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
Abstract
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). "
    [Show abstract] [Hide abstract] ABSTRACT: The intake of food rich in polyphenols is related to a lower incidence in almost all chronic degenerative diseases. However, relatively little is known about the molecular mechanisms involved in its antioxidant properties. The aim of this study was to determine whether the mechanism of action of polyphenols could be related to a modulation in energy uptake and metabolism, and further induced mitochondrial changes. For this purpose, male C57BL6 mice were fed during 3 months with a tea-based beverage rich in polyphenols. Insulin sensitivity, tissue oxidative damage biomarkers, as well as energy-related signaling pathways were determined to evaluate its mechanism of action. As a result, a tissue- and protein-specific subtle reduction in oxidative damage was observed. Skeletal muscle showed mitochondrial changes in respiratory complexes and an increase in AMP-activated protein kinase α levels, suggesting reduced energy availability. These changes were also associated with adipose tissue cellular metabolism. This was confirmed by a decline in the potential of energy uptake, evidenced by a diminished intestinal and systemic absorption of carbohydrates together with an inhibition of insulin sensitivity. Our results suggest that the mechanisms of action of green tea polyphenols may be related to their ability to modulate energy uptake leading to mitochondrial adaptations possibly responsible for the changes in protein oxidative damage.
    Full-text · Article · Mar 2013
    • "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]. "
    [Show abstract] [Hide abstract] ABSTRACT: Oxidative stress impacts multiple systems of the body and can lead to some of the most devastating consequences in the nervous system especially during aging. Both acute and chronic neurodegenerative disorders such as diabetes mellitus, cerebral ischemia, trauma, Alzheimer's disease, Parkinson's disease, Huntington's disease, and tuberous sclerosis through programmed cell death pathways of apoptosis and autophagy can be the result of oxidant stress. Novel therapeutic avenues that focus upon the phosphoinositide 3-kinase (PI 3-K), Akt (protein kinase B), and the mammalian target of rapamycin (mTOR) cascade and related pathways offer exciting prospects to address the onset and potential reversal of neurodegenerative disorders. Effective clinical translation of these pathways into robust therapeutic strategies requires intimate knowledge of the complexity of these pathways and the ability of this cascade to influence biological outcome that can vary among disorders of the nervous system.
    Full-text · Article · Dec 2012
    • "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. "
    [Show abstract] [Hide abstract] ABSTRACT: Evidence shows that the insulin-like growth factor-1 (IGF-1) and leptin reduce β-amyloid (Aβ) production and tau phosphorylation, two major hallmarks of Alzheimer's disease (AD). IGF-1 expression involves the JAK/STAT pathway and the expression of leptin is regulated by the mammalian target of rapamycin complex 1 (mTORC1). We have previously shown that Aβ reduces leptin by inhibiting the mTORC1 pathway and Aβ was also suggested to inhibit the JAK/STAT pathway, potentially attenuating IGF-1 expression. As IGF-1 can activate mTORC1 and leptin can modulate JAK/STAT pathway, we determined the extent to which IGF-1 and leptin can upregulate the expression of one another and protect against Aβ-induced downregulation. We demonstrate that incubation of organotypic slices from adult rabbit hippocampus with Aβ42 downregulates IGF-1 expression by inhibiting JAK2/STAT5 pathway. Leptin treatment reverses these Aβ42 effects on IGF-1 and treatment with the STAT5 inhibitor completely abrogated the leptin-induced increase in IGF-1. Furthermore, EMSA and ChIP analyses revealed that leptin increases the STAT5 binding to the IGF-1 promoter. We also show that IGF-1 increases the expression of leptin and reverses the Aβ42-induced attenuation in leptin expression via the activation of mTORC1 signaling as the mTORC1 inhibitor rapamycin completely precluded the IGF-1-induced increase in leptin expression. Our results demonstrate for the first time that Aβ42 downregulates IGF-1 expression and that leptin and IGF-1 rescue one another from downregulation by Aβ42. Our study provides a valuable insight into the leptin/IGF-1/Aβ interplay that may be relevant to the pathophysiology of AD.
    Full-text · Article · Jun 2011
Show more