Endocrine Abstracts

Neurotensin is a 13-amino acid peptide expressed in both the brain and the gastrointestinal tract where it acts as a neuropeptide and gut hormone, respectively. Centrally, neurotensin plays a role in appetite, analgesia and thermoregulation, whereas peripheral neurotensin regulates lipid absorption, gastric emptying and exocrine pancreatic secretion. The role of neurotensin in the control of glucose homeostasis currently remains unclear. We found peripheral administration of neurotensin dose-dependently improved acute glucose tolerance in lean and obese mice. This effect was lost in the presence of a NTSR1-specific antagonist. Interestingly, oral administration of olive oil similarly improved glucose control, and this effect was also lost in the presence of a NTSR1-specific antagonist. Neurotensin administration increased circulating insulin levels. Together these data suggest a crucial role for peripheral neurotensin in mediating the glucoregulatory response to lipid. There are three main neurotensin receptors of which the NTSR1 has the highest-affinity for neurotensin. We found the NTSR1 to be highly expressed in the vagal nodose ganglia, hypothalamic arcuate nucleus and enteric nervous system, with negligible expression in pancreatic islets. Using a range of models, we identified that neurotensin did not improve glucose tolerance via activation of pancreatic-, vagal- or brain-NTSR1. Blockade of the muscarinic-3 receptor, a receptor expressed on pancreatic β cells that drives cholinergic-mediated insulin secretion, blunted neurotensin-mediated insulin secretion, suggesting a role for neurotensin in the enteropancreatic axis. Using NTSR1-Cre:tdTomato mice, NTSR1 expression was identified in the myenteric plexus of the murine enteric nervous system and in vitro calcium imaging using cultured myenteric neurons confirmed NTSR1-mediated neurotensin activation. Our data suggest that gut to pancreas neuronal signalling mediates the effects of neurotensin on glucose control, and we are currently testing this hypothesis using cre-dependent retrograde adeno-associated viruses expressing chemogenetic excitatory and inhibitory DREADD receptors in the pancreas of NTSR1-Cre mice.