title: Neural sirtuin 6 (Sirt6) ablation attenuates somatic growth and causes obesity.
abstract: 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.
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Schwer
authors.forename: Bjoern
authors.initials: B
authors.lastname: Schumacher
authors.forename: David B
authors.initials: DB
authors.lastname: Lombard
authors.forename: Cuiying
authors.initials: C
authors.lastname: Xiao
authors.forename: Martin V
authors.initials: MV
authors.lastname: Kurtev
authors.forename: Jun
authors.initials: J
authors.lastname: Gao
authors.forename: Jennifer I
authors.initials: JI
authors.lastname: Schneider
authors.forename: Hua
authors.initials: H
authors.lastname: Chai
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
mesh_terms: D000107:Acetylation; D000818:Animals; D001835:Body Weight; D001921:Brain / Q000166:cytology / Q000378:metabolism; D005260:Female; D006128:Growth / Q000502:physiology*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D009765:Obesity / Q000503:physiopathology*; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
chemical_list: D006657:Histones; C501860:Sirt6 protein, mouse; D037761:Sirtuins; D008239:Lysine