PT  - JOURNAL ARTICLE
AU  - Cecilia Martin
AU  - Víctor M. Navarro
AU  - Serap Simavli
AU  - Linh Vong
AU  - Rona S. Carroll
AU  - Bradford B. Lowell
AU  - Ursula B. Kaiser
TI  - Leptin-Responsive GABAergic Neurons Regulate Fertility through Pathways That Result in Reduced Kisspeptinergic Tone
AID  - 10.1523/JNEUROSCI.3003-13.2014
DP  - 2014 Apr 23
TA  - The Journal of Neuroscience
PG  - 6047--6056
VI  - 34
IP  - 17
4099  - http://www.jneurosci.org/content/34/17/6047.short
4100  - http://www.jneurosci.org/content/34/17/6047.full
SO  - J. Neurosci.2014 Apr 23; 34
AB  - The adipocyte-derived hormone leptin plays a critical role in the central transmission of energy balance to modulate reproductive function. However, the neurocircuitry underlying this interaction remains elusive, in part due to incomplete knowledge of first-order leptin-responsive neurons. To address this gap, we explored the contribution of predominantly inhibitory (GABAergic) neurons versus excitatory (glutamatergic) neurons in the female mouse by selective ablation of the leptin receptor in each neuronal population: Vgat-Cre;Leprlox/lox and Vglut2-Cre;Leprlox/lox mice, respectively. Female Vgat-Cre;Leprlox/lox but not Vglut2-Cre;Leprlox/lox mice were obese. Vgat-Cre;Leprlox/lox mice had delayed or absent vaginal opening, persistent diestrus, and atrophic reproductive tracts with absent corpora lutea. In contrast, Vglut2-Cre;Leprlox/lox females exhibited reproductive maturation and function comparable to Leprlox/lox control mice. Intracerebroventricular administration of kisspeptin-10 to Vgat-Cre;Leprlox/lox female mice elicited robust gonadotropin responses, suggesting normal gonadotropin-releasing hormone neuronal and gonadotrope function. However, adult ovariectomized Vgat-Cre;Leprlox/lox mice displayed significantly reduced levels of Kiss1 (but not Tac2) mRNA in the arcuate nucleus, and a reduced compensatory luteinizing hormone increase compared with control animals. Estradiol replacement after ovariectomy inhibited gonadotropin release to a similar extent in both groups. These animals also exhibited a compromised positive feedback response to sex steroids, as shown by significantly lower Kiss1 mRNA levels in the AVPV, compared with Leprlox/lox mice. We conclude that leptin-responsive GABAergic neurons, but not glutamatergic neurons, act as metabolic sensors to regulate fertility, at least in part through modulatory effects on kisspeptin neurons.