Cell Metabolism
Previews TORCing Up Metabolic Control in the Brain Ville Hietakangas1,* and Stephen M. Cohen1,2,* 1Temasek
Life Sciences Laboratory, 1 Research Link, Singapore 11706 of Biological Sciences, National University of Singapore, Singapore 11706 *Correspondence:
[email protected] (V.H.),
[email protected] (S.M.C.) DOI 10.1016/j.cmet.2008.04.006 2Department
Transducer of regulated CREB activity 2 (TORC2) is a coactivator of CREB and an important regulator of energy balance in mammals through control of gluconeogenesis in the liver. In this issue of Cell Metabolism, Wang and coworkers (2008) report an intriguing role for Drosophila TORC in the neuronal regulation of metabolism. Levels of circulating glucose are determined by the balance between glucose uptake and utilization and glucose production. This balance is maintained by hormones that regulate intracellular signaling pathways. For most of us well-fed animals, circulating glucose levels are periodically elevated, leading to insulin production, which in turn activates programs needed for glucose uptake and energy storage in the form of glycogen and triglycerides. A constant supply of ready energy has not always been the norm, and mechanisms have evolved to ensure that levels of circulating glucose are sufficient under conditions of nutrient deprivation. The pancreatic hormone glucagon activates the gluconeogenic program in the liver in response to low glucose levels. A key regulator of the gluconeogenic program is the cAMPresponsive transcription factor CREB (Herzig et al., 2001). One important mediator in the CREB-regulated gluconeogenic transcriptional program is the CREB coactivator transducer of regulated CREB activity 2 (TORC2; Conkright et al., 2003). In this issue of Cell Metabolism, Wang and coworkers (2008) examine the function of Drosophila TORC, the single Drosophila ortholog of the mammalian TORC family (Iourgenko et al., 2003). Wang et al. (2008) find that TORC regulation is the same in flies and mammals, but the biological context in which TORC works may differ. TORC2 is a nodal point in the regulation of CREB-mediated transcription, as it is regulated by multiple signaling mechanisms responsive to levels of glucagon, insulin, and intracellular energy status. TORC2 is a transcriptional coactivator, and the key to its regulation lies in the control of its subcellular location: in or out of
the nucleus. When phosphorylated on Ser171, mammalian TORC2 is bound by 14-3-3, which keeps it in the cytoplasm, while dephosphorylation of Ser171 allows
Figure 1. Regulation of TORC Activity by Phosphorylation Nuclear localization of TORC2 is regulated by phosphorylation of Ser171, which determines TORC2 binding to the cytoplasmic scaffold protein 14-3-3. Ser171 is phosphorylated by SIK2, which is regulated by glucagon and insulin through PKA and AKT, respectively. Under nutritional stress, TORC2 is inhibited by AMPK-mediated phosphorylation of Ser171. SIK1 is a CREB target gene that acts as a negative feedback regulator of CREBmediated transcription by phosphorylating TORC2. Ser171 is dephosphorylated by the calcium-dependent phosphatase calcineurin/ PP2B (Cn).
TORC2 to enter the nucleus and coactivate transcription of CREB target genes (Figure 1; Screaton et al., 2004). Ser171 of TORC2 is phosphorylated by the members of the salt-inducible kinase (SIK) family (Figure 1). SIK2 activity is controlled through glucagon- and insulin-regulated phosphorylation events. SIK2 is inhibited by cAMP-responsive protein kinase A (PKA), which is activated by glucagon in conditions of low circulating glucose (Screaton et al., 2004). Conversely, SIK2 is activated by insulin through AKT-mediated phosphorylation (Dentin et al., 2007). Ser171 can also be phosphorylated by another SIK family member, SIK1, which is itself a CREB target gene upregulated by glucagon (Koo et al., 2005). Thus, SIK1 acts as a negative feedback regulator of TORC2 activity and, consequently, CREB-regulated gene expression. Under conditions of cellular energy stress, the gluconeogenic transcriptional program is inhibited. This is mediated through activation of AMP-activated protein kinase (AMPK). AMPK can also phosphorylate Ser171 in TORC2 and inhibit gluconeogenic transcription by preventing TORC2 nuclear entry (Koo et al., 2005). Thus, there appear to be multiple mechanisms by which TORC2 activity can be limited through phosphorylation. Reciprocally, TORC2 activity can be restored by dephosphorylation. Calcineurin/PP2B dephosphorylates Ser171 in a calcium-dependent manner and thereby renders TORC2 able to enter the nucleus (Figure 1). Flies lacking TORC are viable and fertile, but they display striking metabolic problems. TORC mutants are strongly sensitive to starvation and oxidative stress, and they have severely reduced levels of stored glycogen and lipids. In
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Cell Metabolism
Previews earlier mammalian studies, the main focus on TORC2 was on its role in the liver as the major site of gluconeogenesis (Canettieri et al., 2005; Koo et al., 2005; Dentin et al., 2007). In this context, it was perhaps surprising that the metabolic phenotypes observed in Drosophila were not due to TORC function in the fat body, the functional counterpart of liver and adipose tissue in the fly. In contrast, TORC is highly expressed in the fly brain, and the nutritional stress sensitivity observed in the mutants can be fully rescued by neuronal expression of TORC. A plausible mechanism for the neuronal function of TORC in controlling metabolism would be through affecting the production of insulin-like peptides. However, Wang et al. (2008) show that insulin production remains unchanged in TORC mutant animals and that depletion of the insulin-producing cells does not change the starvation sensitivity of the TORC mutant flies. Thus, the mechanism by which neuronal TORC controls metabolic stress resistance remains to be elucidated. Interestingly, two recent studies have revealed that TORC1, another member of the mammalian TORC family, is required for late-phase long-term potentiation of hippocampal neurons (Zhou et al., 2006; Kovacs et al., 2007). Similar to TORC2, the neuronal TORC1 coactivates CREB target genes, and its nuclear entry is regulated by cAMP and calcium. Thus, the metabolic and neuronal functions of the distinct mammalian TORC family members appear to be mediated by the single TORC ortholog in Drosophila. At the molecular level, regulation of TORC is highly conserved. Drosophila TORC displays phosphorylation-regulated subcellular localization, determined by 14-3-3 binding. Inhibition of the Dro-
sophila SIK2 ortholog, either by a chemical inhibitor or by activation of adenylyl cyclase, leads to dephosphorylation, dissociation of 14-3-3, and subsequent nuclear localization of TORC. Further supporting the role of SIK2 in suppressing TORC, the authors show that neuronal knockdown of SIK2 enhances the stress resistance of the flies. Also similar to mammalian systems is the observation that insulin signaling suppresses TORC activity in Drosophila. For example, phosphorylation of TORC upon refeeding was shown to be insulin dependent. A second line of evidence was provided by experiments in which overexpression of TORC caused a ‘‘rough eye’’ phenotype. This TORC gain-of-function phenotype was strongly enhanced by limiting insulin signaling by RNAi-mediated knockdown of AKT (see Figure 1). In sum, the study by Wang and coworkers (2008) shows a significant degree of conservation in the molecular mechanisms by which phosphorylation is used to regulate TORC activity. In both flies and mammals, this mechanism is used to control energy balance. However, there are intriguing differences. In mammals, a major target of TORC2 action is in the liver to control gluconeogenesis. In flies, the major site of TORC action is in the brain, and the specific process under control remains to be defined. An analogous difference in organization is also seen in the insulin-producing cells. In mammals, the site of insulin production is the islet b cells in the pancreas, whereas in flies, it is neuroendocrine cells in the brain. Despite these differences in tissue organization, the neuroendocrine cells controlling metabolism likely share a common evolutionary origin (Wang et al., 2007). Future studies will undoubtedly
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