AR CAREER DEVELOPMENT COBRE: THE ROLE OF LEPTIN IN OBESITY AND SLEEP

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Leptin is a hormone produced by fat that plays a key role in regulating energy intake and expenditure. Leptin levels rise to a peak at mid gestation in the human and during the equivalent postnatal period of development in the rodent. This rise precedes the timing of the proliferation of pituitary cells vital for the regulation of growth and reproduction (somatotropes and gonadotropes). After puberty, leptin is secreted in an oscillatory manner, with 32 pulses/24 hour period and peak amplitude between midnight and 3 AM in normal lean individuals. This study focuses on the identification of the cells responsible for the pulsatile leptin secretion. Because the leptin rise coincides with the expansion in pituitary somatotropes, we will test the hypothesis that somatotropes are mostly responsible for the oscillatory pulses. To test this hypothesis, leptin will be ablated selectively in somatotropes by innovative Cre-LoxP technology. The impact of this deletion on leptin secretion, nocturnal pulses and somatotrope and gonadotrope development will be investigated in Aim 1 studies. Aim 2 studies will focus on the potential role of somatotrope leptin in the regulation of pituitary gonadotropes and the timing of puberty. Aim 3 studies will focus on the significance of the nocturnal surge of leptin and will include an investigation of the role leptin may play in cellular events that drive sleep. Leptin's importance to growth, reproduction, energy conservation and sleep patterns is well established. Obesity may be correlated with low leptin and the absence of normal pulses. This study will address leptin's role in normal events that lead to optimal body composition and sleep, which will aid our understanding of processes that lead to obesity. Dr. Akhter has developed the leptin analyses and the proposed studies will provide the preliminary data for an independent grant application, while Dr. Syed will develop electrophysiological skills for a separate line of research in which he could collaborate with Dr. Akhter.