Translational and Post-translational Control of Leptin Production by Fat Cells
Expression of leptin in adipocytes is a subject to the multi-level post-transcriptional control. Available evidence suggests that the insulin-sensitive mTORC1-mediated signaling pathway regulates leptin expression at the level of translation thus coupling
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Konstantin V. Kandror
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Introduction
Leptin, a 16 kDa product of the ob gene, is synthesized predominantly in adipocytes and targets central nervous system regulating food intake, energy expenditure, and several other important physiological functions of mammalian organisms (Dalamaga et al. 2013; Ahima and Flier 2000; Friedman 2009). Discovery of leptin 20 years ago (Zhang et al. 1994) opened a new era in obesity research. Originally, it has been thought that leptin works as a “lipostat”, as food intake and accumulation of energy stores in fat cells result in an increase in leptin production thus leading to inhibition of appetite and elevation of energy expenditure. Conversely, when fat stores decline, adipocytes reduce leptin production, and food intake is increased. This simple or better, over-simplified model has nonetheless triggered a great interest to leptin as a potential anti-obesity medication. However, in spite of early impressive results obtained in rodents and several promising studies in humans (Friedman 2009) it appears that human obesity is, for the most part, accompanied by elevated circulating leptin levels and is often resistant to exogenous leptin. At the same time, other human studies have convincingly demonstrated that weight loss results in a decrease in plasma leptin concentrations, and that low leptin levels predispose human patients to weight gain. These and other experiments have suggested that although humans may be resistant to increased leptin levels, a fall in plasma leptin stimulates food intake, so that leptin’s main role in humans may be to protect fat stores in order to improve survival when food is scarce (Unger 2004). In agreement with this idea, it was shown that in humans, feeding increases and starvation decreases leptin levels which may explain the high failure rate of dieting (Ahima and Flier 2000). Indeed,
K.V. Kandror (*) Boston University School of Medicine, Silvio Conte Building, K120D, 72 E. Concord Street, Boston, MA 02118, USA e-mail: [email protected] © Springer International Publishing Switzerland 2016 K.M.J. Menon, A.C. Goldstrohm (eds.), Post-transcriptional Mechanisms in Endocrine Regulation, DOI 10.1007/978-3-319-25124-0_10
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administration of low doses of leptin may help to lose weight without the anguish and distress that usually accompany this process (Rosenbaum et al. 2005). Regardless of how leptin exerts its biological activity, it is clear that nutrient uptake/status is directly coupled to leptin production in adipocytes. The mechanism(s) of this phenomenon are only beginning to emerge. Since this understudied and inadequately discussed regulatory connection is central to all proposed mechanisms of leptin action, it will be the main focus of our review. The problem has at least two aspects: a short term and a long term connection. First, circulating leptin levels increase within hours after feeding and decrease shortly after food deprivation. Although in humans, this effect may not be as fast and robust as in rodents, all mamm
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