ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Elife. 2018 Jun 15;7. pii: e35960.

Using transgenic mice, this team discover a new role for Pituitary adenylate cyclase activating polypeptide (PACAP) in female puberty and reproduction. This neuropeptide relays nutritional state information in the hypothalamus to regulate gonadotropin-releasing hormone release.

Metabolic cues play a critical role in the regulation of pubertal timing and reproduction by modulating the release of kisspeptin and/or (GnRH) at the hypothalamic level (1). While leptin receptors are expressed in a subset of kisspeptin neurons (2), genetic studies have shown that the main site of leptin’s action to regulate reproduction is not on kisspeptin neurons directly, but rather on cells in the ventral premammillary nucleus (PMV) (3–6). Because PACAP is expressed in the PMV and appears to play a role in the regulation of GnRH secretion and energy balance, the authors hypothesized that it could be involved in the regulation of reproduction by energy availability. They showed that PACAP-expressing neurons of the PMV make direct contact with kisspeptin neurons in the arcuate and AVPV nuclei and respond to leptin stimulation. Mice with PACAP deleted conditionally from leptin receptor expressing neurons showed delayed onset of puberty and irregular estrus cycles with a blunted LH surge. The data shows that PACAP is responsible for transducing some, but not all, of the metabolic information relayed by leptin to the hypothalamic-pituitary-gonadal axis. In order to investigate the role of PACAP in the PMV directly, they showed that targeted deletion of the PACAP in the PMV in adult females led to increased estrus cycle length and decreased fertility. The magnitude of the LH increase after leptin administration centrally did not differ in control and injected animals, indicating that PACAP from the PMV is necessary for normal reproductive function but not for the relay of leptin signal from this nucleus.

This study sheds a light on the complex crosstalk between energy balance and reproduction, and brings the first evidence of a role for PACAP in the control of puberty, and more specifically in the PMV in ovulatory cycling and subsequent fertility in females. Kisspeptin neurons in the arcuate nucleus and the AVPV are heterogeneous populations, which can be defined by their response to PACAP.

References: 1. Navarro VM, Kaiser UB. 2013. Metabolic influences on neuroendocrine regulation of reproduction. Current Opinion in Endocrinology & Diabetes and Obesity 20:335–341.

2. Smith JT, Acohido BV, Clifton DK, Steiner RA. 2006. KiSS-1 neurons are direct targets for leptin in the ob/ob mouse. Journal of Neuroendocrinology 18:298–303.

3. Cavalcante JC, Bittencourt JC, Elias CF. 2014. Distribution of the neuronal inputs to the ventral premammillary nucleus of male and female rats. Brain Research 1582:77–90.

4. Donato J, Cravo RM, Frazão R, Gautron L, Scott MM, Lachey J, Castro IA, Margatho LO, Lee S, Lee C, Richardson JA, Friedman J, Chua S, Coppari R, Zigman JM, Elmquist JK, Elias CF. 2011. Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. Journal of Clinical Investigation 121:355–368.

5. Donato J, Silva RJ, Sita LV, Lee S, Lee C, Lacchini S, Bittencourt JC, Franci CR, Canteras NS, Elias CF. 2009. The ventral premammillary nucleus links fasting-induced changes in leptin levels and coordinated luteinizing hormone secretion. Journal of Neuroscience 29:5240–5250.

6. Cravo RM, Frazao R, Perello M, Osborne-Lawrence S, Williams KW, Zigman JM, Vianna C, Elias CF. 2013. Leptin signaling in Kiss1 neurons arises after pubertal development. PLoS One 8: e58698.