Diet-responsive NtsR1-expressing enteropancreatic neurons mediate a glucoregulatory effect of monounsaturated fatty acids

Leah Meyer; Anna Roberts; Jieruo Liu; Mariana Norton; Cecilia Dunsterville; Yuxuan Tao; Victoria Salem; Murphy Kevin G.

doi:10.1530/endoabs.109.OC6.1

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Endocrine Abstracts (2025) 109 OC6.1 | DOI: 10.1530/endoabs.109.OC6.1

SFEBES2025 Oral Communications Metabolism, Obesity and Diabetes (6 abstracts)

Diet-responsive NtsR1-expressing enteropancreatic neurons mediate a glucoregulatory effect of monounsaturated fatty acids

Leah Meyer ¹ , Anna Roberts ² , Jieruo Liu ¹ , Mariana Norton ¹ , Cecilia Dunsterville ¹ , Yuxuan Tao ¹ , Victoria Salem ¹ & Kevin G. Murphy ³

Author affiliations

¹Imperial College London, London, United Kingdom; ²University College London, London, United Kingdom; ³Imperial College London, Lonndon, United Kingdom

The ingestion of foods rich in monounsaturated fatty acids (MUFAs), such as olive oil, stimulates the secretion of neurotensin, a neuropeptide and gut hormone, from intestinal enteroendocrine cells. Neurotensin has established effects in the central nervous system, and has been more recently implicated in peripherally promoting lipid abortion, but its role in glucose homeostasis remains unclear. Neurotensin acts via three receptors including the NtsR1. We hypothesise that neurotensin mediates the glucoregulatory effects of specific MUFAs. Administration of exogenous neurotensin acutely improved glucose tolerance in both lean and diet-induced obese mice and stimulates insulin release via the NtsR1. The glucoregulatory effect of oral olive oil was blocked by an NtsR1 antagonist or a lipase inhibitor. Oleic acid, known to stimulate neurotensin release, is the major MUFA constituent of olive oil and also improved glucose tolerance in mice. Using NtsR1 reporter mice, we visualised NtsR1-expressing neurons which originate in the proximal duodenum and extend towards islets in the pancreas. The function of enteropancreatic neurons is currently unknown, and they have been found in both mice and humans. Surgical separation of the proximal duodenum and adjacent pancreas blocked the glucoregulatory effects of oral olive oil and exogenous neurotensin. Specific ablation of NtsR1-expressing enteropancreatic neurons through injection of cre-dependant diptheria toxin receptor-encoding AAV into the pancreas of NtsR1-NeoCre mice also blocked the glucoregulatory effects of olive oil and neurotensin and enhanced the glucose excursion in mice in a fast-refeed study. These data suggest that NtsR1-expressing enteropancreatic neurons mediate the glucoregulatory effects of exogenous neurotensin and endogenous neurotensin release following olive oil ingestion and are therefore potential targets for future interventions to improve glucose homeostasis.