OR04-4 The Gonadotrope as a Metabolic Sensor: Ablation of Leptin Receptor (LEPR) Signaling in Gonadotropes Blunts Responses to Gonadotropin Releasing Hormone (GnRH), Reducing Serum Luteinizing hormone (LH), Growth hormone (GH) and Litter Size

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR04-GnRH & Gonadotroph Biology & Signaling
Basic/Translational
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 12:15 PM
Room 135 (Moscone Center)
Tyler CarlLee, Michael Cozart, Mohsin M Syed, Noor Akhter, Anessa Haney, Angela Katherine Odle, Melody Lyn Allensworth and Gwen V Childs*
University of Arkansas for Medical Sciences, Little Rock, AR
Leptin regulates appetite and metabolism and is permissive for the onset of puberty and reproduction. Defining a role for leptin in the regulation of pituitary gonadotropes has been challenging (1,2).  To determine its significance to gonadotropes, we crossed mice bearing LEPRexon17 loxP/loxP with mice bearing Cre-recombinase (Cre) driven by the LHβ promoter (Cre-LHβ) (3), thereby ablating LEPR signaling selectively in gonadotropes. Organ genotyping proved no extra-pituitary expression in females. Mutant males showed extra-pituitary Cre-expression in the testes, because LH is expressed in that organ (4-6). This caused global deletion of LEPR in a subset of progeny from mutant males, resulting in a db/db-like phenotype. Therefore, experimental animals derived only from Cre-LHβ bearing females were used in this study. Serum LH and GH were lower in 19 deletion mutant males (ng/ml--0.9±0.2 LH; 3.5±1 GH) compared with 26 littermate controls (ng/ml--2.2±0.5 LH; 11.2±2.8 GH) p<0.01; with no differences in follicle stimulating hormone (FSH).  In vitro studies showed that, after 1 h exposure to 0-30 nM GnRH, cultures from mutants secreted 63% less LH and 55% less FSH basally than controls and showed a blunted response to 0.1-1 nM GnRH with 30-64% less LH and 27% less FSH. Mutant and control cultures secreted similar levels of LH and FSH in response to 10-30 nM GnRH.  Breeding studies detected the impact of gonadotrope-specific loss of LEPR on reproduction. The timing of puberty, first litter, or time between litters was normal in male and female mutants. Litters (n=9) from mutant (Cre-LHβ+) males and Cre-negative females averaged 8.8±0.7 pups/ litter, which was not different from the average seen in 6 litters from the same-strain control animals (FVB.129S--9.3±0.7 pups/litter).  In contrast, 9 litters from mutant Cre-LHβ+ females and Cre negative males averaged only 5.5 ±1.4 pups/ litters, which was significantly lower than those from the mutant males or the control strain (p<0.03).  No further reduction was seen in 9 litters from two mutant parents (6.2±1 pups/litter). These studies suggest that leptin’s signaling to pituitary gonadotropes helps maintain serum levels of LH and GH, in vivo. No obvious reproductive or metabolic phenotype was seen in mutant males, (which expressed Cre only in the pituitary and testes). However, mutant females, (which expressed Cre only in the pituitary) clearly show a 40% reduction in number of pups/litter. The impact of lack of leptin signaling is also seen dramatically in vitro by the relatively low basal gonadotropin secretion and blunted responses to physiological doses of GnRH. Perhaps, when the timing of development and metabolic conditions are right, leptin signaling optimizes trafficking or storage of gonadotropins to facilitate responses to physiologically relevant pulses of GnRH and insure reproductive success.

(1)Akhter N et al., J Histochem Cytochem. 2007; 55(2):151. (2) Crane C et al., J Histochem Cytochem. 2007;55(10):1059. (3) Charles MA et al. Genesis 2008; 46:507. (4) Berger P et al. FEBS Letters 1994;343:229. (5) Zhang FP et al. Endocrinology. 1995a;136:2904. (6) Zhang FP et al. Biochem Biophys Res Commun. 1995b;210:858.

Nothing to Disclose: TC, MC, MMS, NA, AH, AKO, MLA, GVC

*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 Grant R01 HD-059056; NIH Grant R03 HD059066; Molecular Core-COBRE P20 GM103425; and Core facilities in P30 NS047546