AZD-9291 mesylate br Consequences of central apelin APJ modu

Consequences of central apelin/APJ modulation Regarding extra-hypothalamic actions, recent data demonstrate that the central apelin/APJ system could be a potential new target for the regulation of memory (Han et al., 2014). Then, intracerebroventricular (icv) apelin administration in mice impairs both short- and long-term memory. Using the same model of icv injection, Lv et al. showed that apelin injection generates depression-like behavior in mice mediated through APJ and opioid receptors, without any effect on motor behavior (Lv et al., 2012a). Central apelin exerts antinociceptive effect that is reversed by naloxone treatment (Lv et al., 2012b) and anxiolytic action (Telegdy and Jaszberenyi, 2014). Concerning apelin effects in the hypothalamus, food and water intakes are the most studied behavioral effects of apelin/APJ system described in the literature. Major reviews from the group of Dr. Llorens-Cortes clearly describe its effects on body fluid homeostasis (Galanth et al., 2012, Llorens-Cortes and Moos, 2008). To summarize, central apelin is able to inhibit the electrical activity of vasopressin neurons and then, the secretion of vasopressin that leads to water diuresis (De Mota et al., 2004). Regarding the role of apelin in the control of food intake, its precise function remains to be established. Studies demonstrate a stimulatory effect on food intake (Lin et al., 2014, Valle et al., 2008), an inhibitory effect (Sunter et al., 2003) or neutral action (Taheri et al., 2002). Such discrepancies could be justified by the injected quantity of apelin into the brain, the route of injection and animal species. To unravel the role of hypothalamic apelin, we have generated a mouse model invalidated for apelin gene specifically in the forebrain. These mice present increased food intake demonstrating the definitive anorexigenic effect of apelin (unpublished data). In addition to its behavioral functions, central apelin controls peripheral activities of various tissues. Thus, it is difficult to make a precise mapping of all the peripheral effects modulated by apelin/APJ system in the brain, but we are able to reference the main target tissues. First, the intestine is a target of AZD-9291 mesylate apelin since icv administration of apelin inhibits gastric emptying and gastrointestinal transit in mice via APJ (Lv et al., 2011). Second, arterial blood pressure and heart rate are increased in response to icv apelin (Kagiyama et al., 2005). Recently, we have demonstrated that hypothalamic apelin/APJ system was involved in the control of glucose metabolism. Then, low-dose of icv apelin was able to decrease fed glycemia and improved glucose tolerance via a nitric oxide pathway (Duparc et al., 2011). These data suggest that, in addition to the rise of plasma apelin observed during the night period (corresponding to the fed period in mice) (Duparc et al., 2011), a physiological rise of apelin in the hypothalamus could participate to the maintenance of glucose homeostasis, and then improves glucose utilization. Similarly to plasma concentration, the level of hypothalamic apelin is also increased during metabolic disorders, (Cudnoch-Jedrzejewska et al., 2015, Reaux-Le Goazigo et al., 2011). At the opposite, icv apelin injection in obese/diabetic mice did not improve the diabetic state, but generated a significant increase in fasted glycemia (Duparc et al., 2011). This study demonstrated that (1) central apelin is implicated in the establishment of T2D, and (2) there is an absence of apelin resistance in the brain during metabolic disorders in contrast to the effect of leptin. This deleterious effect of central apelin on glucose homeostasis is reinforced by the fact that icv acute and chronic injections of apelin (at a high-dose, similar to that observed in the hypothalamus of obese/diabetic mice) in normal lean mice generate fasted hyperglycemia, one characteristic of a type 2 diabetes phenotype (Duparc et al., 2011). Indeed, high-dose of icv apelin in normal mice generates an over-activation of sympathetic nervous system leading to an increase of hepatic glucose production (Drougard et al., 2014). Then, fasted hyperglycemia observed in this experiment was clearly linked to the stimulation of liver glycogenolysis and gluconeogenesis measured by a decrease in hepatic glycogen content and an elevated glycemia in response to a pyruvate tolerance test respectively (Drougard et al., 2014). Moreover, these mice presented a significant rise of the activity of glucose 6-phoshatase in the liver, an enzyme implicated in the positive control of glycogenolysis and gluconeogenesis. In conclusion, the liver appears to be a major target of central apelin action on glucose metabolism. Whether central apelin could modulate the activity of other tissues remains to be determined.