(2012) extend these findings to implicate mTOR in age-induced deterioration of POMC neurons leading to hyperphagic obesity. Nevertheless, it remains unclear how hypertrophy of POMC neurons leads to dysregulation of neuronal projections and neurotransmitter release and what the intracellular and extracellular triggers of this process are. An intriguing recent finding was the observation of peroxisome proliferation in POMC neurons associated with diet-induced obesity ( Diano et al., 2011). This process is related to glucose and lipid overload to POMC neurons ( Diano et al., 2011), which is also a fundamental prerequisite of cellular growth. In that case, reversal of peroxisome proliferation resulted in restoration of POMC

neuronal firing by enhancing generation of reactive oxygen species ( Diano et al., VX-770 cost 2011). Thus, it is possible that mTOR-related cellular growth of POMC neurons may also impair cellular metabolism and ROS control. Yang et al. (2012)

explored whether constant Imatinib concentration elevation of mTOR signaling in either POMC neurons or NPY/AgRP neurons may lead to obesity or weight loss using an elegantly designed mouse model. To accomplish cell-selective upregulation of mTOR signaling in either of these cell populations, they crossed POMC-Cre or AgRP-Cre mice with floxed TSC1 mice. TSC1 is a negative regulator of mTOR; hence, its cell-specific knockdown in either POMC or AgRP neurons would lead to chronically elevated mTOR signaling in these cells. They confirmed the findings of Mori

et al. (2009), showing that elevation of mTOR signaling induced by deletion of the Tsc1 gene in POMC neurons silenced POMC neuron activity and resulted in hyperphagic obesity even in young mice. Intriguingly, however, deletion of the Tsc1 gene in NPY/AgRP neurons had no effect on the firing rate and soma size of these neurons. They further corroborated these findings by investigating the effect of intracerebral infusion of rapamycin, an inhibitor of mTOR signaling, on metabolic phenotype and neuronal activity. Rapamycin has been proposed as a putative promoter of longevity and suppressor of metabolic disorders and neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Central administration of rapamycin rescued silencing and hypertrophy of POMC neurons during chronological aging and suppressed STK38 age-dependent obesity. On the other hand, consistent with patterns of the conditional KO mice deleting Tsc1 gene in NPY/AgRP neurons, rapamycin had no effect on NPY/AgRP neuronal activity. One possible explanation for the “insensitivity” of NPY/AgRP neurons to rapamycin is that NPY/AgRP neurons may be more reliant on other intracellular pathways for their firing, such as fatty acid metabolism ( Andrews et al., 2008). To elucidate an underlying mechanism for the observed phenomenon, Yang et al. (2012) revealed a contribution of KATP channel activity in the age-related silencing of POMC neurons.