Turning food into usable energy and then utilizing it makes up the basis of an organism’s energy metabolism. Conversely, a nutrient surplus contributes to the early development of several disorders, including obesity, diabetes, cardiovascular disease, and Alzheimer’s disease (AD). The nutrient surplus observed to be associated with these diseases also leads to the modification of key proteins in the mitochondria, thus leading to energy dysregulation. Consequently, many scientists study these metabolic pathways, and then use the resulting knowledge to better understand diseases and develop new treatments.
When asked how scientists typically use studies of energy metabolism in drug discovery and development, Raj Amin, associate professor at Auburn University’s Harrison School of Pharmacy, says, “There are so many ways of doing it!”
For example, Amin and his colleagues at the AU Neuroscience Center, study AD through energy metabolism. As Amin asks, “How does energy dysregulation promote the neurons from communicating properly and thus lead to memory impairment?” To find out, Amin and his team are trying to correlate diabetes—a disease connected to energy metabolism—with AD. To do that, these scientists use micro-PET/CT (positron emission tomography/computer tomography) to track labeled glucose and it’s uptake. “The brain uses glucose as a major form of energy,” Amin says. “As Alzheimer’s progresses, the utilization of energy is severely reduced—similar to advanced aging, as well as insulin resistance found in diabetic patients.”
Amin hopes to find ways to improve energy utilization in the brains of people with AD. For example, he says, “exercise can induce neurotrophins that improve synaptic activity in the brain.” Maybe scientists can develop new drugs that also improve brain function by better understanding the organ’s use of energy.
That’s just one aspect of how energy metabolism might be used in developing new medical treatments—even ones that might address diseases that have been largely untreatable, like AD. Let’s see what else people are trying.
Looking at lipids
Processing energy from food involves various classes of molecules, including lipids. So, Promega “is introducing three new assays to quantitate lipid metabolites: the Glycerol-Glo™ Assay, the Triglyceride-Glo™ Assay, and the Cholesterol/Cholesterol Ester-Glo™ Assay,” says senior research scientist Mike Valley. “These assays are based on a core bioluminescent technology used in other Promega Energy Metabolism assays in which the quantity of a specific metabolite is directly proportional to the light generated by the assay.” Researchers can use these assays with samples in various forms, including cultured cells, cell-culture medium, tissue samples, and plasma or serum samples. “With the emergence of 3D microtissues as a key model system in drug discovery and development, finding assays that are compatible with these complex model systems is important, and Promega’s new lipid metabolism assays can be used with these 3D model systems to support drug discovery research,” Valley says.
Valley points out several reasons that scientists might select one of these lipid-metabolism assays. “First, the assays do not require organic extraction from the starting samples,” he says. “Removing the need for organic extraction simplifies sample preparation and increases the amount of samples that can be processed at the same time.” He adds, “The bioluminescent detection mode is sensitive with a large linear range of detection, allowing drug discovery researchers to use 384-well plates to increase sample throughput.”
Scientists working in drug discovery and development might analyze the lipid content of samples for various reasons. “For example, researchers evaluating drugs targeting NAFLD—non-alcoholic fatty liver disease—or NASH—non-alcoholic steatohepatitis—will want to quantitatively measure changes in intracellular triglyceride levels, and this can easily be done with the Triglyceride-Glo™ Assay,” Valley says. “Researchers in the metabolic-disorder field can also use these lipid metabolism assays to determine the impact of insulin on lipolysis and lipogenesis pathways.”
Degrees of change
An organism’s metabolic rate is proportional to the heat that it’s generating. So, TA Instruments makes platforms that “measure the heat being produced by a system,” says Neil Demarse, product manager, microcalorimetry. “There’s no labeling of proteins or any other biomolecules, no specific targets—it’s more of a global characteristic.”
Scientists can grow cells in one of TA Instruments’ microcalorimeters, such as the TAM IV. Then, the environment can be changed to see if or how that affects the metabolic rate of the cells. “You could also change the media or add a drug and then analyze the resulting heat production,” Demarse says. The experiment can run for hours or weeks—as long as needed or as long as the cells survive. For more control, a scientist can accessorize a system. “You could add the ability to titrate a sample, perfuse different gases or liquids, for example,” Demarse explains.
Biotechnology and pharmaceutical companies can use this technology for stability and compatibility studies, as well as formulation research and more. After the microcalorimetry experiments, a sample could be accessed for further analysis.
Computational creations
In addition to running experiments on the energy metabolism of AD, Amin and his colleagues develop new drugs to test. “We develop the drugs computationally, and then see how they work—testing them in cell lines and then in animal models,” Amin explains.
The computational process starts with picking a good target. “We consider targets like certain proteins or things associated with diabetes that get impaired over time,” Amin says. “If it’s something that is overexpressed, we try to stop that.” A receptor could also serve as a target, and then Amin might want to activate or inhibit it, depending on the receptor’s function.
In today’s computationally based drug design, Amin says, “the software is so good, because it integrates lots of information in one giant package, which can do a much better job of designing these molecules and deciding what could be influenced.” Getting that done right, though, still takes a chemist who understands the compounds and the computation.
In fact, the concept of energy metabolism covers a wide range of life science and beyond, and that takes experts with different backgrounds. Remember what Amin said about using energy metabolism studies in drug discovery and development: “There are so many ways of doing it!” Consequently, many different angles of attack can be made on diseases from an energetic perspective. That means that different kinds of technology and methods can be applied to the same question. So, consider tackling a disease through a new focus on energy metabolism.
Hero image at top: The brain changes in Alzheimer’s disease—such as protein clumps called plaques (blue)—could be related to energy metabolism. Image courtesy of Alvin Gogineni, Genentech.