Obesity is a common disease that dramatically increases morbidity and mortality, and that has few effective treatments. Drugs such as Semaglutide (Ozempic/Wegovy) that mimic the endogenous hormone glucagon-like 1 peptide (GLP1) can durably suppress appetite and food intake, likely by acting on brain cell types that express the GLP1 receptor (GLP1R). However, these drugs have side effects such as nausea and diarrhoea that limit widespread use, their efficacy has room for further improvement, and their mechanism of action in the human brain is not clearly understood. To address these issues, we generated functionally mature GLP1R-expressing hypothalamic neurons from human induced pluripotent stem cells (hiPSCs). We found that they not only express GLP1R, but that they show robust electrophysiological responses to GLP1R agonists like Semaglutide, providing valuable insights into their mechanisms of action. Furthermore, we leveraged the scalability and human genetic background of this cellular models system to identify a new candidate drug that potently suppresses appetite and reduces body weight in a mouse model of obesity, and appears to further increase the efficacy of Semaglutide. Together these findings suggest that hiPSC-derived cellular models can provide mechanistic insight to improve the efficacy of existing drugs, as well a discovery tool to identify new candidate drugs.

SPEAKER BIOGRAPHY

Florian Merkle is a Sir Henry Dale Fellow and Robertson Stem Cell Investigator at the University of Cambridge, where his group has three main research interests. First, he studies the genomic stability of human pluripotent stem cells and establishes resources to improve the safety and efficacy of stem cell-based research and clinical work. Second, he uses stem-cell derived hypothalamic neurons to study the biology of metabolic sensing and to identify candidate anti-obesity drug targets. Third, his team is exploring the shared mechanisms between metabolic and neurodegenerative disease using a combination of human stem cell-based and animal models, with the aim of identifying neuroprotective drugs. Florian’s research programme builds on his training at Caltech, UCSF, and Harvard University and is supported by the Wellcome Trust, Medical Research Council, Chan Zuckerberg Initiative, and New York Stem Cell Foundation.