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  • Researchers identified a blood metabolite known as “Lac-Phe,” that can reduce food intake in obese mice by about 50%.
  • When injected, Lac-Phe reduces weight without affecting energy expenditure, water intake, and movement levels.
  • The researchers say that further study of Lac-Phe is needed to understand its potential to treat metabolic diseases such as obesity.

Physical activity increases the risk for obesity, metabolic disease, and all-cause mortality.

Exercise is an effective intervention for obesity and cardiometabolic diseases, etoposide and cisplatin for lung cancer including cardiovascular disease and diabetes.

Some research has begun to generate molecular maps of biological molecules regulated by physical activity.

Further research into these molecules could help researchers design treatments for conditions like obesity that mimic the effects of exercise.

Recently, researchers found that exercise stimulates the production of a blood metabolite, N-lactoyl-phenylalanine (Lac-Phe), that suppresses feeding and obesity in mice.

Mice treated with Lac-Phe for 10 days reduced cumulative food intake, lowered body fat, and improved glucose tolerance, experiencing a significant weight loss.

The study was published in the journal Nature.

Lac-Phe 

For the study, the researchers performed a metabolomic analysis of blood plasma from mice running on a treadmill until exhaustion.

They noted that exercise increased levels of several blood metabolites, including lactate, fumarate, and succinate.

The most significantly induced among all the metabolites, however, was Lac-Phe. The same molecule was also detected in metabolomic analyses from race horses after racing.

From further tests, the researchers found that plasma levels of Lac-Phe in mice and race horses peaked at around 2µM after exercise and returned to baseline after an hour.

The researchers hypothesized Lac-Phe might function as a molecular signal which regulates energy balance. They thus administered Lac-Phe to obese mice.

In doing so, they noted that their food intake decreased by around 50% over 12 hours compared to control mice. Their movement levels, however, were unaffected.

The researchers further noted that Lac-Phe did not alter other measures among treated mice, including:

  • oxygen consumption
  • carbon dioxide production
  • respiratory exchange ratios
  • water intake
  • appetite-regulating hormones such as leptin and ghrelin.

They also found that administering Lac-Phe in obese mice for 10 days reduced food intake and body weight relative to control mice. It also improved glucose homeostasis and reduced adiposity — amounts of fatty tissue — without changing the weight of other organs.

They noted, however, that while injected Lac-Phe exhibited positive effects, oral dosing produced no effect on food intake or body weight, likely due to decomposition in the digestive system.

The researchers next analyzed Lac-Phe levels in a human cohort of 36 people following exercise. Similar to mice, Lac-Phe levels peaked in humans following exercise and returned to baseline after one hour.

Further tests found that Lac-Phe levels were highest after sprinting — remaining above baseline for three hours —followed by endurance exercise and resistance training.

Underlying mechanisms

As little research has been conducted on Lac-Phe, the researchers wrote that its mechanisms are poorly understood. From tests conducted in this study, however, they found that its effects on obesity and adiposity are solely due to its impact on energy intake.

When asked further about these mechanisms, Jon Long, Ph.D., assistant professor of Pathology at Stanford University and one of the study’s authors, told Medical News Today, “We think Lac-Phe acts in the brain to control feeding. But we don’t have much of an idea right now. We are now trying to understand what are the brain circuits that Lac-Phe turns on, and what is the brain Lac-Phe receptor.”

To the same question, Dr. Paresh Dandona, Ph.D., distinguished professor and head of Endocrinology, Diabetes and Metabolism at the University at Buffalo, the State University of New York (SUNY), not involved in the study, told MNT:

“Lac-Phe is induced by exercise in mice and other mammals, including horses and humans. It is likely that its effect on weight is induced by hypothalamic mechanisms involved in the regulation of hunger and satiety as well as the reward zones of the brain. GLP-1 receptor agonists act through these mechanisms and induce weight loss […] that it is confined to adipose tissue and does not affect lean body mass.”

“However, studies need to be carried out in humans either with Lac-Phe infusions or with its stable analogs in the future. I am sure the pharmaceutical industry will jump at this opportunity. This is the beginning of a novel story and mechanism for weight loss, and I hope that it will work out,” Dr. Dandona continued.

The researchers concluded that Lac-Phe treatment reduces adiposity and obesity, and improves glucose tolerance in obese mice.

When asked about limitations to the findings, Dr. Lawrence J. Cheskin, professor and chair of the Department of Nutrition and Food Studies at George Mason University, not involved in the study, told MNT:

“This is based largely on studies in a special strain of obese mice. Side effects and long-term efficacy in humans are not known.”

Dr. Cheskin added that while these findings may outline a potential mechanism for curbing food intake, more research is needed.

Nevertheless, Dr. Long hopes that drugs targeting the Lac-Phe pathway will one day be able to “capture” the anti-obesity effects of exercise and thus serve as an alternative treatment for obesity.

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