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

ArticleinMolecular Endocrinology 22(10):2260-7 · October 2008with113 Reads
DOI: 10.1210/me.2008-0148 · Source: PubMed
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.
    • "In accordance with this, circulating levels of leptin were significantly increased, despite no general increase in body weight and adiposity was evidenced (Fig. 4B). As leptin secretion in adipocytes is diminished by oxidative stress [25], the level of oxidative damage in adipose tissue from TBB animals was evaluated, demonstrating a significant decrease in DNPreactive carbonyl immunoreactivity (Fig. 4B). These changes were associated with increased plasma NEFA levels in TBB group but unchanged cholesterol, LDL, and HDL fractions (Fig. 4C). "
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    • "Nutrient availability and insulin regulate leptin expression. Yet, mTORC1 also plays a role in leptin expression in adipose cells, since up-regulation of mTORC1 in 3T3-L1 adipocytes via stable expression of either constitutively active Rheb or dominant-negative AMP activated protein kinase (AMPK) results in a significant increase in leptin expression [239]. AMPK can phosphorylate tuberin (TSC2) and inhibit mTORC1 [240]. "
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    • "This suggests that mTORC1 activation and signaling are a requisite for IGF-1 induced increase in leptin expression. IGF-1 treatment enhances translation and increases levels of the transcription factor C-EBPa, which mediates increased leptin transcription Several lines of evidence suggest that mTORC1 regulates leptin biosynthesis at the level of translation202122. In this study and our previous studies [15] we have demonstrated that treatment of organotypic slices with rapamycin , in addition to reducing leptin protein levels, also reduced leptin mRNA. "
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