Lac-Phe, a weighty new discovery.
Exercise is a bona fide wonder drug that reduces the risk of heart disease, type 2 diabetes, osteoporosis, depression, anxiety and even some cancers. As the supreme way to burn calories, you’d also think the link between exercise and weight loss would be clear, but it’s not.
Do the minimum recommended weekly exercise of 150 minutes and you might lose a meagre two to three kilograms. Increase that to more than 225 minutes and you could be tipping the scales five to 7.5 kilograms lighter. But, even if you’re in this latter category, your joy may be short-lived.
Around 80% of people fail to maintain weight loss, thanks to a host of body responses that stubbornly defend your original weight. You eat more, thanks to increases in the appetite hormone ghrelin; you want to move less; and, infuriatingly, your basal metabolic rate drops. The weight just creeps back.
Into that exasperating fray comes a startling new finding, published in Nature. A recently discovered and little-studied molecule, called Lac-Phe, undergoes a major production boost during certain types of exercise and, in an animal model, profoundly suppresses appetite, potentially informing exercise programs or, tantalisingly, efforts to find an anti-obesity drug.
The study’s lead author, Jonathan Long, assistant professor in the Department of Pathology at Stanford University School of Medicine, California, works in the emerging field of “metabolomics”. It’s the study of small molecules known as metabolites that are key inputs to, and outputs of, reactions in cells – collectively called metabolism. Exercise, of course, has major effects on cell metabolism, including a ramp-up in the processes that turn nutrients into energy.
Long wanted to answer one, broad question: what changes in the blood of mice after a single bout of exercise? So he and graduate student Veronica Li had mice run on a treadmill. Then they took a blood sample and analysed it using a technique called liquid chromatography–mass spectrometry, which produces pretty, multi-coloured graphs with “peaks” representing detected molecules. They found something odd.
“We’d see all these changes in the blood, and the top peak is this thing that we have no idea what it is,” says Long. “All we see is a mass. I was like, ‘is this really real? What’s going on?’”
He had an idea to find out, but it was a long shot.
Long knew one mammal could workout harder than any other. The horse can increase its maximal oxygen consumption an incredible 45-fold during intense exercise. And, just across San Francisco Bay from Long’s lab at Stanford, is Golden Gate Fields, a horse-racing track. “So we call them and we’re like, ‘hey, we’re a metabolism lab at Stanford and…we’re really interested in trying to get some blood from racehorses. Is this possible?’”
To Long’s surprise and delight, it was. The horses were routinely drug-tested after races. The ‘A’ samples were all sent for analysis but, Long was told, there was also an ample supply of ‘B’ samples. He duly ran the horse blood through his metabolomics screen. “Lo and behold, it’s the same molecule that shows up in the mice that were running [in the lab] downstairs and the racehorses across the bay,” he says.
The molecule was a combination of lactate, which is made when cells use glucose in the absence of oxygen (for example, when muscles work hard during exercise – “anaerobic metabolism”), and the essential amino acid phenylalanine. Hence the moniker, “Lac-Phe”.
What did Lac-Phe do? Long’s team began a series of experiments to find out. They confirmed that Lac-Phe was made in cells that possess an enzyme called CNDP2. Then they showed that the cells used CNDP2 to make Lac-Phe when they were exposed to lactate. But the cells were not, as you might expect, muscle cells. They included immune cells, such as macrophages, and epithelial cells found in the bladder and kidney.
Long also knew that human studies had shown that genetic changes in CNDP2 are linked to body mass index, a measure of weight. The precise function of Lac-Phe was still a mystery but, Long surmised, it must have something to do with regulation of body weight.
So his team fed mice a high-fat diet until they became obese, and then injected Lac-Phe into their furry abdomens. Something remarkable happened. “They stopped eating,” Long says. “But otherwise they were totally normal. They moved the same, they were peeing the same, they pooped the same. They just were eating less.” The mice lost body fat, had better glucose control and, crucially, lost weight.
Long and his team were excited. There was an emerging causal chain – exercise produced lactate, triggered production of Lac-Phe in a wide range of cells possessed of CNDP2, and Lac-Phe suppressed appetite. Now they had to address the question: did any of this apply to people?
