Endocrine Abstracts

Neurotensin is expressed throughout the gastrointestinal tract and acts as a gut hormone. Recent work has established neurotensin modulates lipid absorption at the gastrointestinal lumen, but its role in the control of glucose homeostasis remains unclear. Neurotensin acts via three receptors, including the NtsR1 and is endogenously released following the ingestion of olive oil. Previous work in our group has identified that neurotensin acutely improves glucose tolerance in both lean and diet-induced obese mouse models via the NtsR1. This glucoregulatory effect is mediated by increased levels of insulin. We have previously demonstrated that this effect is unaffected by central administration of an antagonist or ablation of vagal NtsR1 and is therefore peripherally mediated. Using a NtsR1::Ai9 reporter model and RTF tissue clearing, we have visualised a population of NtsR1-expressing neurons extending from the proximal duodenum to the pancreas. Though these enteropancreatic neurons were first identified in the 1970s and subsequently found to be present in both mice and humans, their function has remained unknown. To investigate a functional role for these neurons, we used a diphtheria toxin receptor (DTR)-mediated ablation approach. Cre-dependant DTR-AAV or control was surgically injected into the pancreas adjacent to the proximal duodenum of NtsR1 NeoCre mice. Ablation of these neurons prevented the glucoregulatory effect of both neurotensin at pharmacological doses, and exacerbates the glucose excursion following a fast-refeed study in which mice were given chow rich in carbohydrate and olive oil. Surgical separation of the pancreas from the proximal duodenum also prevents the glucoregulatory effect of neurotensin, providing strong evidence that these effects are mediated by NtsR1-expressing enteropancreatic neurons which originate from the proximal duodenum. These data suggest that neurotensin modulates glucose homeostasis in response to lipid ingestion via enteropancreatic neurons and that these neurons represent potential targets for interventions to improve glucose homeostasis.