Cellular Distribution, Regulated Expression, and Functional Role of the Anorexigenic Peptide, NUCB2/Nesfatin-1, in the Testis

Abstract

Nesfatin-1, product of the precursor NEFA/nucleobindin2 (NUCB2), was initially identified as anorectic hypothalamic neuropeptide, acting in a leptin-independent manner. In addition to its central role in the control of energy homeostasis, evidence has mounted recently that nesfatin-1 is also produced in peripheral metabolic tissues, such as pancreas, adipose, and gut. Moreover, nesfatin-1 has been shown to participate in the control of body functions gated by whole-body energy homeostasis, including puberty onset. Yet, whether, as is the case for other metabolic neuropeptides, NUCB2/nesfatin-1 participates in the direct control of gonadal function remains unexplored. We document here for the first time the expression of NUCB2 mRNA in rat, mouse, and human testes, where NUCB2/nesfatin-1 protein was identified in interstitial mature Leydig cells. Yet in rats, NUCB2/nesfatin-1 became expressed in Sertoli cells upon Leydig cell elimination and was also detected in Leydig cell progenitors. Although NUCB2 mRNA levels did not overtly change in rat testis during pubertal maturation and after short-term fasting, NUCB2/nesfatin-1 content significantly increased along the puberty-to-adult transition and was markedly suppressed after fasting. In addition, testicular NUCB2/nesfatin-1 expression was up-regulated by pituitary LH, because hypophysectomy decreased, whereas human choriogonadotropin (super-agonist of LH receptors) replacement enhanced, NUCB2/nesfatin-1 mRNA and peptide levels. Finally, nesfatin-1 increased human choriogonadotropin-stimulated testosterone secretion by rat testicular explants ex vivo. Our data are the first to disclose the presence and functional role of NUCB2/nesfatin-1 in the testis, where its expression is regulated by developmental, metabolic, and hormonal cues as well as by Leydig cell-derived factors. Our observations expand the reproductive dimension of nesfatin-1, which may operate directly at the testicular level to link energy homeostasis, puberty onset, and gonadal function.

Role of nesfatin-1 in the metabolism of skeletal tissues

“…The anatomical location of neurons expressing nesfatin-1 and its coexistence with neurotransmitters suggests that the physiological role of nesfatin-1 is not limited to the regulation of food intake, but also includes the regulation of neuroendocrine and autonomic control of internal organs and emotional reactions (14,22,34). The expression of NUCB2/nesfatin-1 mRNA was also observed in peripheral tissues, including the stomach, duodenum, pancreas, heart, adipose tissue, and testis (19,23,44,48,65). Gastric NUCB2/ nesfatin-1 mRNA expression levels were higher than expression levels in other peripheral organs and brain (48).…”

“…This peptide influences water intake (64), energy expenditure (56), sleep (54), blood pressure (61,63), and reproduction (18,19). Serum nesfatin-1 levels correlated positively with increasing BMI, demonstrating that systemic nesfatin-1 levels may be influenced by the body fat (1,44).…”

Nesfatin Role as Possible New Anti Obesity Treatment

“…Ongoing pre-clinical data suggest the possible use of subcutaneous and intranasal routes of nesfatin-1 administration (Shimizu et al, 2009c), which needs to be further explored. Another important aspect to be unraveled is the weight loss upon chronic administration of nesfatin-1 (Li et al, 2010;Gonzalez et al, 2012;Li et al, 2013;Dong et al, 2013) and possible related changes in energy balance and/or basal metabolic rate (Foo et al, 2008;García-Galiano et al, 2010;Gonzales et al, 2011;Pałasz et al, 2012;Kerbel and Unniappan, 2012;García-Galiano et al, 2012;Ghanbari Niaki et al, 2013;Vas et al, 2013) for which studies so far are limited. In fact, nesfatin-1 has a remarkably prolonged effect on food intake and body temperature (Könczöl et al, 2012).…”

“…Nesfatin-1 injected intracerebroventricularly significantly decreased gastric emptying (García-Galiano et al, 2012). Goebel-Stengel and Wang (2012) showed that NUCB2/ nesfatin-1 immunoreactivity is distributed in mouse brain areas involved in the regulation of stress response and visceral functions activated by an acute psychological stressor suggesting that nesfatin-1 might play a role in the efferent component of the stress response.…”

Recent progress in research on the distribution and function of NUCB2/Nesfatin-1 in peripheral tissues [Review]

“…García-Galiano et al [29] documented the expression of NUCB2 mRNA in rat, mouse, and human testes, where the NUCB2/Nesfatin-1 protein was found in interstitial mature Leydig cells. Although NUCB2 mRNA levels did not overtly change in the rat testis during pubertal maturation and after short-term fasting, NUCB2/Nesfatin-1 content significantly increased (~10-fold increase) along the puberty-to-adult transition and was markedly suppressed (~4-fold decrease) after fasting.…”