Fat accumulation in C. elegans is regulated by many signalling pathways including those involving insulin/insulin-like or TGFb-family ligands, nuclear hormone receptors, or the nutrient sensor, TOR. The mechanisms by which these pathways affect fat accumulation, and the way in which the different pathways interact is incompletely understood. To address these questions, we have studied fat regulation in mutants lacking
rsks-1, which encodes S6 kinase. Vertebrate S6 kinase is a major target of TOR protein kinase. We find that
rsks-1 mutants have dramatically increased fat accumulation in the intestine. Quantification of fat accumulation by TLC/GC revealed that the mutants have more than two-fold higher levels of triglycerides than wild type and disproportionately high levels of C16:1n9 and C18:1n9. Genetically
rsks-1 acts either downstream or in parallel to the insulin and TGFb pathways to affect fat levels. The
rsks-1 defect is partially rescued by expression of
rsks-1 in the germline, where
rsks-1 is required to promote fertility (1). Thus the increase in fat accumulation in the mutant may partly be the result of redirection of resources from the germline to the soma. Metabolomics analyses revealed that the mutants have increased levels of many amino acids and of certain acylcarnitines, molecules required for the transport of fatty acid intermediates into mitochondria during b-oxidation. In genomics-and proteomics-based approaches, we have identified genes and peptides that are differentially regulated in
rsks-1 mutant worms. We have performed genetic screens for mutations that suppress the increased fat accumulation in the mutant. Two allelic suppressor mutations map close to the right of
unc-73 and are strongly phenocopied by RNAi of a gene in this region, R12E2.2, which encodes a conserved protein with a SAD/UNC domain. Two other suppressor mutations are alleles of
aex-5, which encodes a calcium-dependent serine endoprotease. 1. Korta et al. Development. 2012;139:859-70.