title: Cell size and fat content of dietary-restricted Caenorhabditis elegans are regulated by ATX-2, an mTOR repressor.
abstract: Dietary restriction (DR) is a metabolic intervention that extends the lifespan of multiple species, including yeast, flies, nematodes, rodents, and, arguably, rhesus monkeys and humans. Hallmarks of lifelong DR are reductions in body size, fecundity, and fat accumulation, as well as slower development. We have identified atx-2, the Caenorhabditis elegans homolog of the human ATXN2L and ATXN2 genes, as the regulator of these multiple DR phenotypes. Down-regulation of atx-2 increases the body size, cell size, and fat content of dietary-restricted animals and speeds animal development, whereas overexpression of atx-2 is sufficient to reduce the body size and brood size of wild-type animals. atx-2 regulates the mechanistic target of rapamycin (mTOR) pathway, downstream of AMP-activated protein kinase (AMPK) and upstream of ribosomal protein S6 kinase and mTOR complex 1 (TORC1), by its direct association with Rab GDP dissociation inhibitor β, which likely regulates RHEB shuttling between GDP-bound and GTP-bound forms. Taken together, this work identifies a previously unknown mechanism regulating multiple aspects of DR, as well as unknown regulators of the mTOR pathway. They also extend our understanding of diet-dependent growth retardation, and offers a potential mechanism to treat obesity.
authors.affiliation: Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 9190401, Israel;
authors.forename: Daniel Z
authors.identifier: 0000-0003-4074-2802
authors.initials: DZ
authors.lastname: Bar
authors.affiliation: Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 9190401, Israel;
authors.forename: Chayki
authors.initials: C
authors.lastname: Charar
authors.affiliation: Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 9190401, Israel;
authors.forename: Jehudith
authors.initials: J
authors.lastname: Dorfman
authors.affiliation: Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 9190401, Israel;
authors.forename: Tam
authors.initials: T
authors.lastname: Yadid
authors.affiliation: RNA Molecular Biology, Fonds de la Recherche Scientifique (F.R.S.-FNRS), Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles (ULB), BioPark Campus, Gosselies B-6041, Belgium.
authors.forename: Lionel
authors.initials: L
authors.lastname: Tafforeau
authors.affiliation: RNA Molecular Biology, Fonds de la Recherche Scientifique (F.R.S.-FNRS), Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles (ULB), BioPark Campus, Gosselies B-6041, Belgium.
authors.forename: Denis L J
authors.identifier: 0000-0001-7295-6288
authors.initials: DL
authors.lastname: Lafontaine
authors.affiliation: Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 9190401, Israel; gru@vms.huji.ac.il.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Gruenbaum
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D000067698:Ataxin-2 / Q000502:physiology*; D017173:Caenorhabditis elegans / Q000166:cytology / Q000254:growth & development*; D048429:Cell Size; D004032:Diet; D019893:Ribosomal Protein S6 Kinases / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D000067698:Ataxin-2; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: Caenorhabditis elegans; TORC1; mTOR pathway; metabolism