Title: Profiling neurogenic potential of a new anti-obesity compound
Funder: The Academy of Medical Sciences

Abstract: We will determine how a novel anti-obesity compound, a lipidized Prolactin Releasing Peptide (LiPrRP) affects electrophysiology and transcriptomics of new adult-generated and pre-existing neurons in the hypothalamus. To achieve this, we will pursue the following aims: 1. To record and collect individual neurons for creation of cDNA libraries. 2. To perform and analyse single-cell RNA sequencing (scRNAseq). 3. To confirm expression of selected target genes. Our preliminary results show that LiPrRP (palm11-PrRP31) reduces weight gain in a mouse model of diet-induced obesity (DIO). This promising anti-obesity effects have prompted Novo Nordisk, a major pharmaceutical company, to include it in their pathway-to-clinic research tract. LiPrRP activates neurons in specific hypothalamic nuclei (e.g. Paraventricular or Arcuate Nuclei), which regulate satiety and appetite. In addition, we demonstrated that LiPrRP increases survival of neurons generated from resident adult neural stem cells (aNSCs) in the medial basal hypothalamus (MBH) and activates aNSCs lining the 3rd brain ventricle. To understand its mechanism of action, we will determine how acute and long-term administration of LiPrRP will alter electrophysiology and gene expression of new, adult-generated, and pre-existing, embryo-generated neurons in MBH. We will utilize the patch-seq method, which combines patch-clamp electrophysiology with scRNAseq, to record and collect neurons. We will use a specific transgenic mouse line (GLAST-CreERT2 x R26R-tdTomato) to distinguish new and pre-existing neurons in MBH brain sections. We will analyse the patch-clamp and scRNAseq data and confirm selected genes by RT-qPCR and In Situ Hybridization. Our goal is to approximate LiPrRP to its clinical testing.

Lay abstract: Obesity represents one of the biggest health challenges. It increases the risk of many diseases, including heart disease, cancer, or depression, and it is one of the leading causes of disability. Obesity is caused by elevated energy consumption, which is regulated by the brain. Yet, there is no currently NHS-approved anti-obesity medication acting on the brain. To address this clinical need, we have developed a new anti-obesity compound. Our goal is to understand how it works and to bring it closer to clinical use for people suffering from obesity. The food consumption and appetite are regulated by nerve cells in a specific brain region called the hypothalamus. Some of these nerve cells are newly generated during adulthood. Their survival protects against the development of obesity. Our results show that the novel compound increases survival of new nerve cells in mice kept on obesity-inducing diet. The compound also reduces weight gain. We think that the compound reduces obesity by protecting new nerve cells. However, we need to understand how the compound works in greater details. This proposal will determine how the compound influences functions of new nerve cells in the mouse hypothalamus. On the level of individual cells, we will use a cutting-edge method called the patch-seq to measure their electrical properties and activity of the genes, which are altered by the anti-obesity compound. This will provide an essential understanding of how the compound reduces weight gain, which is a very important step towards clinical testing in people suffering from obesity.

Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: NEUROLOGICAL