Nesfatins

Definition
Nesfatin-1, corresponding to nucleobindin2 (NUCB2) is a novel satiety molecule that is associated with melanocortin signaling in the hypothalamus. It is a feeding inhibitory peptide encoded in the precursor protein, nucleobindin 2 (pronesfatin) 1.

Related peptides
NUCB2, a 396 aa peptide, is highly conserved between humans and rodents, and mRNA and immunoreactive cell bodies can be found in several hypothalamic nuclei; however, only the paraventricular nucleus expression was decreased by fasting. NUCB2 has several sites for posttranslational cleavage by prohormone convertases, and intracerebroventricular (i.c.v.) injection of NUCB2 or its first 82 amino acids (termed nesfatin-1 for NEFA/nucleobindin2-encoded satiety factor) acutely, transiently, and dose dependently inhibited dark phase food intake in rats. Other posttranslational products of NUCB2, or a NUCB2 mutant that cannot be cleaved at aa 82–83, did not inhibit food intake. These NUCB2 fragments (termed nesfatin-2 and -3) have structures similar to that of DNA or calcium binding proteins2.

Discovery
Oh-I et al in 2006 reported the discovery of a novel satiety molecule called Nesfatin, corresponding to NEFA/NUCB2, a secreted protein of unknown function, expressed in the appetite-control hypothalamic nuclei in rats3.

Structural Characteristics
NUCB2 (also called NEFA for DNA binding /EF-hand /acidic protein) is a hypothalamus-secreted protein that is highly conserved in human, mice and rat. NUCB2/Nesfatin is composed of a signal peptide of 24 amino acids and a protein structure containing 396 amino acids4. NUCB2 is cleaved post translationally by prohormone convertases into an N-terminus-fragment Nesfatin-1 and two C-terminal peptides, Nesfatin-2 and Nesfatin-32.

Mode of Action
Nesfatin-1 is found in discrete nuclei of the hypothalamus where it probably activates a leptin-independent melanocortin pathway. Nesfatin-1 crosses the Blood Brain Barrier (BBB) in both the blood-to-brain and brain-to-blood directions by a nonsaturable system4.. Calcium binding nesfatins mediate their action through G-protein coupled receptors5.

Functions
Nesfatin is a satiety molecule with anorexigenic properties4. Nesfatin-1 in rat stimulates calcium influx and interacts with a G protein-coupled receptor still to be characterized5. Nesfatin has potential clinical applications. It could be used as a diagnostic index in various diseases Nesfatin-1-related drugs may improve metabolic disorders by reducing body weight of patients with obesity and metabolic syndrome4.

References
1.Gonzalez R, Tiwari A, Unniappan S. (2009). Pancreatic beta cells colocalize insulin and pronesfatin immunoreactivity in rodents. Biochem Biophys Res Commun., 381(4):643-648.
2.Cowley MA and Grove KL (2006). To be or NUCB2, is nesfatin the answer? Cell Metab., 4(6):421-422.
3.Oh-I S, Shimizu H, Satoh T, Okada S, Adachi S, Inoue K, Eguchi H, Yamamoto M, Imaki T, Hashimoto K, Tsuchiya T, Monden T, Horiguchi K, Yamada M, Mori M. (2006). Identification of nesfatin-1 as a satiety molecule in the hypothalamus. Nature, 443(7112):709-712.
4.Shimizu H, Oh-I S, Okada S, Mori M (2009). Nesfatin-1: An Overview and Future Clinical Application. Endoc J., 56(4):537-543.
5.Brailoiu GC, Dun SL, Brailoiu E, Inan S, Yang J, Chang JK, Dun NJ. (2009). Nesfatin-1: Distribution and Interaction with a G Protein-Coupled Receptor in the Rat Brain. Endocrinology,148(10):5088–5094.