Cell size and fat content of dietary-restricted Caenorhabditis elegans are regulated by ATX-2, an mTOR repressor

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 32; pp. E4620 - E4629
• Main Authors: Bar, Daniel Z., Charar, Chayki, Dorfman, Jehudith, Yadid, Tam, Tafforeau, Lionel, Lafontaine, Denis L. J., Gruenbaum, Yosef
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 09.08.2016
• Series: PNAS Plus
• Subjects: Adipose Tissue - metabolism; AMP-Activated Protein Kinases - physiology; Animals; Ataxin-2 - physiology; Biological Sciences; Caenorhabditis elegans - cytology; Caenorhabditis elegans - growth & development; Cell Size; Diet; Genes; Genotype & phenotype; Kinases; Nematodes; Obesity; PNAS Plus; Ribosomal Protein S6 Kinases - physiology; Signal Transduction - physiology; TOR Serine-Threonine Kinases - physiology; mTOR pathway; Caenorhabditis elegans; TORC1; metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1512156113

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.