title: SIRT1 Limits Adipocyte Hyperplasia through c-Myc Inhibition.
abstract: The expansion of fat mass in the obese state is due to increased adipocyte hypertrophy and hyperplasia. The molecular mechanism that drives adipocyte hyperplasia remains unknown. The NAD(+)-dependent protein deacetylase sirtuin 1 (SIRT1), a key regulator of mammalian metabolism, maintains proper metabolic functions in many tissues, counteracting obesity. Here we report that differentiated adipocytes are hyperplastic when SIRT1 is knocked down stably in mouse 3T3-L1 preadipocytes. This phenotype is associated with dysregulated adipocyte metabolism and enhanced inflammation. We also demonstrate that SIRT1 is a key regulator of proliferation in preadipocytes. Quantitative proteomics reveal that the c-Myc pathway is altered to drive enhanced proliferation in SIRT1-silenced 3T3-L1 cells. Moreover, c-Myc is hyperacetylated, levels of p27 are reduced, and cyclin-dependent kinase 2 (CDK2) is activated upon SIRT1 reduction. Remarkably, differentiating SIRT1-silenced preadipocytes exhibit enhanced mitotic clonal expansion accompanied by reduced levels of p27 as well as elevated levels of CCAAT/enhancer-binding protein β (C/EBPβ) and c-Myc, which is also hyperacetylated. c-Myc activation and enhanced proliferation phenotype are also found to be SIRT1-dependent in proliferating mouse embryonic fibroblasts and differentiating human SW872 preadipocytes. Reducing both SIRT1 and c-Myc expression in 3T3-L1 cells simultaneously does not induce the adipocyte hyperplasia phenotype, confirming that SIRT1 controls adipocyte hyperplasia through c-Myc regulation. A better understanding of the molecular mechanisms of adipocyte hyperplasia will open new avenues toward understanding obesity.
authors.affiliation: From the Departments of Microbiology and Immunology.
authors.forename: Houari
authors.initials: H
authors.lastname: Abdesselem
authors.affiliation: From the Departments of Microbiology and Immunology.
authors.forename: Aisha
authors.initials: A
authors.lastname: Madani
authors.affiliation: From the Departments of Microbiology and Immunology.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Hani
authors.affiliation: Biochemistry, and.
authors.forename: Muna
authors.initials: M
authors.lastname: Al-Noubi
authors.affiliation: Biochemistry, and.
authors.forename: Neha
authors.initials: N
authors.lastname: Goswami
authors.affiliation: Biochemistry, and.
authors.forename: Hisham
authors.initials: H
authors.lastname: Ben Hamidane
authors.affiliation: Biochemistry, and.
authors.forename: Anja M
authors.initials: AM
authors.lastname: Billing
authors.affiliation: Genetic Medicine, Weill Cornell Medicine Qatar, Qatar Foundation, Education City, P.O. Box 24144, Doha, Qatar.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pasquier
authors.affiliation: the Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Bonkowski
authors.affiliation: Genetic Medicine, Weill Cornell Medicine Qatar, Qatar Foundation, Education City, P.O. Box 24144, Doha, Qatar.
authors.forename: Najeeb
authors.initials: N
authors.lastname: Halabi
authors.affiliation: From the Departments of Microbiology and Immunology.
authors.forename: Rajaa
authors.initials: R
authors.lastname: Dalloul
authors.affiliation: From the Departments of Microbiology and Immunology.
authors.forename: Mohamed Z
authors.initials: MZ
authors.lastname: Sheriff
authors.affiliation: Biochemistry, and.
authors.forename: Nasrin
authors.initials: N
authors.lastname: Mesaeli
authors.affiliation: the Life Sciences Research Division, Anti-Doping Lab Qatar, P.O. Box 27775, Doha, Qatar.
authors.forename: Mohamed
authors.initials: M
authors.lastname: ElRayess
authors.affiliation: the Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: David A
authors.initials: DA
authors.lastname: Sinclair
authors.affiliation: Biochemistry, and.
authors.forename: Johannes
authors.initials: J
authors.lastname: Graumann
authors.affiliation: From the Departments of Microbiology and Immunology, nam2016@qatar-med.cornell.edu.
authors.forename: Nayef A
authors.initials: NA
authors.lastname: Mazloum
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism*; D006984:Hypertrophy / Q000378:metabolism; D007249:Inflammation; D051379:Mice; D009765:Obesity / Q000378:metabolism; D040901:Proteomics; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D016271:Proto-Oncogene Proteins c-myc; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Myc (c-Myc); adipogenesis; cell proliferation; hyperplasia; sirtuin 1 (SIRT1)