Research Division, Joslin Diabetes Center, Boston, United States; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, United States
Sri Devi Narasimhan
Research Division, Joslin Diabetes Center, Boston, United States; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, United States
Stacey Robida-Stubbs
Research Division, Joslin Diabetes Center, Boston, United States; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, United States
Lorenza E Moronetti Mazzeo
Research Division, Joslin Diabetes Center, Boston, United States; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, United States
Jonathan M Dreyfuss
Research Division, Joslin Diabetes Center, Boston, United States; Department of Biomedical Engineering, Boston University, Boston, United States
John M Hourihan
Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, United States
Prashant Raghavan
Research Division, Joslin Diabetes Center, Boston, United States; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, United States
Theresa N Operaña
Research Division, Joslin Diabetes Center, Boston, United States; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, United States
Reza Esmaillie
Research Division, Joslin Diabetes Center, Boston, United States; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, United States
T Keith Blackwell
Research Division, Joslin Diabetes Center, Boston, United States; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, United States
In Caenorhabditis elegans, ablation of germline stem cells (GSCs) extends lifespan, but also increases fat accumulation and alters lipid metabolism, raising the intriguing question of how these effects might be related. Here, we show that a lack of GSCs results in a broad transcriptional reprogramming in which the conserved detoxification regulator SKN-1/Nrf increases stress resistance, proteasome activity, and longevity. SKN-1 also activates diverse lipid metabolism genes and reduces fat storage, thereby alleviating the increased fat accumulation caused by GSC absence. Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction. We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids. This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.
