Abstract
The cAMP-responsive transcription factor CREB functions in adipose tissue and liver to regulate glycogen and lipid metabolism in mammals. While Drosophila has a homolog of mammalian CREB, dCREB2, its role in energy metabolism is not fully understood. Using tissue-specific expression of a dominant-negative form of CREB (DN-CREB), we have examined the effect of blocking CREB activity in neurons and in the fat body, the primary energy storage depot with functions of adipose tissue and the liver in flies, on energy balance, stress resistance and feeding behavior. We found that disruption of CREB function in neurons reduced glycogen and lipid stores and increased sensitivity to starvation. Expression of DN-CREB in the fat body also reduced glycogen levels, while it did not affect starvation sensitivity, presumably due to increased lipid levels in these flies. Interestingly, blocking CREB activity in the fat body increased food intake. These flies did not show a significant change in overall body size, suggesting that disruption of CREB activity in the fat body caused an obese-like phenotype. Using a transgenic CRE-luciferase reporter, we further demonstrated that disruption of the adipokinetic hormone receptor, which is functionally related to mammalian glucagon and β-adrenergic signaling, in the fat body reduced CRE-mediated transcription in flies. This study demonstrates that CREB activity in either neuronal or peripheral tissues regulates energy balance in Drosophila, and that the key signaling pathway regulating CREB activity in peripheral tissue is evolutionarily conserved.
Highlights
Energy balance is maintained by concerted changes in behavior and metabolism, which are often regulated by gene expression [1,2,3,4]
We found that a mutation in dCREB2 caused a reduction in stored glycogen levels and a reduction in lipid levels (Figure 1B and C), as was seen in TORC mutants
To test whether AKHR plays a role in the regulation of cAMP responsive element binding protein (CREB) activity, we examined whether CRE-mediated transcription is altered in AKHR mutant flies using the CRE-Luciferase reporter transgene
Summary
Energy balance is maintained by concerted changes in behavior and metabolism, which are often regulated by gene expression [1,2,3,4]. The cAMP responsive element binding protein (CREB) is an evolutionarily conserved transcription factor that is involved in many physiological functions including energy metabolism [4,5,6,7]. CREB belongs to the activating transcription factor (ATF)/ CREB family of proteins. ATF-2 activates transcription of the phosphoenolpyruvate carboxykinase-cytosolic (PEPCK-C) gene, which encodes a key enzyme of both gluconeogenesis [10] and glyceroneogenesis [11]. It has been reported that ATF-2 regulates fat metabolism in Drosophila: knock-down of the Drosophila homolog of ATF-2 reduced, and overexpression of ATF-2 increased, lipid stores [12]
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