Recently mapped protein may help to solve the global obesity epidemic

Disease and treatment 18. dec 2018 3 min Associate Professor Pontus Emanuel Gourdon Written by Kristian Sjøgren

Membrane protein aquaglyceroporin 10 (AQP10) plays a major role in developing obesity. Researchers from the University of Copenhagen have now mapped the protein’s structure and how it functions in controlling fat levels in the body’s cells. The next step involves determining how this new knowledge can be used for developing anti-obesity medicines and for combating type 2 diabetes and related diseases.

Researchers at the University of Copenhagen have mapped the structure of a membrane protein. This may not sound very sexy, but it is, because this protein plays a role in how the body metabolizes fat. Thus, this protein influences how much of your Christmas food will end up as flab.

Mapping these proteins means that researchers can start to develop medicine that specifically targets such proteins and prevents the body’s fat cells from making us fat.

In the long term, this type of medicine may help to combat the world’s galloping obesity epidemic while also slowing the development of diseases related to obesity and lifestyle diseases such as type 2 diabetes, cardiovascular diseases and cancer.

“We now know how this protein looks and functions, so we can use computation tools to design molecules that either activate or inhibit this protein and thereby also its function in how the body metabolizes fat. This is the overall perspective,” explains a researcher behind the mapping, Pontus Gourdon, Associate Professor, Department of Biomedical Sciences, University of Copenhagen.

This new study, which focuses on the mapping of the protein, was recently published in Nature Communications.

A protein removes broken down fat from the body’s cells

This complex new research describes adipocytes: the cells in the body that store fat. To accumulate or dispose of fat, fat cells need to have several proteins that transport the fat components in and out of the cells, including glycerol.

The process of breaking fat down in cells is called lipolysis, and this releases glycerol and other substances that can be transported out of the cells.

Pontus Gourdon and his colleagues Kamil Gotfryd, Julie Winkel Missel and Kaituo Wang have characterized the structure and function of the aquaglyceroporin 10 (AQP10) protein, which transports glycerol out of the cells.

More complete picture of exercise and fat metabolism

In addition to the structure of AQP10, the new research also shows how the pH of the fluid inside the cells determines how much glycerol AQP10 can transport.

The more acidic the intracellular fluid is, the more rapidly glycerol can be transported out of the cell. Conversely, neutral or basic fluid slows the whole process.

The link between pH and fat metabolism is actually not new. Research had previously shown that exercise makes the fluid inside the fat cells more acidic, which is directly linked to the breakdown of fat.

The new research consolidates this by showing that the activation of AQP10, required for releasing glycerol, is associated with pH.

“Previously, the structure of AQP10 was little understood, as was how the pH of the intracellular fluid affects its function. We know more now, and this makes sense physiologically,” says Pontus Gourdon.

Mapping the structure of a membrane protein is complex

Determining the structure of a protein may sound simple, but it is definitely not. This can best be illustrated by the fact that the researchers from the University of Copenhagen spent more than 3 years on this project, assisted by expertise from many national and international collaborators.

• First, the researchers needed to get yeast cells to produce the protein in sufficient quantities to be able to study its structure.

• Then they had to purify the protein from the cells to a high degree, which is necessary for crystallizing the protein.

• Once the protein was in crystal form, the researchers could generate a model of the atoms in the protein (a structure) using powerful X-rays.

• Then the researchers carried out numerous experiments to characterize the function of AQP10. One type of experiment enabled them to determine how the protein became more active and could thereby transport glycerol more rapidly in more acidic intracellular fluid.

• Finally, the researchers asked collaborating partners in Italy and Portugal to carry out various cell experiments to confirm that the researchers from the University of Copenhagen had found the right mechanism.

“Determining the structure of a protein is no trivial matter. To our knowledge, we actually determined the structure of a human membrane protein for the first time in Denmark. From this perspective, it is unique,” explains Pontus Gourdon.

Developing molecules that can become medicine

Now that the researchers understand the structure and function of AQP10, the next step is to develop molecules that can interact with this protein.

Pontus Gourdon and his colleagues and partners in Portugal want to develop and study molecules that modulate the function of the protein such that the transport of glycerol is affected. If the researchers can develop molecules that can accelerate the transport of glycerol, mimicking acidic pH, this will have great pharmaceutical potential.

“This protein may have an important role in metabolizing fat in the body, and molecules that either stimulate or inhibit the function of AQP10 therefore influence the development of obesity and related diseases. This naturally has long-term perspectives, but we have already begun to study specific molecules that will be interesting to examine in this context,” say Pontus Gourdon.

Pontus Gourdon explains that, since they now know the protein’s structure and function, they will use computational analysis to reveal how they can manipulate the protein’s functions using one or several other molecules: structure-based drug design.

Once the researchers have discovered relevant molecules, they will test them in the laboratory to examine how they affect AQP10, cells and the body.

Human adipose glycerol flux is regulated by a pH gate in AQP10” has been published in Nature Communications. In 2016, the Novo Nordisk Foundation awarded a grant to Pontus Gourdon, a main author, for the project Unravelling Glucose Transceptors Involved in Regulation of Food Intake and Secretion of Incretins and Insulin.

I lead a Membrane Protein Structural Biology Group located at the Department of Biomedical Sciences at University of Copenhagen, and at the Department...

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