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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Available from: Maria Mihaylova
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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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    ABSTRACT: Our recent study (referred as Study 1) showed that the triterpenoid oleanolic acid (OA) was able to produce a sustained correction of hyperglycemia beyond treatment period in type 2 diabetes (T2D) mice with liver as a responsible site. To follow up the previous observations, the present study (referred as Study 2) investigated the possible role of acetylation of FoxO1 and associated events in this therapeutic memory by characterizing the pathways regulating the acetylation status during and post-OA treatments. OA treatment (100 mg/kg/day for 4 weeks, during OA treatment) reduced hyperglycemia in T2D mice by ∼87% and this effect was largely (∼70%) maintained even 4 weeks after the cessation of OA administration (post-OA treatment). During OA treatment, the acetylation and phosphorylation of FoxO1 were markedly increased (1.5 to 2.5-fold) while G6Pase expression was suppressed by ∼80%. Consistent with this, OA treatment reversed pyruvate intolerance in high-fat fed mice. Histone acetyltransferase 1 (HAT1) content was increased (>50%) and histone deacetylases (HDACs) 4 and 5 (not HDAC1) were reduced by 30-50%. The OA-induced changes in FoxO1, G6Pase, HAT1 and HDACs persisted during the post-OA treatment period when the increased phosphorylation of AMPK, SIRT1 content and reduced liver triglyceride had subsided. These results confirmed the ability of OA to control hyperglycemia far beyond treatment period in T2D mice. Most importantly, in the present study we demonstrated acetylation of FoxO1 in the liver is involved in OA-induced memory for the control of hyperglycemia. Our novel findings suggest that acetylation of the key regulatory proteins of hepatic gluconeogenesis is a plausible mechanism by the triterpenoid to achieve a sustained glycemic control for T2D.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "If the availability of nutrients is increased or limited during this time, the program is irreversibly affected, resulting in persistent alterations in energy homeostasis and increased susceptibility to diabetes, cardiovascular and metabolic disease (Remmers and Delemarre-van de Waal, 2011; Grove et al., 2005). Numerous reports (Kennedy and Mitra, 1963; Frisch and Revelle, 1970; Frisch et al., 1975; Ronnekleiv et al., 1978; Sloboda et al., 2009; Castellano et al., 2011; Wang et al., 2011) have also made clear that female puberty is delayed by early life nutritional challenge. A pivotal component of this developmental delay is the hypothalamic Kiss1 system. "
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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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