The neuropeptide 26RFa in the human gut and pancreas: potential involvement in glucose homeostasis

Abstract

Objective Recent studies performed in mice revealed that the neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity. However, in humans, an association between 26RFa and the regulation of glucose homeostasis is poorly documented. In this study, we have thus investigated in detail the distribution of 26RFa and its receptor, GPR103, in the gut and the pancreas, and determined the response of this peptidergic system to an oral glucose challenge in obese patients. Design and methods Distribution of 26RFa and GPR103 was examined by immunohistochemistry using gut and pancreas tissue sections. Circulating 26RFa was determined using a specific radioimmunoassay in plasma samples collected during an oral glucose tolerance test. Results 26RFa and GPR103 are present all along the gut but are more abundant in the stomach and duodenum. In the stomach, the peptide and its receptor are highly expressed in the gastric glands, whereas in the duodenum, ileum and colon they are present in the enterocytes and the goblet cells. In the pancreatic islets, the 26RFa/GPR103 system is mostly present in the β cells. During an oral glucose tolerance test, plasma 26RFa profile is different between obese patients and healthy volunteers, and we found strong positive correlations between 26RFa blood levels and the BMI, and with various parameters of insulin secretion and insulin resistance. Conclusion The present data suggest an involvement of the 26RFa/GPR103 peptidergic system in the control of human glucose homeostasis.

Glucose homeostasis is impaired in mice deficient for the neuropeptide 26RFa (QRFP)

“…More recently, the implication of the 26RFa/GPR103 neuropeptidergic system in the control of glucose homeostasis was reported. We, and others, found that 26RFa and GPR103 are strongly expressed by β cells of the pancreatic islets (24,25,27), and that the neuropeptide prevents cell death and apoptosis of β cells (27). We also showed that 26RFa is abundantly expressed all along the gut and that i.p.…”

“…Accumulated data obtained during the last decade have promoted the evidence that the neuropeptide 26RFa plays a key role in the control of feeding behaviour (10, 13, 14) and the regulation of glucose homeostasis (24, 25, 27, 28). Supporting this notion, it has been recently shown that acute administration of a GPR103 (the 26RFa receptor) antagonist decreases food intake (30) and reduces the global glucose-induced incretin effect as well as the insulin sensitivity (28).…”

“…Deparaffinized sections (15-µm thick) of 26RFa -/- , 26RFa +/- and 26RFa +/+ mice pancreas and duodenum were used for immunohistochemistry. For the observation of the 26RFa immunolabelling, tissue sections were incubated for 1 h at room temperature with rabbit polyclonal antibodies against 26RFa (25) diluted 1:400. The sections were incubated with a streptavidin-biotin-peroxydase complex (Dako Corporation, Carpinteria, CA), and the enzymatic activity was revealed with diaminobenzidine.…”

“…Interestingly, a more sustained orexigenic activity of 26RFa was reported in obese rodents (19,23). In addition, expression of prepro26RFa mRNA is up-regulated in the hypothalamus of genetically obese ob/ob and db/db mice (15), in rodents submitted to a high fat diet (19,23), and plasma levels of the neuropeptide are increased in obese patients (24,25). Finally, 26RFa was found to trigger lipid uptake and to inhibit lipolysis in obese individuals (26).…”

“…We also showed that 26RFa is abundantly expressed all along the gut and that i.p. administration of the neuropeptide attenuates glucose-induced hyperglycemia by increasing plasma insulin via a direct insulinotropic effect on the pancreatic β cells, and by increasing insulin sensitivity (24,25). Finally, we reported that an oral glucose challenge induces a massive secretion of 26RFa by the gut into the blood, strongly suggesting that this neuropeptide regulates glycemia by acting as an incretin (24).…”