The anorexigenic neuropeptide, NUCB2/nesfatin-1, is indispensable for normal puberty onset in the female rat
David Garcia-Galiano1,2, Victor M Navarro1, Juan Roa1, Francisco Ruiz-Pino1, Juan M Castellano1,2, Carlos Dieguez2,3, Leonor Pinilla1,2 & Manuel Tena-Sempere1,2
The hypothalamic peptide, nesfatin-1, derived from the precursor NEFA/nucleobindin2 (NUCB2), was recently identified as central anorexigenic molecule, acting in a leptin-independent manner. Yet, its potential involvement in the regulation of other biological functions gated by body energy status remains unexplored. We show herein that NUCB2/nesfatin-1 is involved in the control of female puberty. NUCB2/nesfatin mRNA and protein were detected at the hypothalamus of pubertal female rats, with prominent signals at lateral hypothalamus (LHA), paraventricular (PVN) and supraoptic (SON) nuclei. Hypothalamic NUCB2 expression raised along pubertal transition, with detectable elevations of its mRNA levels at LHA, PVN and SON, and three-fold increase of its total protein content between late-infantile and peri-pubertal periods. Conditions of negative energy balance, such as 48-h fasting or sustained sub-nutrition, decreased hypothalamic NUCB2 mRNA and/or protein levels in pubertal females. At this age, central administration of nesfatin-1 induced modest but significant elevations of circulating gonadotropins, whose magnitude was notably augmented in conditions of food-deprivation. Continuous i.c.v. infusion of antisense morpholino oligonucleotides (as-MON) against NUCB2 along pubertal maturation, which markedly reduced hypothalamic NUCB2 protein content, delayed vaginal opening and decreased ovarian weights and serum LH levels. Yet, in adult cyclic female rats, a similar as-MON strategy failed to alter pre-ovulatory gonadotropin surges, despite analogous suppression of hypothalamic NUCB2. In sum, our data are the first to disclose the indispensable role of the neuropeptide, NUCB2/nesfatin-1, in the central networks driving pubertal activation of gonadotropic axis; a function that may contribute to the integral control of energy homeostasis and puberty onset.