Investigating the role of neurotensin in glucose control

Abstract

Metabolic syndrome is a global epidemic often characterised by the development of diseases including obesity and type 2 diabetes mellitus (T2DM). Current anti-obesity therapies are lacking and although T2DM treatments are available, individuals still struggle to normalise their blood glucose levels. Together this results in significant morbidity and mortality. Chronic adherence to a Mediterranean diet has proven to promote weight loss and improve remission rates in patients with T2DM. The diet is rich in olive oil, an oil that contains a high percentage of mono-unsaturated fatty acids (MUFAs), such as oleic acid. A link between both olive oil- and oleic acid-induced release of the gut hormone neurotensin has been shown. The work described in this thesis explores the hypothesis that olive oil improves glucose tolerance via the release of neurotensin from the gastrointestinal tract, and investigates the mechanisms behind how this may be controlled. Olive oil improved acute glucose tolerance via a mechanism involving the high-affinity neurotensin receptor 1 (NTSR1). Peripheral administration of neurotensin also improved glucose tolerance in lean and obese mice. These effects were driven by an increase in insulin secretion. The NTSR1 was found to be highly expressed in the vagal nodose ganglia, hypothalamic arcuate nucleus and enteric nervous system of mice, with negligible expression in pancreatic islets. Using a range of models, we identified that neurotensin did not improve glucose tolerance via activation of vagal- or central-NTSR1. NTSR1 expression was also identified in the myenteric plexus of the murine enteric nervous system and blockade of the muscarinic-3 receptor, a receptor expressed on pancreatic β cells, blunted neurotensin-mediated insulin secretion, suggesting a role for neurotensin in the enteropancreatic axis. This study found neurotensin to activate primary cultured myenteric enteric neurons in a NTSR1-mediated manner. However, activation of NTSR1 neurons extending to the pancreas did not influence glucose tolerance. Together these data suggest a role for neurotensin-activated peripheral-NTSR1 in regulating blood glucose in response to the ingestion of specific types of lipid. Future studies are still required to determine the exact NTSR1-linked pathway that drives the observed neurotensin-mediated glucoregulatory effects.