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Articles in PresS, published online ahead of print October 1, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00230.2002
Submitted on May 24, 2002
Accepted on September 24, 2002
1 Biochemistry, Boston University School of Medicine, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: kandror{at}biochem.bumc.bu.edu.
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. We concluded, therefore, that leucine activates leptin expression in adipose cells at the level of translation via an mTOR (mammalian target of rapamycin)-mediated pathway. Since leptin is a secreted protein, its biosynthesis is compartmentalized on the endoplasmic reticulum. In order 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-BP/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.
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