Depending on the dosage and duration, rapamycin may affect glucose

homeostasis in different ways (Blagosklonny, 2011b). Rapamycin has also been proposed to have a hormetic effect on aging and aging-related diseases (Blagosklonny, 2011a). Short-term rapamycin transiently affects intracellular signaling activated by nutrient overload; it does not affect body weight but abrogates the anorexia induced by nutrients such as leucine (Cota et al., 2006). On the other hand, long-term rapamycin treatment has a profound impact on neuronal morphology and functions. Ion channels typically have slow turnover rates (Crane and Aguilar-Bryan, 2004), and any loss of neurite projection may require a few days to be restored (Keck et al., 2011). Similarly, Mori and colleagues have shown that activating mTOR in POMC neurons by deleting the Tsc1 gene also results in enlarged POMC neuron soma and reduced neurite projections to the PVN, and chronic check details intraperitoneal injection of high doses of rapamycin restores the projection ( Mori et al., 2009). In our study, we have identified that aging is one of the physiological factors to activate mTOR in POMC neurons and the genetic activation Selleck CP-868596 of mTOR in conditional knockout mice recapitulates the physiological consequences of aging by activating mTOR in POMC neurons. Glucose intolerance and diabetes are commonly associated with obesity (Mokdad et al.,

2001). Paradoxically, we did not observe such a deleterious metabolic dysfunction in Pomc-cre;Tsc1-f/f mice, despite the fact that they were obese and hyperphagic. Instead, these mice had an improved glucose tolerance ( Figure 4J). Interestingly, a recent study Mephenoxalone has also revealed that direct leptin action in POMC neurons regulates glucose homeostasis independent of body weight ( Berglund et al., 2012). Other than regulating body weight and appetite, the arcuate nucleus is well documented as a central regulator for glucose homeostasis. To keep a constant glucose supply to the

brain, those hypothalamic neurons that are located outside the blood-brain barrier can monitor the glucose level in the periphery and send feedback commands to visceral organs such as the liver and pancreas through the descending autonomic system to counterbalance any fluctuation of the glucose supply to the brain ( Parton et al., 2007). Moreover, activating KATP channels in hypothalamic neurons has been shown to improve glucose metabolism as infusing diazoxide to the third ventricle suppresses hepatic gluconeogenesis ( Pocai et al., 2005) and central GLP-1 reduces peripheral glucose levels by activating KATP channels in POMC neurons ( Sandoval et al., 2008). As obesity impairs glucose tolerance, we suspect that the improved glucose tolerance in the Pomc-cre;Tsc1-f/f mice might be more significant in pair-feeding experiments that ensure matched body weight.