Obesity and type two diabetes are at epidemic levels across the globe. The diseases and their associated pathologies put a huge burden on health care systems around the world. Despite this, a cure for the conditions beyond simply telling patients to ‘eat less’ has not been found.
However, obesity is not just a result of eating more calories than are needed. It has been shown to have a genetic basis. Several of these obesity risk genes are expressed in the brain, specifically in cells that form the neural circuitry that underlies feeding behavior and energy expenditure.
Maintaining a healthy balance
The amount of food or energy we take in versus the energy we expend is known as our energy balance.
Thanks to pioneering studies of the neuroendocrine system in mice, we know a lot about the brain cells that regulate energy balance. We know which genes they express and what sort of receptors they present on their membranes and how they respond to circulating hormones like insulin, for example. We also know a lot about how these cells wire up in the brain to form their circuits.
However, our understanding of the human neurons that regulate energy balance and the behavior of these cells in their circuits is limited. Understanding more about these cells in human brains will enable better-guided therapies in the treatment of obesity.
But, there lies the challenge. How do researchers gain access to these neurons in the human brain to investigate them?
Understanding obesity by growing neurons in a dish
One approach being pioneered by a group at the University of Cambridge’s Metabolic Research Laboratory is deriving human neuroendocrine neurons from human cells, to better understand their function and develop therapies to treat obesity.
We asked the group’s leader, Dr. Florian Merkle, to explain how his team are working to understand human neuroendocrine cells: “If we want to understand how to develop better treatments it makes sense to study the cells that are most relevant for the cause of obesity and it seems that these are cells that regulate food intake and energy expenditure.”
Adding: “My lab are interested in the neuronal control of feeding behavior. A lot of the genes that are mutated in people that have severe obesity are expressed in the brain. And in common forms of obesity the genes are also expressed in the brain.”
Benefits in the dish
I asked Florian about the benefits of this in vitro system in comparison to using in vivo mice models, which have the value of being a whole animal.
Florian highlighted several reasons for using an in vitro model, but the main one being that, although a huge amount of understanding of feeding behavior comes from studies in rodents, “If you want to understand human disease, you need to work with human cells.”
Adding that the benefits of this in vitro system are that you can: “Make the cells in large quantities, which makes it easier to perform higher throughput experiments, or do proteomic analysis, for example.”
These sorts of experiments are harder to do with mouse models.
Another benefit of the system is that you can: “Isolate cells and manipulate their environment to test how they respond to circulating hormones and nutrients. This is more difficult to do in a complex environment such as the brain."
This means the scientists can control the environment of the cells and test their function in detail. An approach that would not be possible in animal models.
There are limitations
Florian also explained the limitations of the stem cell model: "The responsiveness of hypothalamic neurons may be influenced by other resident brain cells such as astrocytes and microglia that are currently missing from our model system, but these could be added in later studies once we understand how neurons function in isolation. Also, stem cell-derived neurons tend to have more immature functional properties."
Adding: “But that doesn’t mean they're so different you can’t learn something from the model. Every model system has strengths and weaknesses”.
Can stem cells replace animal models?
When asked if in vitro stem cell models can replace the use of animals in research Florian explained that you need both approaches to better explore disease. The use of in vitro and in vivo models can be complementary and bring more pieces of the puzzle together when trying to understand mechanisms of disease.
As he explained: “Reductionist in vitro models can’t replace animals, but animals can’t do everything, so you need to work with both model systems to understand disease.”
Adding: “In vitro models can be used to test hypotheses more quickly and cheaply to understand and explore disease. And from these results it’s possible to draw conclusions and make further hypotheses which can then be functionally tested in animals.”
Using an in vitro approach to compliment the strides made in obesity research in animal models will hopefully lead to a better understanding and therapeutic approach to treat obesity. Florian’s lab have recently published their protocols on how to derive hypothalamic stem cells and they say their protocols will enable any lab to reproducibly derive these neurons which include those that control food intake and energy expenditure in humans.
Kirwan, P., Jura, M., & Merkle, F. T. (2017). Generation and Characterization of Functional Human Hypothalamic Neurons. Current Protocols in Neuroscience, 3-33.