mTOR complex 2 in adipose tissue negatively controls whole-body growth.
Mammalian target of rapamycin (mTOR), a highly conserved protein kinase that controls cell growth and metabolism in response to nutrients and growth factors, is found in 2 structurally and functionally distinct multiprotein complexes termed mTOR complex 1 (mTORC1) and mTORC2. mTORC2, which consists of rictor, mSIN1, mLST8, and mTOR, is activated by insulin/IGF1 and phosphorylates Ser-473 in the hydrophobic motif of Akt/PKB. Though the role of mTOR in single cells is relatively well characterized, the role of mTOR signaling in specific tissues and how this may contribute to overall body growth is poorly understood. To examine the role of mTORC2 in an individual tissue, we generated adipose-specific rictor knockout mice (rictor(ad-/-)). Rictor(ad-/-) mice are increased in body size due to an increase in size of nonadipose organs, including heart, kidney, spleen, and bone. Furthermore, rictor(ad-/-) mice have a disproportionately enlarged pancreas and are hyperinsulinemic, but glucose tolerant, and display elevated levels of insulin-like growth factor 1 (IGF1) and IGF1 binding protein 3 (IGFBP3). These effects are observed in mice on either a high-fat or a normal diet, but are generally more pronounced in mice on a high-fat diet. Our findings suggest that adipose tissue, in particular mTORC2 in adipose tissue, plays an unexpectedly central role in controlling whole-body growth.
Cybulski
Nadine
N
Biozentrum, University of Basel, 4056 Basel, Switzerland.
Polak
Pazit
P
Auwerx
Johan
J
Rüegg
Markus A
MA
Hall
Michael N
MN
D015502:Absorptiometry, Photon; D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D017931:DNA Primers; D005234:Fatty Liver / Q000503:physiopathology; D006128:Growth; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D011494:Protein Kinases / Q000502:physiology*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases
D052242:Adiponectin; D002352:Carrier Proteins; D017931:DNA Primers; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; D007334:Insulin-Like Growth Factor I; D002784:Cholesterol; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases