Abstract
Spexin (SPX) is a pleiotropic peptide with highly conserved protein sequence from fish to mammals and its biological actions are mediated by GalR2/GalR3 receptors expressed in target tissues. Recently, SPX has been confirmed to be a novel satiety factor in fish species but whether the peptide has a similar function in mammals is still unclear. Using the mouse as a model, the functional role of SPX in feeding control and the mechanisms involved were investigated. After food intake, serum SPX in mice could be up-regulated with elevations of transcript expression and tissue content of SPX in the glandular stomach but not in other tissues examined. As revealed by immunohistochemical staining, food intake also intensified SPX signals in the major cell types forming the gastric glands (including the foveolar cells, parietal cells, and chief cells) within the gastric mucosa of glandular stomach. Furthermore, IP injection of SPX was effective in reducing food intake with parallel attenuation in transcript expression of NPY, AgRP, NPY type 5 receptor (NPY5R), and ghrelin receptor (GHSR) in the hypothalamus, and these inhibitory effects could be blocked by GalR3 but not GalR2 antagonism. In agreement with the central actions of SPX, similar inhibition on feeding and hypothalamic expression of NPY, AgRP, NPY5R, and GHSR could also be noted with ICV injection of SPX. In the same study, in contrast to the drop in NPY5R and GHSR, SPX treatment could induce parallel rises of transcript expression of leptin receptor (LepR) and melanocortin 4 receptor (MC4R) in the hypothalamus. These findings, as a whole, suggest that the role of SPX as a satiety factor is well conserved in the mouse. Apparently, food intake can induce SPX production in glandular stomach and contribute to the postprandial rise of SPX in circulation. Through GalR3 activation, this SPX signal can act within the hypothalamus to trigger feedback inhibition on feeding by differential modulation of feeding regulators (NPY and AgRP) and their receptors (NPY5R, GHSR, LepR, and MC4R) involved in the feeding circuitry within the CNS.
Highlights
Spexin (SPX) is a neuropeptide first identified using the hiddenMarkov model for data mining of novel peptides in human proteome [1, 2]
SPX treatment by IP/ICV injection was effective in reducing food intake by inhibiting feeding behavior in goldfish, which could be correlated with the drops in Neuropeptide Y (NPY) and Agouti-related neuropeptide (AgRP) with parallel rises of POMC, CCK, and CART signals in brain areas involved in feeding control [9]
Our results reveal that the role of SPX as a satiety factor is well conserved in the mouse, and SPX regulation of feeding is mediated by GalR3 activation coupled to differential modulation of feeding regulators and their receptors expressed in the hypothalamus
Summary
Spexin (SPX) is a neuropeptide first identified using the hiddenMarkov model for data mining of novel peptides in human proteome [1, 2]. Its mature peptide is highly conserved with only 1 to 2 a.a. substitutions from fish to mammals [3, 4] It is widely expressed in different tissues, including the liver, pancreas, visceral fat, intestine, and adrenal gland, e.g., in the rat [5] and human [6], and reported to have regulatory actions on gut motility [7], stomach contraction [1], bile acid synthesis [8], food consumption [9, 10], glucose and lipid homeostasis [11, 12], fatty acid uptake [13, 14], hormone secretion [15, 16], locomotor activity [14], nociception [17, 18], stress/anxiety responses [19], and cardiovascular/renal functions [20]. Our findings on the association of central expression of SPX with food intake, as well as the effects of SPX in regulating the feeding signals expressed in the brain (e.g., AgRP and POMC) have been recently confirmed in other fish
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