Beyond Diets: Molecular Solutions to Metabolic Disorders

Should Fatima Al-Rashed’s research work out how she hopes it will, it could make her popular with many people. As a scientist specializing in immunology and microbiology Al-Rashed studies how the fat we eat in food interacts with the cells of our bodies – and how she can stop some of these interactions from happening. This could result in therapies that help stave off metabolic disorders such as diabetes. But it could also potentially prevent people from gaining weight when they eat fatty foods. “We wouldn’t need to ask people anymore to avoid fats in their diets and could stop asking food producers not to put fats into their products,” said Al-Rashed. Her research might even help people reap some ot the benefits of exercise without having to set foot in a gym.

Al-Rashed’s research focuses on so-called bioactive lipids. “A lot of people think of fat only as unwanted belly fat. But in the scientific view a lipid is anything that doesn't dissolve in water,” the researcher explained. In a water-based system such as the human body, lipids play important roles, for example as messenger molecules. The fatty acids Al-Rashed studies can insert themselves into the regulatory mechanisms of cells, for example, by switching on or off important functions such as inflammation. None of this was “bad,” said Al-Rashed. “It only becomes bad when it happens too much and for too long. When things get out of control.”

Al-Rashed studied Immunology and Medical Microbiology at Leeds University in the United Kingdom, then Biomedical Science at the University of Glasgow and the University of Nottingham, also both in the U.K. Now a Researcher in the Immunology and Microbiology Department of Dasman Diabetes Institute in Kuwait, Al-Rashed has already won several prestigious awards such as the L'Oréal-UNESCO For Women in Science Award in 2017, the Promising Scientist Award in the Dasman Diabetes Institute in 2019 and the Innovative Youth Achievement Award at the 4th Kuwait Youth Achievement Forum 2022. This year, she is being honored with a Jaber Al-Ahmad Prize for Young Researchers.

Al-Rashed is particularly interested in a substance called palmitic acid. “It’s also known as palm oil and added to a lot of processed foods,” she said. “It gives food stability, taste, and a nice structure. But it’s horrible to our overall health.” In many ways, this is because of how palm oil interacts with a protein in our body called peroxisome proliferator-activated receptor delta, or PPARdelta for short. PPARdelta regulates key aspects of our metabolism – how cells in our body use fats and sugars for energy. But PPARdelta also affects the behavior of immune cells such as macrophages.They are a type of white blood cell that can trap and kill foreign microorganisms in the body. Macrophages also clean up dead cells, which limits inflammation.

Palmatic acid works on PPARdelta like a key on an engine, switching it on. Thus activated, PPARdelta stimulates macrophages to take in fat molecules from the bloodstream. In the process, the cell bodies of macrophages often become so laden with fat that they start to look “foamy” under the microscope. “Foaming makes a macrophage unable to work as it should,” said Al-Rashed. “Say there's a toxin in the body. The macrophages should eliminate it. But because of all that fat in them, they’re not doing that job.” With the macrophages not working properly, more inflammation starts happening in the body, increasing a person’s risk for developing diabetes and other metabolic disorders.

Al-Rashed and her colleagues studied the precise pathway in which palmitic acid acts on PPARdelta and discovered that they can block the activation of the protein in very targeted ways – with several interesting results. For one thing, “we’ve found that blocking PPARdelta will make macrophages normal again,” said Al-Rashed. This reduces inflammation and its ensuing risks for the body.

Furthermore, Al-Rashed and her team have found that by preventing PPARdelta activation they can also stop other cells – for example, those in the intestines – from taking up fats. “We're currently developing a drug that can do that,” she said. In effect, this means, “you can indulge in whatever you want to eat but not really gain the weight,” said Al-Rashed. Because PPARdelta is such an important player in the human metabolism, the tricky part is ensuring that it’s only blocked in specific ways. A lot of potential PPARdelta medications failed because they intercepted the protein too broadly, said Al-Rashed. “Then a lot of complications can happen.”

With their detailed understanding of the pathway in which fatty acids interact with PPARdelta, Al-Rashed and her peers have also uncovered how they can let PPARdelta become activated in only specific tissues such as the muscles. This has led to a third potential application of their work: A supplement that could stimulate muscle cells – not to take up or reject fat in this case – but rather to burn more glucose, creating energy. This could be particularly relevant for people on the path to becoming diabetic. Typically, this means that their bodies have started to burn less glucose, allowing this sugar to build up in the blood. “If you can have a supplement that makes muscles pick up more glucose it would massively benefit people with prediabetes,” said Al-Rashed. The effect would be similar to building up more muscles through exercise – something pre-diabetic patients are encouraged to do. “It’s not that we advocate that you don’t go to the gym,” said Al-Rashed. “But with this supplement, you can have exercise in a pill that doesn't require you to go to the gym.”