Current Pharmaceutical Design - Volume 19, Issue 39, 2013

Nesfatin-1, derived from the nucleobindin-2 gene product, is expressed in neurons located in brain centers known to be important in the central regulation of both cardiovascular function and fluid and electrolyte homeostasis. In fact the peptide colocalizes in those neurons with an impressive list of neuropeptides and neurotransmitters known to be important in the regulation of thirst, appetite and central autonomic control. We and others have demonstrated potent sympatho-stimulatory actions of nesfatin-1 in brain and the potential physiologic relevance of those effects. In addition, although nesfatin-1 was originally described as a peptide with potent anorexigenic actions in brain, effects corroborated by several groups, it is possible that the anorexigenic actions of nesfatin-1 are secondary to a primary action to reduce thirst. Progress in unraveling the importance of endogenous nesfatin-1 in cardiovascular function, or fluid and electrolyte homeostasis, has been limited due to the to date unavailability of nesfatin-1 antagonists and the fact that the receptor for nesfatin-1 remains unidentified.

NUCB2 and its proteolytically cleaved product nesfatin-1 were initially identified as hypothalamic neuroproteins that inhibit food intake, via a leptin-independent pathway. Since then recent studies have found NUCB2/nesfatin-1 to be expressed both centrally, as well as in peripheral tissues. The recent implementation of novel experimental approaches has produced a large body of evidence implicating NUCB2/nesfatin-1 in a diverse range of biological functions and in the modulation of food intake, energy homeostasis and metabolism. In this review, we discuss the discovery of NUCB2 and its proteolytic product nesfatin-1, and its expression in both central and peripheral tissues. In addition we shed light on the most recent discoveries supporting the role for NUCB2/nesfatin-1 in peripheral tissues and its association with metabolic alterations. Moreover, we highlight the importance of NUCB2 and nesfatin-1 in adipose tissue, its regulation of adipogenesis and obesity-associated metabolic diseases.

Originally identified in the hypothalamus as a satiety factor, recent studies provide evidence that nefatin-1/NUCB2 is a gutbrain peptide with a broader array of actions. Detection of abundant nesfatin-1/NUCB2 in gastric X/A like endocrine cells, which also produce the orexigenic hormone ghrelin, indicates that gastric mucosa may be one of the predominant sources of nesfatin-1/NUCB2. Functional studies have revealed significant effects of nefatin-1 on inhibition of feeding behavior and on glucose homeostasis. These metabolic functions make nesfatin-1/NUCB2 a novel candidate for treatment of obesity and diabetes. However, deficiencies in our understanding of nesfatin-1/NUCB2 receptor pose a significant hurdle for therapies that target its action. Defining novel pathways to alter the production of nesfatin-1/NUCB2 would shift therapeutic focus to gastric targets. A necessary precondition is improved understanding of the mechanisms by which nesfatin-1/NUCB2 is synthesized and secreted by gastric X/A like cells. Recent studies provide evidence that mTOR is a critical regulatory molecule in these endocrine cells and that its activity is linked to the production of ghrelin and nesfatin- 1/NUCB2. These findings suggest that gastric mTOR is involved in the regulation of food intake and overall energy metabolism through modulation of ghrelin and nesfatin-1/NUCB2. In this review, we first summarize current advances in the relationship between organism energy status and nesfatin-1/NUCB2 levels, and then discuss the novel finding on mTOR as the gastric fuel sensor and its role in the regulation of nesfatin-1/NUCB2 expression.

Nesfatin-1, discovered by Oh-I and his coworkers in 2006, is a multi-functional peptide hormone with an approximate MW of 9.8 kDa and a half-life of 23.5 minutes. This peptide is found in three different forms, nesfatin-1, nesfatin-2 and nesfatin-3, all three of which are formed from the precursor NUCB2 by proteolytic processing. The 30-amino acid middle segment of nesfatin-1 (M30) is responsible for limiting food intake, while the exact physiological role of nesfatin-2 and nesfatin-3 is unknown. This review will focus on nesfatin-1 in relation with tissue and fluid distribution, considerations for its analysis in body fluids, and its potential as a biomarker for some diseases.