The mammalian target of rapamycin complex 1 regulates leptin biosynthesis in adipocytes at the level of translation: the role of the 5'-untranslated region in the expression of leptin messenger ribonucleic acid.
Leptin production by adipose cells in vivo is increased after feeding and decreased by food deprivation. However, molecular mechanisms that control leptin expression in response to food intake remain unknown. Here, we test the hypothesis that leptin expression in adipose cells is regulated by nutrient- and insulin-sensitive mammalian target of rapamycin complex 1 (mTORC1)-mediated pathway. The activity of mTORC1 in 3T3-L1 adipocytes was up-regulated by stable expression of either constitutively active Rheb or dominant-negative AMP-activated protein kinase. In both cases, expression of endogenous leptin was significantly elevated at the level of translation. To investigate the role of leptin 5'-untranslated region (UTR) in the regulation of protein expression, we created bicistronic reporter constructs with and without the 5'-UTR. We found that the presence of leptin 5'-UTR renders mRNA resistant to regulation by mTORC1. It appears, therefore, that mTORC1 controls translation of leptin mRNA via a novel mechanism that does not require the presence of either the 5'-terminal oligopyrimidine tract or the 5'-UTR.
Chakrabarti
Partha
P
Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Anno
Takatoshi
T
Manning
Brendan D
BD
Luo
Zhijun
Z
Kandror
Konstantin V
KV
D041721:3T3-L1 Cells; D020121:5' Untranslated Regions; D055372:AMP-Activated Protein Kinases; D017667:Adipocytes / Q000166:cytology / Q000502:physiology*; D000818:Animals; D006801:Humans; D020738:Leptin / Q000096:biosynthesis / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011506:Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D020121:5' Untranslated Regions; D020738:Leptin; D009097:Multienzyme Complexes; D046912:Multiprotein Complexes; D009479:Neuropeptides; D011506:Proteins; D012333:RNA, Messenger; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D014157:Transcription Factors; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D020559:Monomeric GTP-Binding Proteins