OR47-6 Leptin Action on γ-Aminobutyric Acid (GABA), not Glutamate Neurons is Required for Normal Reproductive Development

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR47-Hypothalamus-Pituitary Development & Biology
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 10:30 AM
Room 130 (Moscone Center)
Wieteke Ameliek Zuure*1, Amy Roberts1, Janette H Quennell2 and Greg M Anderson2
1University of Otago, Dunedin, New Zealand, 2University of Otago School of Medical Sciences, Dunedin, New Zealand
The adipocyte-derived hormone leptin acts in the hypothalamus to modulate the central driver of fertility: the gonadotropin releasing hormone (GnRH) neuronal system. This effect is indirect as GnRH neurons do not express leptin receptors (LEPR) [1]. Here we tested whether glutamatergic or GABAergic neurons provide the intermediate pathway between the site of leptin responsiveness and the GnRH neurons. Leptin receptors were deleted from these two large neuronal cell populations using Cre-lox transgenics; the downstream effects on puberty onset and reproduction were examined. To generate experimental mice, LEPR-floxed mice were crossed with either Vglut2-Cre (targeting vesicular glutamate transporter 2 expressing neurons) or Vgat-Cre (targeting vesicular GABA transporter expressing neurons) mice, resulting in Vglut-LEPR-KO and Vgat-LEPR-KO specific knockout mice. Homozygous LEPR-flox littermates were used as controls. Consistent with other published observations, these mice showed a range of metabolic abnormalities, such as increased bodyweight and food intake [2]. In females the day of vaginal opening and first estrus were taken as measures for puberty onset, and in males the day of the first fertile mating was used. Subsequent fertility was assessed by mating the animals with a wild-type male or female, and recording the number of litters within a period of time. Deletion of LEPR from Vglut2 neurons did not result in any significant effects on puberty onset or fertility. However, in Vgat-LEPR-KO females vaginal opening was significantly delayed by 6.9 ± 2.9 days (p < 0.03) and first estrus by 19.5 ± 1.9 days (p < 0.01) when compared to controls. In male Vgat-LEPR-KO animals puberty onset was delayed by 13.0 ± 3.8 days (p < 0.01), and there was a decrease in fertility with 0.9 ± 0.3 (p < 0.02) fewer litters born over an 85-day period. Parturition in female Vgat-LEPR-KO animals was frequently complicated by dystocia, which compromised fertility analysis. However, we were able to measure a significant delay of 8.9 ± 2.1 days (p < 0.01) in the time to the first litter. In conclusion, leptin signaling in GABAergic not glutamatergic neurons plays a key role in the timing of puberty onset and is involved in fertility regulation throughout adulthood in both sexes. These GABAergic LEPR neurons may be a key intermediate linking leptin signaling to the GnRH system, further studies are needed to dissect out the exact pathway by which these systems interact.

(1) Quennell, J.H., et al., Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology, 2009. 150(6): p. 2805-12. (2)Vong, L., et al., Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron, 2011. 71(1): p. 142-54.

Nothing to Disclose: WAZ, AR, JHQ, GMA

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

Sources of Research Support: Health Research Council of New Zealand
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