title: DAF-16 and TCER-1 Facilitate Adaptation to Germline Loss by Restoring Lipid Homeostasis and Repressing Reproductive Physiology in C. elegans.
abstract: Elimination of the proliferating germline extends lifespan in C. elegans. This phenomenon provides a unique platform to understand how complex metazoans retain metabolic homeostasis when challenged with major physiological perturbations. Here, we demonstrate that two conserved transcription regulators essential for the longevity of germline-less adults, DAF-16/FOXO3A and TCER-1/TCERG1, concurrently enhance the expression of multiple genes involved in lipid synthesis and breakdown, and that both gene classes promote longevity. Lipidomic analyses revealed that key lipogenic processes, including de novo fatty acid synthesis, triglyceride production, desaturation and elongation, are augmented upon germline removal. Our data suggest that lipid anabolic and catabolic pathways are coordinately augmented in response to germline loss, and this metabolic shift helps preserve lipid homeostasis. DAF-16 and TCER-1 also perform essential inhibitory functions in germline-ablated animals. TCER-1 inhibits the somatic gene-expression program that facilitates reproduction and represses anti-longevity genes, whereas DAF-16 impedes ribosome biogenesis. Additionally, we discovered that TCER-1 is critical for optimal fertility in normal adults, suggesting that the protein acts as a switch supporting reproductive fitness or longevity depending on the presence or absence of the germline. Collectively, our data offer insights into how organisms adapt to changes in reproductive status, by utilizing the activating and repressive functions of transcription factors and coordinating fat production and degradation.
authors: Department of Pediatrics, Rangos Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors: Francis Raj Gandhi
authors: FR
authors: Amrit
authors: Department of Pediatrics, Rangos Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors: Elizabeth Marie
authors: EM
authors: Steenkiste
authors: Department of Pediatrics, Rangos Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors: Ramesh
authors: R
authors: Ratnappan
authors: Division of Basic Sciences Fred Hutchison Cancer Research Center, Seattle, Washington, United States of America.
authors: Shaw-Wen
authors: SW
authors: Chen
authors: Department of Obstetrics, Gynecology and Reproductive Sciences, Magee Women's Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors: T Brooke
authors: TB
authors: McClendon
authors: Departments of Developmental Biology and Computational and Systems Biology, Rangos Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors: Dennis
authors: D
authors: Kostka
authors: Department of Obstetrics, Gynecology and Reproductive Sciences, Magee Women's Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors: Judith
authors: J
authors: Yanowitz
authors: Division of Basic Sciences Fred Hutchison Cancer Research Center, Seattle, Washington, United States of America.
authors: Carissa Perez
authors: CP
authors: Olsen
authors: Department of Pediatrics, Rangos Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors: Arjumand
authors: A
authors: Ghazi
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D004032:Diet; D015536:Down-Regulation / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D005298:Fertility / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D005854:Germ Cells / Q000378:metabolism*; D006706:Homeostasis; D050356:Lipid Metabolism; D008136:Longevity; D009154:Mutation / Q000235:genetics; D010445:Peptide Elongation Factors / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000235:genetics; D051880:Receptors, Notch / Q000378:metabolism; D012098:Reproduction; D059467:Transcriptome / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; D005227:Fatty Acids; D051858:Forkhead Transcription Factors; C060620:Glp-1 protein, C elegans; D010445:Peptide Elongation Factors; D051880:Receptors, Notch; D014280:Triglycerides; C108831:daf-16 protein, C elegans; C580768:TCER-1 protein, C elegans