This study provides in vivo
evidence that both neuronal and peripheral CREB activities are involved in the regulation of energy balance in flies. Blocking CREB activity in neurons caused reductions in both glycogen and lipid stores and a higher sensitivity to starvation stress. In contrast, while disruption of CREB function in the fat body also reduced glycogen levels, it increased lipid stores, and did not affect starvation sensitivity (–). Since there was no significant change in overall body size in these flies, disruption of CREB activity in the fat body caused an obese-like phenotype. These results also indicate that CREB activity can both increase and reduce lipid stores in flies depending on its site of action. Recently, two distinct populations of Drosophila
brain neurons that regulate fat deposition were identified in Drosophila 
. It will be interesting to determine in which neurons CREB functions to regulate energy metabolism in flies.
In a recent study, TORC-mediated CREB activity in neurons was shown to positively regulate glycogen and lipid stores in flies 
. This is based on results showing that expression of TORC in neurons rescued the starvation sensitivity of TORC mutant flies. In addition, expression of TORC in neurons partially rescued the lower energy stores of these mutants 
. While supporting the conclusions of this study with respect to the role of neuronal CREB activity, our results also provide evidence that CREB in the fat body plays roles in energy balance. Moreover, in contrast to the normal feeding behavior of a TORC mutant 
, we found that blocking CREB activity in the fat body increased food intake (). Thus, disruption of CREB functions has a broader impact on energy metabolism and feeding behavior than the loss of TORC. It is likely that not all CREB functions depend on TORC. In support of this, although a TORC null mutant is viable and fertile 
, CREB mutants are lethal 
We found that AKH/AKHR signaling in the fat body, which is thought to be functionally related to glucagon/glucogon receptor signaling in the mammalian liver, positively regulates CRE-mediated transcription (). In the mammalian liver, CREB activates the gluconeogenic program following a glucagon stimulus. Recent studies reported that promoting AKH signaling in the fat body significantly reduced, while loss of AKHR function modestly increased, glycogen levels in flies, presumably through AKH/AKHR-mediated carbohydrate catabolism in the fat body 
. However, we found that blocking CREB activity in the fat body significantly reduced glycogen levels (), which would seem to contradict the proposed role of AKH/AKHR in mediating carbohydrate catabolism in the fat body. One possibility is that CREB activity in the fat body regulates multiple aspects of glucose/glycogen metabolism in addition to the AKH/AKHR-mediated pathway, and that blocking all CREB functions in the fat body reduces total glycogen levels as a net effect. In fact, significant CREB activity was remaining in AKHR mutant flies (), suggesting that other signaling pathways might contribute to the activation of CREB activity in the fat body. Further studies will be required to delineate the role of CREB activity in the fat body in carbohydrate metabolism and its relationship with the AKH signaling pathway.
We found that blocking CREB activity in the fat body increased lipid stores (). AKH/AKHR is also thought to be functionally related to β-adrenergic signaling in mammalian adipose tissue, which activates protein kinase A (PKA) and stimulates lipolysis by phosphorylating hormone-sensitive lipase and perilipin 
. In Drosophila
, the promotion of AKH signaling in the fat body reduces lipid levels, whereas loss of AKHR function has the opposite effect; this is partly ascribed to altered activity in lipocatabolic systems 
. In addition, AKH signaling has been shown to repress the lipogenesis pathway in various insects 
. Interestingly, blocking CREB activity in mammalian liver causes excessive fat accumulation, resulting in “fatty liver” through overactivation of liposynthesis 
. Future analysis will unravel whether CREB activity in the fat body represses liposynthesis and/or promotes lipid catabolism under the control of AKH/AKHR signaling.
In summary, our results demonstrate that CREB is involved in both central and peripheral regulation of energy balance and feeding behavior in Drosophila. Future studies of CREB in flies hold great promise for revealing the mechanisms underlying energy balance and feeding behavior. Such studies will likely contribute to our understanding of human metabolic disorders.