The anorexigenic neuropeptide, nesfatin-1, is indispensable for normal puberty onset in the female rat.
The hypothalamic peptide, nesfatin-1, derived from the precursor NEFA/nucleobindin 2 (NUCB2), was recently identified as anorexigenic signal, acting in a leptin-independent manner. Yet its participation 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 threefold increase of its total protein content between late-infantile and peripubertal periods. Conditions of negative energy balance, such as 48 h fasting or sustained subnutrition, 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 intracerebroventricular infusion of antisense morpholino oligonucleotides (as-MONs) against NUCB2 along pubertal maturation, which markedly reduced hypothalamic NUCB2 protein content, delayed vaginal opening and decreased ovarian weights and serum luteinizing hormone (LH) levels. In contrast, in adult female rats, intracerebroventricular injection of nesfatin did not stimulate LH or follicle-stimulating hormone secretion; neither did central as-MON infusion alter preovulatory gonadotropin surges, despite suppression of hypothalamic NUCB2. In sum, our data are the first to disclose the indispensable role of NUCB2/nesfatin-1 in the central networks driving puberty onset, a function that may contribute to its functional coupling to energy homeostasis.
García-Galiano
David
D
Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain.
Navarro
Víctor M
VM
Roa
Juan
J
Ruiz-Pino
Francisco
F
Sánchez-Garrido
Miguel Angel
MA
Pineda
Rafael
R
Castellano
Juan Manuel
JM
Romero
Magdalena
M
Aguilar
Enrique
E
Gaytán
Francisco
F
Diéguez
Carlos
C
Pinilla
Leonor
L
Tena-Sempere
Manuel
M
D000375:Aging / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D007026:Hypothalamic Area, Lateral / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D007276:Injections, Intraventricular; D007986:Luteinizing Hormone / Q000097:blood; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D009479:Neuropeptides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000080866:Nucleobindins; D020320:Oligoribonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D012333:RNA, Messenger; D051381:Rats; D017208:Rats, Wistar; D012741:Sexual Maturation / Q000187:drug effects*; D013495:Supraoptic Nucleus / Q000378:metabolism
D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C000630652:Nucb1 protein, rat; D000080866:Nucleobindins; D020320:Oligoribonucleotides, Antisense; D012333:RNA, Messenger; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone