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            Neural sirtuin 6 (Sirt6) ablation attenuates somatic growth and causes obesity


            PNAS,2010,107(50):21790-2179 | 2010年12月14日 | doi.org/10.1073/pnas.1016306107



            In yeast, Sir2 family proteins (sirtuins) regulate gene silencing, recombination, DNA repair, and aging via histone deacetylation. Most of the seven mammalian sirtuins (Sirt1–Sirt7) have been implicated as NAD+-dependent protein deacetylases with targets ranging from transcriptional regulators to metabolic enzymes. We report that neural-specific deletion of sirtuin 6 (Sirt6) in mice leads to postnatal growth retardation due to somatotropic attenuation through low growth hormone (GH) and insulin-like growth factor 1 (IGF1) levels. However, unlike Sirt6 null mice, neural Sirt6-deleted mice do not die from hypoglycemia. Instead, over time, neural Sirt6-deleted mice reach normal size and ultimately become obese. Molecularly, Sirt6 deletion results in striking hyperacetylation of histone H3 lysine 9 (H3K9) and lysine 56 (H3K56), two chromatin marks implicated in the regulation of gene activity and chromatin structure, in various brain regions including those involved in neuroendocrine regulation. On the basis of these findings, we propose that Sirt6 functions as a central regulator of somatic growth and plays an important role in preventing obesity by modulating neural chromatin structure and gene activity. Sirtuins have been linked to metabolic regulation, stress tolerance, and aging (1, 2). It is still unclear whether mammalian sirtuins function as longevity assurance factors; but they may have therapeutic potential for age-associated diseases (1). Seven mammalian sirtuins (Sirt1–Sirt7) are known and localize to various subcellular compartments (1, 2). Sirt6 is a chromatin-associated nuclear protein affecting DNA repair, telomere maintenance, gene expression, and metabolism (3–9). Sirt6-deficient (Sirt6?/?) mice suffer from a severe, multisystemic phenotype and have a short lifespan (3, 4). This precludes studies of Sirt6 function in adult mice and makes it difficult to distinguish primary versus secondary consequences of Sirt6 loss. Postnatal growth retardation associated with low insulin-like growth factor 1 (IGF1) levels is a prominent feature of Sirt6?/? mice (4). Because brain homeostatic centers control somatic growth and IGF1 levels (10), and Sirt6 is highly expressed in the central nervous system (4, 11, 12), we hypothesized that loss of neural Sirt6 contributes to these aspects of the Sirt6-deficient mouse phenotype.


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