Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans.
Rictor is a component of the target of rapamycin complex 2 (TORC2). While TORC2 has been implicated in insulin and other growth factor signaling pathways, the key inputs and outputs of this kinase complex remain unknown. We identified mutations in the Caenorhabditis elegans homolog of rictor in a forward genetic screen for increased body fat. Despite high body fat, rictor mutants are developmentally delayed, small in body size, lay an attenuated brood, and are short-lived, indicating that Rictor plays a critical role in appropriately partitioning calories between long-term energy stores and vital organismal processes. Rictor is also necessary to maintain normal feeding on nutrient-rich food sources. In contrast to wild-type animals, which grow more rapidly on nutrient-rich bacterial strains, rictor mutants display even slower growth, a further reduced body size, decreased energy expenditure, and a dramatically extended life span, apparently through inappropriate, decreased consumption of nutrient-rich food. Rictor acts directly in the intestine to regulate fat mass and whole-animal growth. Further, the high-fat phenotype of rictor mutants is genetically dependent on akt-1, akt-2, and serum and glucocorticoid-induced kinase-1 (sgk-1). Alternatively, the life span, growth, and reproductive phenotypes of rictor mutants are mediated predominantly by sgk-1. These data indicate that Rictor/TORC2 is a nutrient-sensitive complex with outputs to AKT and SGK to modulate the assessment of food quality and signal to fat metabolism, growth, feeding behavior, reproduction, and life span.
Soukas
Alexander A
AA
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA.
Kane
Elizabeth A
EA
Carr
Christopher E
CE
Melo
Justine A
JA
Ruvkun
Gary
G
D048868:Adaptor Proteins, Signal Transducing; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001896:Boron Compounds / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004032:Diet; D005247:Feeding Behavior / Q000502:physiology*; D005404:Fixatives / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008136:Longevity / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010078:Oxazines / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D012098:Reproduction / Q000502:physiology; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
D048868:Adaptor Proteins, Signal Transducing; D001896:Boron Compounds; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D005404:Fixatives; D017874:Immediate-Early Proteins; D007328:Insulin; D051058:Oncogene Protein v-akt; D010078:Oxazines; D017346:Protein Serine-Threonine Kinases; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D013002:Somatomedins; D000099184:Serum-Glucocorticoid Regulated Kinases; C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; C539011:rict-1 protein, C elegans; C044808:nile red