PMID- 12388166
OWN - NLM
STAT- MEDLINE
DCOM- 20030213
LR  - 20211203
IS  - 0193-1849 (Print)
IS  - 0193-1849 (Linking)
VI  - 284
IP  - 2
DP  - 2003 Feb
TI  - Nutrient-sensing mTOR-mediated pathway regulates leptin production in isolated 
      rat adipocytes.
PG  - E322-30
AB  - Leptin biosynthesis in adipose cells in vivo is increased by food intake and 
      decreased by food deprivation. However, the mechanism that couples leptin 
      production to food intake remains unknown. We found that addition of leucine to 
      isolated rat adipocytes significantly increased leptin production by these cells, 
      suggesting that postprandial leptin levels may be directly regulated by dietary 
      leucine. The effect of leucine was inhibited by rapamycin and not by actinomycin 
      D. Besides, leucine administration did not increase the amount of leptin mRNA in 
      adipocytes. Therefore, we concluded that leucine activates leptin expression in 
      adipose cells at the level of translation via a mammalian target of rapamycin 
      (mTOR)-mediated pathway. Because leptin is a secreted protein, its biosynthesis 
      is compartmentalized on the endoplasmic reticulum. To analyze mTOR signaling in 
      this subcellular fraction, we separated adipose cells by centrifugation into a 
      heavy membrane fraction that includes virtually all endoplasmic reticulum and the 
      cytosolic extract. Phosphorylation of the major mTOR targets, the ribosomal 
      protein S6 and the translational inhibitor 4E-binding protein (BP)/phosphorylated 
      heat- and acid-stable protein (PHAS)-1, was stimulated by leucine in the 
      cytosolic extract, whereas, in the heavy fraction, S6 was constitutively 
      phosphorylated and leucine only induced phosphorylation of 4E-BP/PHAS-1. We also 
      found that 60-70% of leptin mRNA was stably associated with the heavy fraction, 
      and leucine administration did not change the ratio between compartmentalized and 
      free cytoplasmic leptin mRNA. We suggest that, in adipose cells, a predominant 
      part of leptin mRNA is compartmentalized on the endoplasmic reticulum, and 
      leucine activates translation of these messages via the 
      mTOR/4E-BP/PHAS-1-mediated signaling pathway.
FAU - Roh, Cecilia
AU  - Roh C
AD  - Boston University School of Medicine, Boston, Massachusetts 02118, USA.
FAU - Han, Jianrong
AU  - Han J
FAU - Tzatsos, Alexandros
AU  - Tzatsos A
FAU - Kandror, Konstantin V
AU  - Kandror KV
LA  - eng
GR  - AG-00115/AG/NIA NIH HHS/United States
GR  - DK-52057/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20021001
PL  - United States
TA  - Am J Physiol Endocrinol Metab
JT  - American journal of physiology. Endocrinology and metabolism
JID - 100901226
RN  - 0 (Leptin)
RN  - 0 (RNA, Messenger)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adipocytes/*metabolism
MH  - Animals
MH  - Base Sequence
MH  - Eating/physiology
MH  - Gene Expression
MH  - In Vitro Techniques
MH  - Leptin/*genetics
MH  - Male
MH  - Molecular Sequence Data
MH  - Nucleic Acid Conformation
MH  - Protein Kinases/*metabolism
MH  - RNA, Messenger/analysis
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/physiology
MH  - TOR Serine-Threonine Kinases
EDAT- 2002/10/22 04:00
MHDA- 2003/02/14 04:00
CRDT- 2002/10/22 04:00
PHST- 2002/10/22 04:00 [pubmed]
PHST- 2003/02/14 04:00 [medline]
PHST- 2002/10/22 04:00 [entrez]
AID - 00230.2002 [pii]
AID - 10.1152/ajpendo.00230.2002 [doi]
PST - ppublish
SO  - Am J Physiol Endocrinol Metab. 2003 Feb;284(2):E322-30. doi: 
      10.1152/ajpendo.00230.2002. Epub 2002 Oct 1.