hypothalamus, and consequently restored central leptin-mediated hepatic glucose and lipid metabolism. In addition, we also demonstrate that PA and ARA can inhibit, while DHA can improve central leptin action in mediating hypothalamic sympathetic activity, which may associated with the impaired or promoted hepatic energy metabolism. In summary, elevated central PA and ARA concentrations induce leptin resistance and pro-inflammatory response in the central nervous system, which is associated with the dysregulation of the central leptin effect on energy homeostasis and hepatic metabolism. DHA and DHA derivative reverse HFD-induced adiposity, and decrease hypothalamic inflammation, which contributes to an increased central leptin sensitivity and improved regulation of hepatic metabolism. Thus, the administration of distinct fatty acids may provide realistic and alternative therapeutic strategies for the treatment of obesity and associated metabolic disturbances