As the prevalence of obesity is rapidly growing in this country and throughout the world, understanding the mechanisms of weight control becomes an urgent biomedical problem. The adipose-derived hormone, leptin, plays a central role in regulation of body weight and energy expenditure. Food intake and accumulation of energy stores in adipocytes 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. However, the biochemical connection between nutrient intake/storage in adipocytes and the level of leptin secretion remains largely unknown. In the previous funding period, we found that production of leptin is regulated at the level of translation via the mTOR-mediated pathway as well as at the level of secretion. Since mTOR (mammalian target of rapamycin) represents a nutrient sensor in the cell, the first pathway may provide a long sought after physiological connection between food intake and leptin expression. Thus, our first goal for the next funding period is to determine how to manipulate expression levels of leptin mRNA stored in adipose cells using specific nutrient signals. For that, we propose to explore the mTOR-mediated mechanism of the translational control of leptin mRNA by various nutrients. This will give us the opportunity to maintain high levels of circulating endogenous leptin without increasing fat stores in adipocytes. Our second goal is to understand the molecular mechanisms of secretion from adipose cells. In particular, we will test the hypothesis that newly discovered Golgi-localized, gamma-ear-containing, Arf-binding proteins participate in the formation of secretory vesicles in adipocytes and regulate secretion from these cells. We will also determine whether or not Glut4-vesicles contain novel secreted proteins as their soluble cargo and continue our search for novel proteins secreted from adipocytes.
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