It just so happened that Long’s colleague, Michael Snyder, professor of genetics at Stanford University School of Medicine, had led a 2020 study that could help.
Snyder’s team got 36 adult volunteers to do something called Symptom-Limited Cardiopulmonary Exercise Testing.
“This is like the human version of what we did in the mice,” says Long. “They put them on a treadmill, get them to run, and the treadmill keeps going faster until they say, ‘ok I’ve had enough’. In general a person will run about 10 minutes.”
Snyder’s team had taken blood samples and run a metabolomic analysis. “We re-queried their old metabolomics data,” says Long. “And what was really amazing was that what they had previously identified from the data, but they didn’t know how to interpret it, was a peak that exactly matched that of Lac-Phe.”
It was a line in the sand. People made Lac-Phe after exercise, too. But Long still didn’t know which type of exercise did it most effectively. So his group began a collaboration with physiologist Erik Richter at the University of Copenhagen, Denmark.
Richter’s team recruited eight healthy young men and ran each through three exercise protocols. There was an endurance trial – 90 minutes of stationary cycling at 55% of maximum effort. There was a resistance session – leg presses and leg curls in six sets of 10 repetitions at 50% of maximal load. And there was the infamous Wingate test, a five-minute warm up followed by three intense bursts on the bike. “You bike your brains out for 30 seconds”, is how Long puts it.
When they analysed the post-workout blood samples of the young men, one exercise was streets ahead. “Lac-Phe was dramatically increased in the sprint exercise, and increased, but not nearly as much, in both the resistance and endurance exercises,” says Long.
It was a stunning finding, but Long’s study leaves plenty of questions unanswered. It didn’t investigate whether Lac-Phe suppresses appetite in humans. Further, Lac-Phe had no effect on the feeding behaviour of lean mice on a low-fat diet. Long doesn’t know why, but has some thoughts: “One idea is that the blood brain barrier becomes “leaky” in obesity and so there is more Lac-Phe getting to the brain. Another possibility is that the brain Lac-Phe receptor, which we have still not identified, is up-regulated in obesity.”
Why would animals have a mechanism to turn off appetite during exercise? In a linked perspective article, Tahnbee Kim and Scott Sternson, from the Howard Hughes Medical Institute at the University of California, San Diego, suggest it may have evolved to downgrade the importance of energy intake in the face of stressors. “[I]t is better not to be distracted by hunger when trying to escape predators,” they write.
Another question is where Lac-Phe might be targeting appetite in the brain. Kim and Sternson suggest that, because eating high-fat foods is pleasurable, Lac-Phe may act in the reward centres. “Perhaps Lac-Phe is operating on the willingness to consume this high-fat diet relative to the standard low-fat mouse food that the lean mice were eating,” Sternson told Cosmos Weekly.
Sternson also posits that a varying ability to produce Lac-Phe could explain a vexing problem. “Variation in the production of, or response to, this molecule in humans might underlie differences in the efficacy of exercise as a weight-loss strategy for different individuals,” he says. On the upside, while Lac-Phe circulated in the mice’s blood for around an hour, its effects lasted for 12 hours. The pathways responsible aren’t clear, says Sternson, but “it indicates the engagement of a longer-lasting signalling process”.
Uncertainties aside, what ought people do to get any appetite-quelling effect from Lac-Phe? “This story tells you, from a molecular and scientific point of view, why running stadium stairs feels different than taking a walk around the block,” says Long. “If you run stadium stairs, you feel like you’re going to vomit, whereas if you take a nice leisurely walk around the block, you might feel more hungry.” So, what’s the take-home message?
“If you want to use exercise as a way to suppress your [appetite], maybe you should do some high-intensity interval training, rather than a low, slow burn,” says Long.
Paul Biegler is a philosopher, physician and Adjunct Research Fellow in Bioethics at Monash University. He received the 2012 Australasian Association of Philosophy Media Prize and his book The Ethical Treatment of Depression (MIT Press 2011) won the Australian Museum Eureka Prize for Research in Ethics.