Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body.
In Drosophila melanogaster, ageing is slowed when insulin-like signalling is reduced: life expectancy is extended by more than 50% when the insulin-like receptor (InR) or its receptor substrate (chico) are mutated, or when insulin-producing cells are ablated. But we have yet to resolve when insulin affects ageing, or whether insulin signals regulate ageing directly or indirectly through secondary hormones. Caenorhabditis elegans lifespan is also extended when insulin signalling is inhibited in certain tissues, or when repressed in adult worms, and this requires the forkhead transcription factor (FOXO) encoded by daf-16 (ref. 6). The D. melanogaster insulin-like receptor mediates phosphorylation of dFOXO, the equivalent of nematode daf-16 and mammalian FOXO3a. We demonstrate here that dFOXO regulates D. melanogaster ageing when activated in the adult pericerebral fat body. We further show that this limited activation of dFOXO reduces expression of the Drosophila insulin-like peptide dilp-2 synthesized in neurons, and represses endogenous insulin-dependent signalling in peripheral fat body. These findings suggest that autonomous and non-autonomous roles of insulin signalling combine to control ageing.
Hwangbo
Dae Sung
DS
Division of Biology and Medicine, Box G-W, Brown University, Providence, Rhode Island 02912, USA.
Gershman
Boris
B
Gersham
Boris
B
Tu
Meng-Ping
MP
Palmer
Michael
M
Tatar
Marc
M
D000375:Aging / Q000502:physiology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000502:physiology*; D005216:Fat Body / Q000378:metabolism*; D051858:Forkhead Transcription Factors; D017344:Genes, Insect / Q000235:genetics; D007301:Insect Hormones / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D008136:Longevity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D009928:Organ Specificity; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological / Q000503:physiopathology; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D007301:Insect Hormones; D007328:Insulin; D012333:RNA, Messenger; D014157:Transcription Factors; D011972:Receptor, Insulin; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C487101:PTEN protein, Drosophila