UTS2B Defines a Novel Enteroendocrine Cell Population and Regulates GLP-1 Secretion Through SSTR5 in Male Mice.

The gut-pancreas axis plays a key role in the regulation of glucose homeostasis and may be therapeutically exploited to treat not only type 2 diabetes but also hypoglycemia and hyperinsulinemia. We identify a novel enteroendocrine cell type expressing the peptide hormone urotensin 2B (UTS2B). UTS2B inhibits glucagon-like peptide-1 (GLP-1) secretion in mouse intestinal crypts and organoids, not by signaling through its cognate receptor UTS2R but through the activation of the somatostatin receptor (SSTR) 5. Circulating UTS2B concentrations in mice are physiologically regulated during starvation, further linking this peptide hormone to metabolism. Furthermore, administration of UTS2B to starved mice demonstrates that it is capable of regulating blood glucose and plasma concentrations of GLP-1 and insulin in vivo. Altogether, our results identify a novel cellular source of UTS2B in the gut, which acts in a paracrine manner to regulate GLP-1 secretion through SSTR5. These findings uncover a fine-tuning mechanism mediated by a ligand-receptor pair in the regulation of gut hormone secretion, which can potentially be exploited to correct metabolic unbalance caused by overactivation of the gut-pancreas axis.

Neuropeptide expression in rats exposed to chronic mild stresses.

To investigate a possible link between some neuropeptides and depression, we analyzed their mRNA levels in brains of rats exposed to chronic mild stresses (CMS; a stress-induced anhedonia model), a commonly used model of depression. Rats exposed for 3 weeks to repeated, unpredictable, mild stressors exhibited an increased self-stimulation threshold, reflecting the development of an anhedonic state, which is regarded as an animal model of major depression. In situ hybridization was employed to monitor mRNA levels of neuropeptide Y (NPY), substance P and galanin in several brain regions. In the CMS rats, NPY mRNA expression levels were significantly decreased in the hippocampal dentate gyrus but increased in the arcuate nucleus. The substance P mRNA levels were increased in the anterodorsal part of the medial amygdaloid nucleus, in the ventromedial and dorsomedial hypothalamic nuclei and the lateral hypothalamic area, whereas galanin mRNA levels were decreased in the latter two regions. These findings suggest a possible involvement of these three peptides in mechanisms underlying depressive disorders and show that similar peptide changes previously demonstrated in genetic rat models also occur in the present stress-induced anhedonia model.

Deficits in reward sensitivity in a neurodevelopmental rat model of schizophrenia.

RATIONALE: Neonatal ventral hippocampal lesions in rats have been shown to result in behavioral abnormalities at adulthood thought to simulate some aspects of positive and cognitive deficits classically observed in schizophrenic patients. OBJECTIVES: We investigated whether such lesions can also induce deficits in reward sensitivity that are related to the negative symptoms of psychotic disorders. METHODS: To investigate the effects of neonatal and adult lesions of the ventral hippocampus on reward-related behaviors we used the conditioned place preference (CPP) test and the saccharin consumption model. RESULTS: In contrast to adult-lesioned animals, neonatally lesioned rats exhibited a deficit in amphetamine-induced CPP and a significant reduction in saccharin preference. These deficits are unlikely due to lesion-induced motor impairments as both neonatal- and adult-lesioned rats exhibited a similar hyperlocomotor response to amphetamine. CONCLUSIONS: Taken together, these results show that neonatal ventral hippocampal lesions induce a reduction in reward-seeking behaviors in adulthood that mimic some aspects of the negative symptoms (anhedonia) in psychotic patients.