Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity.
Reducing insulin/IGF signaling allows for organismal survival during periods of inhospitable conditions by regulating the diapause state, whereby the organism stockpiles lipids, reduces fertility, increases stress resistance, and has an increased lifespan. The Target of Rapamycin (TOR) responds to changes in growth factors, amino acids, oxygen tension, and energy status; however, it is unclear how TOR contributes to physiological homeostasis and disease conditions. Here, we show that reducing the function of Drosophila TOR results in decreased lipid stores and glucose levels. Importantly, this reduction of dTOR activity blocks the insulin resistance and metabolic syndrome phenotypes associated with increased activity of the insulin responsive transcription factor, dFOXO. Reduction in dTOR function also protects against age-dependent decline in heart function and increases longevity. Thus, the regulation of dTOR activity may be an ancient "systems biological" means of regulating metabolism and senescence, that has important evolutionary, physiological, and clinical implications.
Luong
Nancy
N
The Burnham Institute for Medical Research, Cancer Research Center, Neuroscience and Aging Center, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
Davies
Claire R
CR
Wessells
Robert J
RJ
Graham
Suzanne M
SM
King
M Todd
MT
Veech
Richard
R
Bodmer
Rolf
R
Oldham
Sean M
SM
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D015536:Down-Regulation; D004330:Drosophila; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005947:Glucose / Q000032:analysis; D007333:Insulin Resistance / Q000502:physiology*; D008055:Lipids / Q000032:analysis; D008954:Models, Biological; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011494:Protein Kinases; D016415:Sequence Alignment; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation
D029721:Drosophila Proteins; D051858:Forkhead Transcription Factors; D005947:Glucose; D008055:Lipids; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; C477334:FOXO protein, Drosophila; C416303:target of rapamycin protein, Drosophila