Development of cellular models of hypothalamic disorders

Obesity affects over 10 million adults in the UK and is arguably the greatest challenge facing our health care system. Efforts to treat obesity are hampered by the fact that the biological causes of obesity are still poorly understood. Body weight is regulated by a complex network of signals and cell types. A particularly important role is played by specific cell types in the brain that regulate food intake and energy expenditure. It has been known for decades that lesions in a region of the brain known as the hypothalamus can cause extreme obesity or anorexia. More recently, elegant studies in animal models have identified the cell types responsible for feeding behaviour. One of these cell types produces signals known as neuropeptide Y (NPY) and agouti-related peptide (AgRP). These so-called NPY/AgRP neurones so potently stimulate feeding that if they are experimentally killed off in adult mice, the mice completely stop eating. On the other hand, if NPY/AgRP neurones are artificially activated, mice will immediately start eating voraciously.

Animal models suggest that in models of obesity caused by a high-fat "Western diet", NPY/AgRP stop responding to the appropriate signals and become abnormally active, thus leading to more food intake and stabilising the state of obesity. It is unclear to what extent human NPY/AgRP are involved in common forms of human obesity. If the pathways that cause these cells to behave abnormally were known, it might possible to correct the abnormalities with targeted drug therapy and generate new therapies for obesity.

Since cells in the human brain are inaccessible, it has been very difficult to study human NPY/AgRP neurons. I recently developed a method to generate human NPY/AgRP neurons from pluripotent stem cells. These stem cells can be generated by "reprogramming" adult stem cells such as skin cells back to a naïve state where they can be directed to produce virtually any other cell type in the body. The ability to generate human NPY/AgRP neurons thus opens up a wide array of new approaches to better understand the cause of obesity.

As a New Blood MRC fellow, I will study how much NPY and AgRP these neurons release in response to external signals. NPY and AgRP activate other cells to promote feeding, so measuring the release of neuropeptides is a powerful way to understand how they might regulate feeding. In particular, I will study how mutations in genes that have been linked to obesity might affect NPY and AgRP release. These studies will provide an important link between mouse studies and human cells, and may reveal why some people are more prone to obesity than others. A long-term goal of this work is to understand the biological root causes of obesity in order to develop better therapies. I am honoured to be working toward this goal with the support of the MRC.

Obesity affects over 10 million adults in the UK and is arguably the greatest challenge facing our health care system. Efforts to treat obesity are hampered by the fact that the mechanisms causing obesity are still poorly understood. A large body of evidence ranging from animal lesion and genetic studies to monogenic and GWAS studies have identified as obesity as largely a disease of the brain. In particular, neurones in the hypothalamus are central regulators of feeding behaviour whose loss or dysfunction is sufficient to cause severe obesity. I have developed a method to generate human hypothalamic neurones from pluripotent stem cells. Human stem cell-derived hypothalamic neurones share cardinal features of their counterparts in the brain. Furthermore, I used the CRISPR/Cas9 system to modify the genomes of human stem cells to generate knock-in reporters for cell types of interest.

One cell type of particular interest is the hypothalamic neurone that produces neuropeptide Y (NPY) and agouti-related peptide (AgRP). These NPY/AgRP neurones so potently stimulate feeding that their ablation in the adult brain leads to a cessation of feeding to the point of starvation, and their specific activation via pharmacogenetic or optogenetic methods stimulates immediate and voracious feeding.

As a New Blood MRC fellow, I will develop human stem cell-derived NPY/AgRP neurones into a tractable system for studying obesity. In particular, the secretion of NPY and AgRP peptides from these cells is detectable by ELISA. I will test the hypothesis that candidate obesity-associated mutations in genes that are highly enriched in NPY/AgRP neurones alter neuropeptide release. Since AgRP is a melanocortin peptide that directly inhibits the MC4R receptor found on feeding-inhibitory second order neurones, this phenotype would have a clear mechanistic link to obesity.