Emerging Roles of NUCB2/Nesfatin-1 in the Metabolic Control of Reproduction

Nesfatin-1, derived from the precursor NEFA/nucleobindin2 (NUCB2), was initially identified as a feeding-suppressing neuropeptide, acting at central (mainly, hypothalamic) levels in a leptin-independent manner. However, recent experimental evidence strongly suggests that, rather than being a simple anorectic hypothalamic signal, nesfatin-1 operates at different tissues as an integral regulator of energy homeostasis and closely related neuroendocrine functions. On the latter, growing, albeit as yet fragmentary, evidence has pointed out recently that NUCB2/ nesfatin-1 is involved in the regulation of different aspects of reproductive maturation and function, by acting probably at different levels of the hypothalamic-pituitary-gonadal (HPG) axis. As documented by rodent studies, the reproductive facet of nesfatin-1 likely includes (i) a permissive role in (female) pubertal maturation, (ii) stimulatory effects on the gonadotropic axis, whose magnitude, in terms of LH responses, varies depending on the maturational stage and probably the sex and species, and (iii) direct expression and actions in the gonads. These features, together with the proven expression of NUCB2/nesfatin-1 in tissues with essential roles in the metabolic control of reproduction, such as the hypothalamus, adipose and pancreas, support a putative role of nesfatin-1 as neurohormonal signal linking body metabolic status, puberty and fertility. Curiously enough, although its reproductive dimension seems to be conserved in non-mammalian vertebrates, recent studies in goldfish have surfaced predominant inhibitory actions of nesfatin-1 at different levels of the HPG axis in fish. These findings illustrate our as yet limited understanding of this aspect of nesfatin-1 physiology, whose relevance in the joint control of metabolism and reproduction in health and disease warrants further investigation.