The Anorexigenic Neuropeptide, Nesfatin-1, Is Indispensable for Normal Puberty Onset in the Female Rat

Abstract

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 folliclestimulating 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.

Nesfatin-1 exerts long-term effect on food intake and body temperature

“…As nesfatin-1 is expressed in human, acts as anorexigen, and its role has recently been suggested in many other functions such as, epilepsy and puberty onset, our data may be relevant regarding nesfatin-1, as a potential pharmacotherapeutical target. 7,39,40 …”

ENDOCRINOLOGY AND ADOLESCENCE: Deciphering puberty: novel partners, novel mechanisms

“…Yet, as highlighted elsewhere in this review, experimental work in different species has also defined the important contribution of other central transmitters and peripheral hormones, such as glutamate, GABA, and ghrelin (just to name but a few examples) in the physiological control of puberty onset (72,73). A recent addition to the growing list of pubertal modulators is nesfatin-1, as revealed by recent data on pubertal female rats (74,75). The major features of this neuropeptide as a putative regulator of the timing of puberty in the female are summarized below and synoptically presented in Table 3.…”

“…In this sense, central injection of low doses of nesfatin-1 evoked moderate but significant increases in serum LH levels in peripubertal female rats fed ad libitum. Intriguingly, gonadotropin responses to nesfatin-1 were substantially enhanced in conditions of short-term fasting, despite the significant decrease in the prevailing gonadotropin levels and of the hypothalamic expression of NUCB2/nesfatin-1 (74). Moreover, greater LH responses have been detected in pubertal male and female rats after infusion of higher doses nesfatin-1 (Navarro, Ruiz-Pino & Tena-Sempere, unpublished observations).…”

“…Hypothalamic NUCB2/nesfatin-1 expression increased during the pubertal transition, with a significant elevation of its mRNA levels in the LHA, PVN, and the supraoptic nucleus, and a threefold increase of its total protein content (74). In addition, conditions of negative energy balance known to perturb puberty, such as chronic sub-nutrition or acute fasting, decreased hypothalamic NUCB2 mRNA and protein levels in pubertal females (74).…”

“…In good agreement, suppression of the endogenous tone of nesfatin-1 in the hypothalamus during the pubertal transition, using an antisense morpholino oligonucleotide (as-MON) against NUCB2, impaired the normal timing of puberty, as evidenced by a delay in vaginal opening and the lowering of LH levels and ovarian weights. The possibility that such reproductive changes might be due to a primary metabolic impact of the as-MON treatment can be ruled out as, despite the substantial decrease in the content of NUCB2 protein in the hypothalamus, this treatment did not modify body weight gain or daily food intake during puberty (74).…”