A Hormone-Dependent Module Regulating Energy Balance

Peptide Biology Laboratories, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Cell (Impact Factor: 32.24). 05/2011; 145(4):596-606. DOI: 10.1016/j.cell.2011.04.013
Source: PubMed


Under fasting conditions, metazoans maintain energy balance by shifting from glucose to fat burning. In the fasted state, SIRT1 promotes catabolic gene expression by deacetylating the forkhead factor FOXO in response to stress and nutrient deprivation. The mechanisms by which hormonal signals regulate FOXO deacetylation remain unclear, however. We identified a hormone-dependent module, consisting of the Ser/Thr kinase SIK3 and the class IIa deacetylase HDAC4, which regulates FOXO activity in Drosophila. During feeding, HDAC4 is phosphorylated and sequestered in the cytoplasm by SIK3, whose activity is upregulated in response to insulin. SIK3 is inactivated during fasting, leading to the dephosphorylation and nuclear translocation of HDAC4 and to FOXO deacetylation. SIK3 mutant flies are starvation sensitive, reflecting FOXO-dependent increases in lipolysis that deplete triglyceride stores; reducing HDAC4 expression restored lipid accumulation. Our results reveal a hormone-regulated pathway that functions in parallel with the nutrient-sensing SIRT1 pathway to maintain energy balance.

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    • "Activation of AMPK has been shown to induce the inhibitory acetylation of FoxO1 via phosphorylation of HDAC 4 and 5, and down-regulate G6Pase expression in the liver [14], [45]. Consistent with our previous reports [4], [10], the present study found that AMPK pathway was activated during OA administration. "
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    • "At the same time, altered IIS activity is also associated with abnormal lipid metabolism (Kitamura et al., 2003; Teleman, 2010), yet the cell-and tissue-specific mechanisms by which IIS regulates lipid metabolism are only partially understood. In both Drosophila and mammals, Foxo regulates the transcription of lipases in adipose tissue required for the lipolysis of stored lipids (Vihervaara and Puig, 2008; Chakrabarti and Kandror, 2009; Wang et al., 2011), as well as the expression of enzymes and other transcription factors involved in lipid catabolism (Deng et al., 2012; Xu et al., 2012). Accordingly, changes in IIS/Foxo regulated lipases (such as adipose triglyceride lipase) and lipogenic transcription factors (such as SREBP-1c) have been linked to the dyslipidemia associated with type 2 diabetes and other metabolic syndromes (Shimomura et al., 2000; Schoenborn et al., 2006; Badin et al., 2011). "
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