A somatic checkpoint through NHR-49/HNF4α governs reproductive investment and longevity in C. elegans

The nuclear hormone receptor NHR-49, a homolog of mammalian PPARα and HNF4α, is a key transcriptional regulator of nutrition sensing and fatty acid metabolism in Caenorhabditis elegans. Here, we examine the role of NHR-49 in reproduction, including oocyte activation and ovulation. Loss of NHR-49 causes inappropriate oocyte activation and laying of unfertilized oocytes in the absence of sperm, resulting in rapid loss of yolk and stored fat, and drastic shortening of lifespan. Conversely, prevention of yolk transfer into the oocytes largely restores fat storage and partially rescues lifespan in the nhr-49 mutants. Additionally, NHR-49 couples germline proliferation to nutritional status, as evidenced by its requirement for pausing germline proliferation upon starvation. Interestingly, NHR-49 primarily acts in somatic cells, rather than the germline itself, to regulate oocyte activation and ovulation. Combined genomic analyses identify GSA-1, a G protein alpha s subunit (Gαs), as a direct transcriptional target of NHR-49 highlighting a mechanistic link between metabolic sensing, fertility and longevity maintenance.