Ghrelin, des-acyl ghrelin and nesfatin-1 in gastric X/A-like cells: role as regulators of food intake and body weight

Abstract

Numerous peptides released from endocrine cells in the intestinal mucosa were established early on to be involved in the physiological regulation of food intake with a prominent role in termination of food ingestion when nutrients pass along the intestinal tract. Recently, peptides released from X/A-like endocrine cells of the gastric oxyntic mucosa were recognized as additional key players in the regulation of feeding and energy expenditure. Gastric X/A-like cells release the octanoylated peptide, ghrelin, the only known peripherally produced hormone stimulating food intake through interaction with growth hormone secretagogue 1a receptor (GHS-R1a). Additionally, non-octanoylated (des-acyl) ghrelin present in the circulation at higher levels than ghrelin is currently discussed as potential modulator of food intake by opposing ghrelin's action independent from GHS-R1a although the functional significance remains to be established. Obestatin, a ghrelin-associated peptide was initially reported as anorexigenic modulator of ghrelin's orexigenic action. However, subsequent reports did not support this contention. Interesting is the recent identification of nesfatin-1, a peptide derived from the nucleobindin2 gene prominently expressed in gastric X/A-like cells in different vesicles than ghrelin. Circulating nesfatin-1 levels vary with metabolic state and peripheral or central injection inhibits dark phase feeding in rodents. Overall, these data point to an important role of gastric X/A-like cells in food intake regulation through the expression of the orexigenic peptide ghrelin along with des-acyl ghrelin and nesfatin-1 capable of reducing food intake upon exogenous injection although their mechanisms of action and functional significance remain to be established.

Fig. 1

Immunohistochemical picture of neuroendocrine cells in the rat gastric oxyntic mucosa of ad libitum fed male rats. While the majority of neuroendocrine cells reside in the lower part of gastric glands, ghrelin positive X/A-like cells are evenly distributed throughout the entire length of the glands. Somatostatin-positive D cells are mostly localized in the lower half of the oxyntic glands. Serotonin-positive EC cells are rare. Scale bar represents 100 μm.

Fig. 2

Peptide products of the rat gastric X/A-like cell and their effects on food intake in rodents. ↑, stimulation; ↓, inhibition; =, no effect; GHS-R1a, growth hormone secretagogue receptor 1a; GOAT, ghrelin-O-acyltransferase; NUCB2, nucleobindin2

Fig. 3

Schematic representation of factors influencing ghrelin release and mediating ghrelin’s effects on food intake and fat storage. ↑, increase; ↓, decrease; +, stimulation; −, inhibition, AgRP, agouti-related peptide; AP, area postrema; ARC, arcuate nucleus; DMH, dorsomedial nucleus of the hypothalamus; GHS-R1a, growth hormone secretagogue receptor 1a; NPY, neuropeptide Y; NTS, nucleus of the solitary tract; PVN, paraventricular nucleus of the hypothalamus.

Fig. 4

Schematic illustration of the interaction of ghrelin with other gut peptides and transmitters. ↑, increase; +, stimulation; −, inhibition.

Fig. 5

NUCB2 mRNA is significantly higher expressed in the gastric oxyntic mucosa than in brain and heart. Data are expressed as mean ± SD, * p < 0.001 vs. brain and heart. (Reproduced with permission from reference [137]; Copyright 2009, The Endocrine Society).

Fig. 6

High resolution confocal image of a single gastric mucosal endocrine cell co-expressing ghrelin (green) and nesfatin-1 (red) immunoreactivity. Confocal microscopy was performed using a 100 × objective and digital zoom, 8 images in z-axis (stack size 24 × 24 × 7 μm) with dual laser excitation at 488 and 543 nm. Images were collected in two optical channels and photomultiplier tubes using FITC and TRITC filter sets, de-convoluted and reconstructed into a 3-dimensional image. The scale bar represents 1 μm. (Reproduced with permission from reference [137]; Copyright 2009, The Endocrine Society).