Scientists have discovered a pathway behind the known effect of exercise suppressing appetite: a lactate-related metabolite that acts directly on certain neurons.
Not just more calories burned
It has been long known that, somewhat counterintuitively, exercise transiently suppresses appetite. Scientists suspect that this contributes to exercise-related weight loss. However, the exact mechanisms behind this effect, which can possibly be used to help treat obesity and metabolic disorders, were not well understood. In this new study published in Nature Metabolism, researchers from Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, Stanford University School of Medicine, and collaborating institutions, reveal one such mechanism that works through the brain.
“Regular exercise is considered a powerful way to lose weight and to protect from obesity-associated diseases, such as diabetes or heart conditions,” said co-corresponding author Dr. Yang He, assistant professor of pediatrics – neurology at Baylor and investigator at the Duncan NRI. “Exercise helps lose weight by increasing the amount of energy the body uses; however, it is likely that other mechanisms are also involved.”
The two-stage neuronal pathway
Prior work demonstrated that intense exercise raises blood levels of N-lactoyl-phenylalanine (Lac-Phe, a small molecule made from lactate and the amino acid phenylalanine) and that dosing mice with Lac-Phe suppresses appetite without obvious side effects [2]. Another study found that Lac-Phe gets elevated by the anti-diabetes drug metformin [3]. The researchers of this new study set out to answer which brain cells Lac-Phe acts on to curb feeding.
First, they reconfirmed its basic effect by injecting Lac-Phe into the abdomen and brain ventricles of mice. This resulted in reduced food intake in both normal-diet and high-fat-diet mice, suggesting a brain-based mechanism of action rather than something related to gut distress. They also ran behavioral tests to show that the compound wasn’t just making mice feel sick.
The team then stained brains for c-Fos, a protein used as a marker of recently activated neurons, after Lac-Phe administration. Two regions showed increased activity: the nucleus tractus solitarius (NTS) and the paraventricular nucleus of the hypothalamus (PVH). This marked both as potential relay points.
The researchers then selectively silenced the exact NTS neurons or PVH neurons that Lac-Phe had activated. Silencing the NTS neurons did not change appetite suppression by Lac-Phe, while silencing the PVH neurons blunted it. This suggested that PVH activation is required for feeding suppression, while NTS activation is incidental.
However, PVH neurons turned out to be the downstream part of the pathway. Experiments showed that a large fraction of their input comes from Agouti-related peptide (AgRP) neurons in the arcuate nucleus (ARH). These neurons are classic “hunger” cells, well known for their role in appetite regulation through AgRP, neuropeptide-Y (NPY), and the neurotransmitter GABA. Indeed, applying AgRP or NPY directly inhibited PVH neurons.
Direct application of Lac-Phe to AgRP neurons dose-dependently reduced their firing, and a set of further experiments confirmed their role. This suggested that when Lac-Phe inhibits AgRP neurons, PVH neurons become disinhibited, causing animals to eat less. The researchers then showed that the post-exercise dip in feeding depended on the inhibition of AgRP neurons.
“Understanding how Lac-Phe works is important for developing it or similar compounds into treatments that may help people lose weight,” He said. “We looked into the brain as it regulates appetite and feeding behaviors.”
Fight or flight, but don’t eat
The researchers were also able to show that Lac-Phe directly quiets AgRG hunger neurons by opening KATP: energy-sensing potassium channels on cell membranes that inhibit neuronal activity when energy is plentiful.
“We found that Lac-Phe acts on a protein on AgRP neurons called the KATP channel, which helps regulate cell activity. When Lac-Phe activates these channels in AgRP neurons, the cells become less active,” Dr. He said. “When we blocked the KATP channels using drugs or genetic tools, Lac-Phe no longer suppressed appetite. This confirmed that the KATP channel is essential for Lac-Phe’s effects.”
These results suggest a specific ion-channel mechanism that can be targeted by future therapies to recapitulate the weight loss associated with exercise. “This finding is important because it helps explain how a naturally produced molecule can influence appetite by interacting with a key brain region that regulates hunger and body weight,” said co-corresponding author Dr. Jonathan Long at Stanford University School of Medicine.
Interestingly, according to the researchers, previous studies have shown that Lac-Phe is most elevated by sprinting, followed by resistance training and then endurance training. There might be a deep evolutionary reason here: if you have to run, it is possible that this is not an isolated event but rather a sign that you are in a dangerous environment that might require more running. Keeping appetite down for a while should make future sprinting easier.
Literature
[1] Liu, H., Li, V. L., Liu, Q., Liu, Y., Su, C., Wong, H., … & Xu, Y. (2025). Lac-Phe induces hypophagia by inhibiting AgRP neurons in mice. Nature Metabolism, 1-14.
[2] Li, V. L., He, Y., Contrepois, K., Liu, H., Kim, J. T., Wiggenhorn, A. L., … & Long, J. Z. (2022). An exercise-inducible metabolite that suppresses feeding and obesity. Nature, 606(7915), 785-790.
[3] Xiao, S., Li, V. L., Lyu, X., Chen, X., Wei, W., Abbasi, F., … & Long, J. Z. (2024). Lac-Phe mediates the effects of metformin on food intake and body weight. Nature metabolism, 6(4), 659-669.
View the article at lifespan.io
