Investigating the interactions of incretin hormone mimetics with hypothalamo-neurohypophysial system arginine vasopressin and oxytocin release

Our research focus over decades has been the osmoregulatory function of a special collection of neurones in a part of the brain called the hypothalamus. Magnocellular neurones (MCNs) make the peptide hormones arginine vasopressin (AVP) and oxytocin (OXT) and release them peripherally into the blood circulation from nerve terminals in the pituitary gland. Once secreted, these peptides modulate physiological parameters such as blood osmolality, blood pressure and blood glucose by acting on specific receptors in the periphery to maintain homeostasis. There is a resurgence in interest in AVP and OXT, which stem from clinical associations with body mass index, and consequently diabetes, obesity, and metabolic syndrome.

When we eat a meal the gut releases hormones, aptly grouped as gut peptides, to control the amount of food and fluid we ingest by acting on specific receptors to promote a feeling of fullness. Interestingly, MCNs express receptors for gut peptides GLP-1 and GIP at the cell body and nerve terminals in the pituitary, so integrate signals from endogenous gut peptides as well as new pharmacological circuits created by incretin mimetics. There is currently a dearth of information about how gut peptides and incretin mimetics interact with receptors expressed by this crucial axis.

Aims and objectives

We hypothesise that hypothalamo-neurohypophysial system gut peptide receptors regulate AVP and OXT release.

The following aims are to be addressed for each receptor;

• To investigate the physiological, metabolic, and behavioural responses to knockdown of MCN gut peptide receptors.
• To establish the effects of short and long-term treatment with gut peptide receptor agonists on hypothalamo-neurohypophysial system hormone synthesis, release, and cellular signalling pathways.
• To leverage large-scale genome-wide association study (GWAS) data derived from various tissues and cell-types to guide proteomics target identification towards clinical significance.

Methodology

• To gain further understanding of this gut peptide signalling axis, adeno-associated viruses will be used to deliver genetic tools (shRNAs) to MCNs in the supraoptic nucleus and paraventricular nucleus to reduce gut peptide receptor expression in the rat. Parameters to be measured include food and fluid intake, hormone release and blood electrolytes.
• Measuring the release of neuropeptides from the pituitary ex vivo. A sniffer cell is made by co-transfection of cells with the endogenous receptor for a neuropeptide together with a calcium fluorescent indicator such as GCaMP7. The level of fluorescence output then will be used to measure release.
• Working with the University Proteomics Facility we will investigate the short and long-term effects of GIP receptor agonist and dual pharmacological effects of receptor agonism (tirzepatide) on the rat hypothalamo-neurohypophysial system phosphoproteome. Phosphoproteomics data is already available for the GLP-1 receptor agonist liraglutide.
• We will apply innovative causal inference approaches to proteomics datasets pioneered at the MRC Integrative Epidemiology Unit to a wealth of GWAS data derived from different tissue- and cell-types. These endeavours will facilitate insight into the mechanisms and downstream consequences to targeting GLP-1 and GIP pathways, both independently and based on a dual therapy approach.

Apply for this project

This project will be based in Bristol Medical School - Translational Health Sciences.

Please contact brms-pgradmin@bristol.ac.uk for further details on how to apply.

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