Endocrine Abstracts

Neurotensin is widely expressed in the brain and gastrointestinal tract. Centrally, neurotensin acts as a neuropeptide to suppress appetite, induce hypothermia and modulate analgesia. Peripherally, neurotensin inhibits gastric emptying and is reported to aid lipid absorption. There is also evidence that neurotensin can influence glucose homeostasis, though this role is contentious. We have found that neurotensin acutely improves insulin release and glucose tolerance in mice, and that this effect is mediated via the neurotensin receptor 1 (NtsR1) but does not require central or vagal NtsR1 signalling. We therefore investigated peripheral NtsR1 neurons in the enteric nervous system and their connections to the pancreas. Using a NtsR1-Cre: Ai9 reporter mouse model, we have visualised NtsR1-expressing entero-pancreatic neurons. NtsR1-Cre: Ai9 mice express Tdtomato red fluorescent protein, which is flanked by a loxP STOP cassette within the Ai9 construct, exclusively in NtsR1-expressing cells as a result of cre-mediated recombination. From these mice, the first centimetre of the proximal duodenum and adjacent pancreatic section was harvested and cleared for whole-mount imaging using RTF tissue clearing, a simple immersion type technique to homogenise the overall refractive index of the tissue. Confocal imaging revealed that a population of NtsR1-expressing neurons extend from the myenteric plexus of the duodenum into the pancreas. Whole-mount immunostaining, using the iDISCO technique for labelling large volumes, revealed that NtsR1-expressing neurons within the pancreas approach and surround islets and appear to innervate them directly. Further work is now required to determine whether neurotensin mediates its effect on glucose homeostasis via these neurons and whether this system can be exploited pharmacologically to treat metabolic disease.