OR44-2 Leptin-Responsive GABAergic Neurons Are Necessary For Pubertal Maturation In Female Mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR44-Female Reproductive Endocrinology
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 9:30 AM
Room 256 (Moscone Center)
Cecilia Martin*1, Victor Manuel Navarro2, Linh Vong3, Rona S. Carroll2 and Bradford Barr Lowell4
1Brigham & Women Hospital/Harvard Medical School, Boston, MA, 2Brigham and Women's Hospital, Boston, MA, 3Beth Israel Deaconess Medical Center, Boston, MA, 4Beth Israel Deaconess Med Ctr, Boston, MA
The adipocyte-derived hormone leptin has a profound influence on energy homeostasis and fertility. Mice deficient in (ob/ob) or resistant to (db/db) leptin are infertile and obese. Humans with congenital leptin deficiency present a similar phenotype, and recombinant leptin treatment restores normal body weight and triggers the onset of puberty. The underlying neurocircuitry responsible for the influence of leptin on reproductive function is poorly understood, in part because of incomplete knowledge regarding first-order, leptin-responsive neurons. To address this knowledge gap, we performed reproductive phenotype analysis of Vgat-Cre;Leprlox/lox and Vglut2-Cre;Leprlox/lox mice, which have selective deletion of the leptin receptor in GABAergic (inhibitory) or glutamatergic (excitatory) neurons, respectively. Female Vgat-Cre;Leprlox/lox mice were obese and showed delayed and only partial vaginal opening compared to control littermates. Furthermore, these mice had abnormal estrous cycles with persistent diestrus and atrophic reproductive tracts, suggesting reduced levels of circulating estradiol, as well as absent corpora lutea in the ovaries. In contrast, female Vglut2-Cre;Leprlox/lox mice exhibited no difference in body weight, timing of vaginal opening, or estrous cyclicity, as well as grossly normal ovaries (including the presence of corpora lutea) and uteri when compared with Leprlox/lox littermate controls. Based on the abnormal reproductive phenotype observed in Vgat-Cre;Leprlox/lox mice, we hypothesized that the mice had an impairment in central activation of the HPG axis, potentially as a result of reduced kisspeptin drive. To test this possibility, we injected 1 nmol kisspeptin-10 (Kp10) or vehicle (saline) centrally (intracerebroventricularly) in two-month-old Vgat-Cre;Leprlox/lox females and control littermates (Leprlox/lox). We found that serum LH and FSH levels were significantly increased 20 minutes after Kp10 administration in both groups. Similarly, ovariectomized Vgat-Cre;Leprlox/lox females showed a compensatory rise in gonadotropin levels comparable to control females, indicating that the negative feedback effect of sex steroids was still present. In conclusion, our findings indicate that leptin-responsive GABAergic neurons – but not glutamatergic neurons – act as metabolic sensors to regulate the reproductive axis.

Nothing to Disclose: CM, VMN, LV, RSC, BBL

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