A Proton-Transporting Protein As An Obesity Drug Target

No matter how disappointing obesity drug research seems to be these days, I can’t resist a good story about a hot biological target in the obesity area. And if obesity isn’t a hot enough topic for you, add in the fact that the company chasing this target, Energesis Pharmaceuticals, happens to be co-founded by a veteran of Sirtris Pharmaceuticals, and the spotlights shining on this story start to look mighty bright.

But I won’t be talking about red wine compounds today. Instead, the focus is on brown fat. Today in Xconomy, Ryan McBride gives a great overview of Energesis, which is aiming to treat obesity, diabetes, and metabolic syndrome by harnessing brown fat’s power.

McBride’s article has a good amount of detail on the company itself but I was intrigued by what seems to be an important molecular target for the company’s strategy: uncoupling protein-1.

So what is this protein? It “helps dissipate energy and contributes to weight loss,” according to Energesis.

Uncoupling protein-1 is specific to brown fat, and it’s known to regulate body temperature by generating heat in animals. Scientists now think the protein might be involved in metabolism in human adults. Like many popular drug targets, it is a membrane-spanning protein. It can be found on the inner membrane of the cell’s tiny energy-producing organelles called mitochondria, which are abundant in brown fat.

When a fatty acid binds to uncoupling protein-1, the protein becomes a transporter for protons, moving them to the core, or matrix, of the mitochondria. This dissipates the electrochemical energy the body needs to generate ATP, the all-purpose molecular fuel of life. (This dissipation is also how heat is generated). But the body still needs ATP. So to generate that ATP, the body must burn more fuel from other sources, perhaps including fat reserves. That could be where the weight loss would come in.

I speculate part of Energesis’ strategy might entail artificially activating uncoupling protein-1, mimicking the natural uncoupling process to induce weight loss. (I wonder whether the activators need to resemble fatty acids to work!)

Bonus obesity tidbit: Another of Energesis’s co-founders was also a co-founder of Zafgen, yet another outfit with an obesity focus, which only recently unveiled the target of its experimental drugs.

More reading:
Background on how the body generates ATP for energy: Lehninger Principles of Biochemistry
More on uncoupling protein-1: The Biology of Mitochondrial Uncoupling Proteins, Diabetes, DOI: 10.2337/diabetes.53.2007.S130

Author: Carmen Drahl

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