We know that regular exercise carries myriad benefits, boosting everything from weight loss to metabolic health to cognitive function. Yet age-old obstacles such as motivation or various physical or time restraints can often get in the way.
Now, however, a new study led by USF Health researcher Yong Xu, MD, PhD, and a multi-site team of investigators, recently published in Nature Metabolism, provides a deeper understanding of a specific molecule, known as Lac-Phe, and how it produces the physiological benefits from exercise while suppressing weight gain as well.
The paper builds on the group’s breakthrough study three years ago in Nature, which received national attention in the New York Times and other media outlets after the study’s findings raised the possibility that a pill could one day be developed to produce the same physiological and weight loss benefits as exercise itself.
“One of the things we were trying to do then was identify what we call an exercise memetic — the things that play a critical role in mediating the benefits of exercise,” explained Dr. Xu, professor of Psychiatry & Behavioral Neurosciences in the USF Health Morsani College of Medicine and director of USF Health’s new Center for Molecular Psychiatry.
Other authors on the study include researchers from Baylor College of Medicine (Dr. Xu’s former home), Stanford University, Texas Children’s Hospital, McGovern Medical School at the University of Texas, and Harvard Medical School.
“We felt if we could identify this molecule, we could understand the mechanism related to the benefit of exercise,” Dr. Xu said. “And we could develop pills that people could take and benefit without doing the actual exercise.”
In addition, as part of that 2022 study, the team discovered that the level of Lac-Phe rises significantly after high-intensity exercise.
“We also reported that this molecule, if injected, can prevent weight gain and suppress food intake,” Dr. Xu said.
Dr. Xu and his team were confident that Lac-Phe was doing “amazing things” in this regard. But they didn’t understand how the molecule worked its magic in curbing appetite. The new paper solves that problem.
“What we discovered is that Lac-Phe, once it enters the circulation after exercise, will go into the brain and act on a small group of neurons in the hypothalamus,” he said.
The hypothalamus is the area of the brain that coordinates involuntary actions of the nervous system, as well as such essential elements as body temperature, thirst, hunger and sleep.
“These are called AgRP neurons and normally, once activated, they will drive animals to find food and eat,” he said. “What Lac-Phe does is suppress the activity of these AgRP neurons, thereby suppressing appetite.”
But the team went a step further to show how Lac-Phe inhibits AgRP.
“What we discovered is Lac-Phe can lead to opening up a channel – called an ATP sensitive potassium channel,” he said. “What happens is that the potassium will go from the inside of the cells to the outside of the cells through this channel, thereby inhibiting the AgRP neuron and ultimately reducing food intake. That’s the major discovery of this paper — identifying the cellular basis of how Lac-Phe works to curb appetite.”
But in addition to having gained a greater understanding of the cellular workings, Dr. Xu and his team now want to study the molecular functions of Lac-Phe.
“In other words, what is the molecule that Lac-Phe acts upon to induce this event?” he said. “Perhaps it’s an intracellular enzyme or a signaling molecule inside the cell. We don’t know yet, so that’s what we are working on right now.”
Meanwhile, propelled by the insights of the new study, they are exploring other benefits of Lac-Phe produced by exercise beyond losing weight.
“For example, is there an increase in cognitive function or enhancing the outcomes of certain cancers?” he said. “We’re also working in the lab to explore whether Lac-Phe can make animals smarter or live longer if they have a tumor.”
The ramifications of their work could have a positive widespread impact on individuals who can’t do regular exercise for whatever reason. It has also already spurred other research teams into action.
“Lac-Phe, since our discovery, has been a very attractive target and replicated by different groups and in human studies,” he said. “and we have patented Lac-Phe as a potential treatment for metabolic disease, including obesity and diabetes.”
For people facing challenges getting to the gym, for whatever the reason, that may be just what the doctor ordered.
Other USF Health researchers working on the study were: Hailan Liu, Qingzhuo Liu, Kristine M. McDermott, Longlong Tu, Yongxiang Li, Mengjie Wang, Yue Deng, Yuxue Yang, and Yongjie Yang.