Nesfatin-1: An Affair of the Heart

Abstract

Nesfatin-1 is an 82-amino acid peptide that was identified in 2006 in the rat hypothalamus by Mori and coworkers (1). The polypeptide is proteolytically cleaved from its precursor protein, nucleobindin2 (NUCB2) and named after its initially described function to reduce food intake after third-brain ventricular injection in rats [nucleobindin 2 encoded satiety and fat influencing protein (nesfatin-1)] (1). NUCB2 can be cleaved into three polypeptides: nesfatin-1, nesfatin-2, and nesfatin-3, whereas an anorexigenic effect has so far been described only for nesfatin-1 (1). The brain-inhibitory effect on food intake was confirmed by several independent groups in rodent models (2, 3) as well as nonmammalian vertebrates (4). These initial data fostered research on this peptide, and as observed for many brain peptides before, the role of nesfatin-1 is not restricted to one effect (inhibition of food intake) but also comprises the inhibition of gastric emptying (2) and water intake (5), the modulation of stress-related endocrine and anxiogenic responses (6, 7) and sympathetic outflow (8) and also an involvement in reproduction (9). After the initial reports all focused on NUCB2/nesfatin-1 as a brain peptide, subsequent studies investigated the expression of this peptide in the periphery and detected high levels in the gastric mucosa (10), pancreas (11), adipocytes (12), gonads (13), and blood (14). Interestingly, the levels in the stomach were even higher than those detected in the brain (10), indicating a predominant expression of NUCB2/nesfatin-1 in the periphery. Possible functions attributed to peripheral nesfatin-1 encompassed the modulation of food intake (15), adipogenesis (12), and an involvement in the regulation of glucose homeostasis (16–18). Recently one study reported the expression of NUCB2/ nesfatin-1 in rat cardiac extracts (19). These data were corroborated and extended by a study of Feijoo-Bandin et al published in this issue of Endocrinology (20). The authors present a comprehensive set of experiments using a truly translational approach by means of studying mouse, rat, and human cardiac tissues. First, they show that NUCB2 mRNA is expressed in mouse, human, and rat heart occurring in both atrial and ventricular cardiomyocytes (20). Interestingly, although in mouse and rat, NUCB2 mRNA expression levels are markedly lower in the heart compared with the stomach [the presumed major source of peripheral NUCB2/nesfatin-1 (10)], expression levels are similar in the heart and stomach of humans (20), giving rise to an important role of heart-derived NUCB2/ nesfatin-1 in humans. This expression was also confirmed at the protein level. It is important to note that so far the mature, fully processed 82-amino acid nesfatin-1 has been described only in cerebrospinal fluid of rats (1), rat heart (19), and human plasma using a nesfatin-1 specific sandwich-type ELISA (14). All other studies did not distinguish between full-length NUCB2 and nesfatin-1 or detected the precursor protein, NUCB2, only in tissue extracts (4, 10, 21), whereas exogenous synthetic nesfatin-1 was clearly visible on the Western blot (10). In addition, because NUCB2 is functionally active (1), this led to the assumption that NUCB2 might not be processed at all or might be cleaved more distant from its production site. However, in the present study of Feijoo-Bandin et al (20), mature nesfatin-1 was clearly detectable by Western blot as a 9.5-kDa band in protein samples from mouse, rat, and human cardiomyocytes, indicating the processing of NUCB2 into nesfatin-1 within the heart. This hypothesis was further