Nesfatin 1

Nesf-1 is posttranslationally cleaved from the 420 aa protein NUCB2 by the prohormone-convertase into N-terminal nesf-1[1–82], nesf-2[85–163], and the C-terminal nesf-3[166–396]. The structure of nesfatin-1 consists of three parts: the first part begins from the N-terminal end and continues to the 23rd aa (N23); the second part includes the mid-segment of 30 aa (M30) between 23 and 53; and the third part includes the C-terminal segment of 29 aa (C29) between 53 and 82. M30 is effective in food intake and appetite control. Human nesf-1[1–82]: Mr 9551.9; pI 5.28, soluble in water.

The gene encoding nesf-1, NUCB2, maps to human chromosome 11p15.1. The human NUCB2 gene is 55 kb in length, and has 14 exons and 13 introns. Human NUCB2 mRNA is 2300 bp long, and the product is a 420 aa protein consisting of a 24 aa signal peptide and a 396 aa protein termed NUCB2. Although nesf-1 cleaved from NUCB2 has a variety of biological functions, it is still unknown whether the putative cleavage products nesf-2 and nesf-3 exist and are secreted in vivo. Within the CNS, Nucb2 mRNA is expressed in the hypothalamus and brainstem. In peripheral tissues, Nucb2 mRNA is mainly expressed in the gastric mucosa, pancreas, white adipose tissue, heart, pituitary, and reproductive organs. NUCB2/nesf-1 immunoreactivity is detected in the intracellular vesicles of gastric mucosa, the endocrine cells of pancreatic islets, and the anterior pituitary. Nesf-1 is able to cross the blood-brain barrier by nonsaturable transmembrane diffusion, suggesting that peripheral nesf-1 may access the CNS to exert biological actions.

Fasting leads to a decrease in hypothalamic Nucb2 mRNA levels.1 Refeeding activates NUCB2/nesf-1 positive neurons in the supraoptic nucleus. In vitro, glucose elevates Nucb2 mRNA expression and NUCB2/nesf-1 secretion from cultured stomach ghrelinoma cells10 and isolated pancreatic islets. On the cellular level in the hypothalamic paraventricular nucleus (PVN), nesf-1 is located mainly in secretory vesicles in perikarya near the Golgi apparatus but not in axon terminals, suggesting a dendritic release and eventually autocrine or paracrine actions.

The putative NUCB2/nesf-1 receptor has not yet been identified. Autoradiography using 125I-nesf-1 as a surrogate for the putative expression of the receptor showed nesf-1 binding in the brain, including the cortex, PVN, area postrema, dorsal motor nucleus of the vagus nerve, and cerebellum as well as in peripheral endocrine organs including the pituitary, stomach, small intestine, pancreas, adrenal gland, testis, and visceral adipose tissue. In cultured rat hypothalamic neurons, nesf-1 induced an elevation of intracellular Ca2+ concentration, and the responseis abolished by pertussis toxin treatment,indicating the participation of a Gi/o protein-coupled receptor. Nesf-1 increases the phosphorylation of CREB without inducing cAMP formation in a neuroblastoma cell line. Additionally, nesf-1 stimulates MAPK signaling.

NUCB2/nesf-1 expression sites have been found in both central and peripheral tissues. NUCB2/nesf-1 affects the glucose metabolism by increasing insulin sensitivity. The peripheral infusion of nesf-1 reduces adiposity and plasma levels of triglyceride and cholesterol. The administration of nesf-1 increases the heart rate and blood pressure in rats and fear- and anxiety-related behaviors. The inhibition of hypothalamic NUCB2/nesf-1 signaling by using an adenoviralmediated RNA interference markedly increased food intake and hepatic glucose flux, and decreased glucose uptake in peripheral tissues.19 The inhibition of endogenous NUCB2/nesfatin-1 signaling using ICV anti-nesf-1 antiserum or anti-NUCB2 antisense oligo reduced REM sleep in the rat.

Clinical research in male humans found that the plasma NUCB2/nesf-1 levels of patients with general anxiety disorder (GAD) were lower than healthy male controls. In patients with panic disorder (PD), plasma NUCB2/nesf-1 levels were obviously elevated compared to the levels in control subjects. A positive correlation between NUCB2/nesf-1 levels and PD was observed in the patient group. Dysfunction of NUCB2/nesf-1 might be involved in the pathology of some psychiatric disorders.

Nesfatin-1(nesf-1), the 82 aa peptide processed from nucleobindin 2 (NUCB2), is involved in the regulation of feeding behavior, gastrointestinal motility, glucose homeostasis, anxiety and depression, cardiovascular functions, thermoregulation, and reproductive functions. Nesf-1 was discovered in 2006 as a potent anorexigenic peptide in the rat hypothalamus. The 82 aa peptide is cleaved from its precursor protein NUCB2. In addition to birds and amphibians, NUCB2 was identified in Cyprinidae, including goldfish and zebrafish. NUCB2 is widely distributed in the central nervous system (CNS) and peripheral tissues of vertebrates.