Project Reference: ICS27-PHA-FM1

Project title: Human cellular models of leptin signalling and resistance 

Project outline

Obesity is a major public health issue that is highly heritable. Genes associated with obesity often affect hormones and cell types that regulate appetite, especially the hormone leptin, which binds to the leptin receptor (LEPR) on specific brain cell types (neurons). Leptin signalling is frequently impaired in people with obesity, but the fundamental mechanisms have been difficult to study. Recently it has become possible to generate and manipulate large numbers of LEPR-expressing and leptin-responsive neurons from human induced pluripotent stem cells (iPSCs). We will use this system to address fundamental questions including:

Aim 1) Define the signalling networks activated by leptin

We will test for the immediate targets of leptin signal transduction in human neurons using AlphaLISA, phosphoproteomics, RNA sequencing, and single-cell multi-omics to gain insight into cell type-specific effects. We will test for functional effects of acute and chronic leptin signalling such as altered morphology using high-content imaging and altered activity using calcium imaging.

Aim 2) Define genetic regulators of human leptin signalling.

To identify which genes identified from animal studies impact human leptin signalling, we will use established CRISPR/Cas9 tools to knock out these candidates in LEPR-expressing human neurons and test for altered leptin signalling as described above. Next, we will extend this study to include other candidate genes associated with human obesity, and other genes that emerge from Aim 1. 

Aim 3) Test for factors the potentiate leptin signalling. 

Humans with obesity often have impaired responses to leptin, but the underlying mechanisms remain controversial. Using the scalable assays developed in Aim 1 and genetic models from Aim 2, we will test for candidate genetic and small molecule that can potentiate leptin signalling. These studies have both fundamental biological importance, but also have the potential to identify new therapeutic targets.

Principal Supervisor

Dr Florian Merkle

Email address: fm436@cam.ac.uk

Department / Partner Institute: Pharmacology

Website: https://www.phar.cam.ac.uk/human-stem-cell-models-obesity-and-neurological-disease

Industrial Partner

NovoNordisk

BBSRC strategic theme

Bioscience for an integrated understanding of health