Together, these data underscore a possible link of FA saturation in the pathogenesis of the metabolic syndrome. However, FA chain length appears to be an important characteristic which specifies FA regulatory activity. The length of the carbon chain of FAs can be modulated by elongases which show substrate specificity for the degree of saturation. Kitazawa et al. have shown that ELOVL1, 3 and 6 show high substrate specificity for long chain saturated FAs which they can elongate to C22–C26 carbon chain length. Interestingly, a recent study in mice by Zadravec et al. has demonstrated that ablation of elongase 3, leading to decreased very-long-chain saturated FAs, protects mice from dietinduced obesity, an AZ 960 effect largely attributable to increased resting metabolic rates. However, whether this was a central or a peripheral effect has not been elucidated. Recent studies in rodents do indicate a potential role for FA sensing in the central nervous system, specifically in the hypothalamus, which in turn regulates peripheral glucose and energy homeostasis. These data support the novel concept that lipids may be sensed in the central nervous system leading to profound changes in peripheral metabolism and hunger. Haywood et al. even showed that central but not peripheral lipid infusion augments the counter-regulatory secretion of epinephrine and glucagon in response to hypoglycemia. Moreover, central administration of specific FA species such as oleic acid markedly improves insulin action, inhibits glucose production and reduces food intake in rats. Interestingly, this effect appears to be dependent on chain length and degree of saturation of the FA species being administered. Intervention studies have also provided evidence that inhibition of hypothalamic FA synthesis triggers fatty acid oxidation in skeletal muscle and potently increases whole body energy expenditure underscoring the importance of a brain-muscle axis in energy homeostasis in rodents. Together, these animal data indicate that FAs in the CNS may be regulators of peripheral glucose and energy metabolism. Therefore, we explored associations of individual FA species in human CSF and plasma with metabolic features in a metabolically phenotyped group of individuals. We hypothesized that very-longchain saturated FAs would be associated with lower resting metabolic rates and that monounsaturated FAs in the CSF would be associated with lower glucose concentrations during an oral glucose tolerance test. Indeed, the data presented in this manuscript demonstrate that in humans FA species in the CNS stratified by chain length and degree of saturation are associated with peripheral metabolism. However, to date supporting data specifically in humans are scarce and limited in their statistical power, which is why these data need to be viewed as preliminary and interpreted with caution. Nevertheless, this association may support the concept that FAs may act as signaling molecules between the CNS and the periphery and implies that specific lipid transport mechanisms exist across the blood brain barrier. It is believed that FAs enter the CNS by at least two transport mechanisms: diffusion and/or protein-mediated transport. The regulation of these pathways appears to be dependent on chain length and saturation of the substrate which may support the concept that the transfer of FAs across the BBB is highly regulated. To date the exact regulatory mechanism of FA metabolism at the interface of the BBB is not clear.