ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This study used chemogenetics and transgenic mouse models to show that glutamatergic neurotransmission in leptin responsive neurons in the premammillary nucleus is required for normal puberty and ovulation.

Puberty and the acquisition of reproductive functions result from the reawakening of a complex neuroendocrine machinery eventually leading to the activation of GnRH secretion. Metabolic cues play a crucial role in regulating this system with leptin being one of the main actors of the crosstalk between energy balance and reproduction¹. Recent data showed that the premammilary nucleus (PMv) in the hypothalamus is the relay of nutritional state information to the GnRH neurons^2,3 as leptin does not act directly onto GnRH neurons. The current study further characterizes the hypothalamic circuits involved in the modulation of GnRH secretion by metabolic cues.

The authors first showed that stimulation of neurons expressing the leptin receptor in the PMv using stimulatory form of designer receptor exclusively activated by designer drugs (DREADDS) approaches induced LH release. The data also indicate that females with deletion of vGlut2, a glutamate transporter, in neurons expressing the leptin receptor showed normal vaginal opening but delayed age at first estrus, disrupted estrous cycles, increased gonadotropin-releasing hormone (GnRH) concentration in the axon terminals and disrupted LH secretion, suggesting disruption of GnRH secretion. To evaluate if glutamate neurotransmission is required for leptin-induced pubertal development, the researchers produced a dual-floxed mouse model in which a stereotaxic delivery of a viral vector restored leptin receptor expression while deleting VGLUT2 in the PMv. Using this approach, they showed that leptin action on pubertal development requires Vglut2.

Together, these data indicate that glutamate signalling in leptin sensitive neurons in the PMv is required for normal puberty and ovulation. The relationship between kisspeptin neurons and these neuronal populations in the PMv remains to be determined.

References: 1. Anderson GM, Hill JW, Kaiser UB, Navarro VM, Ong KK, Perry JRB, Prevot V, Tena-Sempere M, Elias CF. Metabolic control of puberty: 60 years in the footsteps of Kennedy and Mitra’s seminal work. Nat Rev Endocrinol. 2024; 20(2):111-123.2. Donato J Jr, Cravo RM, Frazão R, Gautron L, Scott MM, Lachey J, Castro IA, Margatho LO, Lee S, Lee C, Richardson JA, Friedman J, Chua S Jr, Coppari R, Zigman JM, Elmquist JK, Elias CF. Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. J Clin Invest. 2011; 121(1):355-68.3. Ross RA, Leon S, Madara JC, Schafer D, Fergani C, Maguire CA, Verstegen AM, Brengle E, Kong D, Herbison AE, Kaiser UB, Lowell BB, Navarro VM. PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse. Elife. 2018; 7:e35960