Photo credit: Dr Florian Merkle
The Merkle lab studies rare human brain cell populations that regulate hunger, whose activity is related to obesity and diabetes. Specifically, they differentiate human pluripotent stem cells (hPSCs) into hypothalamic proopiomelanocortin (POMC) neurons that suppress appetite and then characterize how they respond to existing anti-obesity drugs such as semaglutide/Ozempic, as well as use them to discover novel therapeutic strategies. In the past years, the group has developed scalable methods to measure the functional activity of POMC neurons using calcium imaging on high-content confocal microscopes and by measuring their secretion of the appetite-suppressing neuropeptide MSH in a high-throughput assay. The group expects to harness these models with Pharmacology members as their work moves increasingly toward therapeutic applications.
The group is also interested in the observation that Ozempic and other drugs used to treat metabolic disease appear to be effective in treating neurodegenerative diseases in some animal models and humans. To rigorously explore the hypothesis that these drugs target shared mechanisms in metabolic and neurodegenerative disease, the group used a scrapie (prion) model in which misfolded protein injected into the brain of wild-type mice seeds the misfolding of native protein, leading to protein aggregation and the full spectrum of features that accompany common human neurodegenerative diseases. These features at the cellular level in the brain include neuronal endoplasmic reticulum (ER) stress and synaptic loss, neuroinflammation, and neuronal loss. At the behavioural and physiological level, mice injected with scrapie are initially asymptomatic and then gradually lose weight and start to show abnormal locomotor activity, followed by cognitive defects and loss of motor coordination. Group researchers then developed a pipeline to accurately stage disease progression over time, with rich datasets of histology, biochemistry, and other ‘omics approaches at defined time points. Researchers then tested the effects of candidate drugs that act on diabetes and obesity and found that metformin significantly extends the health span of mouse models of neurodegeneration, regardless of whether mice were lean or obese at the start of treatment. It also reduced markers of ER stress in hippocampal neurons and penetrated the brain, suggesting a direct protective mechanism of action. Since this drug is cheap and already prescribed to over 150 million people worldwide, it has the potential to benefit patients with neurodegenerative disease immediately. Indeed, metformin is now being considered as one of several drugs to be tested in a sizeable multi-arm, multi-stage human clinical trial.