OR30-5 The Role of Leptin on Arousal

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR30-Central Regulation of Appetite & Feeding
Basic/Translational
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:15 PM
Room 304 (Moscone Center)
Paige B Beck*1, Francisco J Urbano2 and Edgar Garcia-Rill1
1University of Arkansas for Medical Sciences, Little Rock, AR, 2IFIBYNE- CONICET, University of Buenos Aires, Argentina, Buenos Aires, Argentina
Leptin, a hormone that regulates appetite and energy expenditure, is increased in obese individuals, although these individuals often exhibit leptin resistance.  Obesity is characterized by sleep/wake disturbances, such as excessive daytime sleepiness in the absence of sleep-disordered breathing, increased REM sleep, increased nighttime arousals, increased total wake time, and decreased percentage of total sleep. Several studies have shown that short sleep duration is highly correlated with decreased leptin levels in both animal and human models.  Arousal and REM sleep are regulated by the cholinergic arm of the reticular activating system, the pedunculopontine nucleus (PPN).  The goal of this project is to determine the role of leptin in the PPN, and thus the possible link between obesity and related sleep disorders. We found that leptin causes a partial blockade of Na+ channel conductance and H-current (IH) in PPN cells, leading to decreased activity in the PPN. We then investigated the intracellular mechanisms by which leptin may act on PPN cells.  Here, we show that the mechanism of leptin’s effect is G-protein dependent and can be blocked by the super-active leptin antagonist (SLAN-4). Whole cell patch clamp recordings were conducted on 9-17 day old rat brainstem slices in the presence of the synaptic blockers gabazine (GABAA antagonist), strychnine (glycine antagonist), 6-cyano-7-nitroquinoxaline-2,3-dione (AMPA/kainate glutamate antagonist), and APV (NMDA antagonist) for Ih experiments; synaptic blockers plus tetraethylammonium chloride (to block K+ channels), cadmium and nickel chloride (to block Ca2+ channels) were used in the Na+ current experiments. We found that the effect of leptin on Na+ currents was blocked by GDP-beta-S, a G-protein inhibitor, (n=16, p<0.001), but the effect of leptin on IH was not blocked by GDP-beta-S (n=10, p>0.05).  We also found that the effect of leptin on both Na+ currents and IH was blocked by the leptin antagonist (n=6, p<0.001; n=10, p<0.001 respectively).  Therefore, these results show that leptin’s effect on PPN cells is not only G-protein dependent, but also leptin receptor mediated. We hypothesize that leptin normally decreases activity in the PPN by reducing IH and Na+ currents, and that in obesity, this effect may be blunted due to leptin resistance, leading to increased arousals and REM sleep drive.

Nothing to Disclose: PBB, FJU, EG

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH awards F30-HL108429 NRSA (to Paige Beck), R01 NS020246, and P20 GM103425 (to Dr. Garcia-Rill). In addition it was supported by ANPCyT-FONCyT-BID 1728 OC.AR. PICT 2008-2019 (to Dr. Urbano)