Scientists identify a fat-derived hormone that drives the mood benefits of exercise

A new study published in Molecular Psychiatry provides evidence that a single thirty-minute session of physical activity can produce immediate antidepressant effects in both humans and mice. The research identifies a specific biological pathway involving a hormone released by fat cells that alters brain plasticity to improve mood. These findings suggest that short-term exercise could serve as an accessible intervention for alleviating depressive symptoms.

Major depressive disorder places a significant burden on global health systems and affects millions of individuals. Current pharmaceutical treatments often require weeks or even months to become effective and can carry unwanted side effects. While consistent physical activity is recognized for its mental health benefits, the immediate impact of a single exercise session is less understood.

The scientific community lacks a complete picture of the neurobiological processes that translate physical movement into rapid mood elevation. The study aimed to map the specific cellular and molecular events that occur in the brain following acute exercise.

“Depression is one of the most devastating disorders, contributing significantly to disability worldwide. Although regular physical exercise is recognized for its antidepressant effects, the immediate impact of a single bout of exercise has often been overlooked, with limited mechanistic evidence supporting its benefits,” said study author Sonata Suk-yu Yau, an associate professor in the Department of Rehabilitation Sciences and a principle investigator in the Mental Health Research Center at Hong Kong Polytechnic University.

“Rapid-acting antidepressant treatments that offer sustained effects and minimal side effects remain scarce. This issue is particularly concerning given the rising prevalence of adolescent depression, highlighting the importance of non-pharmacological preventative measures to reduce the risk of developing depression.

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“This study provides clinical evidence for the effectiveness of a single session of exercise in alleviating depressive symptoms. Additionally, mechanistic support from animal studies demonstrates that a single bout of exercise rapidly increases levels of the adipocyte-secreted hormone adiponectin, which activates neural activity and promotes new spine formation in the prefrontal cortex, ultimately leading to a rapid response.”

The researchers recruited forty university students and staff for the human portion of the experiment. Half of these participants exhibited symptoms of anxiety or depression based on initial screening, while the other half did not. All individuals completed a thirty-minute running session on a treadmill at a moderate intensity.

Psychological assessments conducted before and after the session showed that the exercise reduced total mood disturbance. Participants reported higher levels of vigor and self-esteem alongside reductions in negative feelings such as tension and fatigue.

To investigate the underlying biology, the team utilized a mouse model designed to simulate depression through chronic unpredictable stress. These mice underwent a similar thirty-minute treadmill protocol. Behavioral tests measured the animals’ motivation and mood states.

For example, the forced swim test measures how long a mouse struggles to escape water versus floating passively. The exercised mice displayed significantly reduced depression-like behaviors compared to sedentary controls. This antidepressant response emerged within two hours and persisted for up to twenty-four hours.

The investigators then examined brain tissue to identify which areas were active during the exercise. They mapped the expression of c-Fos, a protein that indicates recent neuronal activity. This mapping revealed increased activity in the anterior cingulate cortex. This region plays a significant role in emotion regulation and mood disorders.

Further analysis pinpointed the specific type of cells activated within this region. The study showed that glutamatergic neurons, which are excitatory nerve cells, were primarily responsible for the increased activity. The researchers sought to determine if this activity was the cause of the mood improvement.

They utilized a technique called chemogenetics, which allows for the remote control of specific cell groups using engineered receptors and specific drugs. They artificially inhibited these specific neurons before the mice exercised. This inhibition prevented the antidepressant effects usually seen after running. This indicates that the activation of these neurons is necessary for the mood benefit. Conversely, chemically activating these neurons in sedentary mice mimicked the antidepressant effects of exercise.

The team investigated chemical signals that might bridge the gap between the body and the brain. They focused on molecules known as exerkines, which are released by peripheral organs during physical activity. They observed that the exercise session led to elevated levels of adiponectin in the medial prefrontal cortex. Adiponectin is a hormone typically secreted by fat tissue.

In the mice, the rise in brain adiponectin levels correlated directly with the reduction in depression-like behavior. This suggests a communication pathway where the body signals the brain to regulate mood. The study established that the glutamatergic neurons in the anterior cingulate cortex possess receptors specifically for adiponectin, known as AdipoR1.

When the researchers genetically removed these receptors, the exercise no longer produced an antidepressant response. This confirmed that the hormone must bind to these specific receptors to initiate the mood-regulating process. The team then looked inside the neurons to understand what happened after the receptor was activated.

They tracked a protein known as APPL1. Under normal conditions, APPL1 resides in the cell’s main body, or cytoplasm. The data showed that following exercise, adiponectin signaling caused APPL1 to move into the cell nucleus. This translocation peaked approximately two hours after the exercise session ended.

Once inside the nucleus, APPL1 appeared to influence how DNA is packaged and read. This process is known as epigenetic regulation. The study found increased acetylation of histone H4, a chemical change that loosens the DNA structure to allow for gene expression. This modification essentially unlocks specific genetic instructions.

This process led to the increased production of proteins essential for building connections between neurons. These proteins included components necessary for synaptic transmission. Consequently, the researchers observed the formation of new dendritic spines. Dendritic spines are small protrusions on neurons that receive signals from other neurons.

The formation of new spines indicates a physical rewiring of the brain, known as neural plasticity. Blocking the movement of APPL1 into the nucleus prevented both the formation of these new connections and the antidepressant behavioral effects. This links the molecular journey of APPL1 directly to the structural changes in the brain and the subsequent improvement in mood.

The findings suggest that “a single bout of exercise lasting 30 minutes at moderate intensity is effective in alleviating depressive mood,” Yau told PsyPost. “Physical exercise is one of the most accessible and low-cost interventions for immediately reducing depressive symptoms, and it may also be effective in preventing the development of depression.”

But the study, like all research, includes some caveats. The human trial involved a relatively small sample size of university students, which may not represent the general clinical population or those with severe depressive disorders.

Additionally, the animal mechanisms were primarily explored in male mice. It remains unclear whether female mice share the exact same biological pathways, as hormonal differences can influence depression and exercise responses.

“Our long-term goal is to provide robust scientific evidence for both the acute and sustained beneficial effects of physical exercise in alleviating depressive mood among the general population with mood disturbances, as well as patients with depression,” Yau explained. “As a next step, we plan to investigate the optimal intensity and shortest duration of a single bout of exercise to enhance its practicality and accessibility.”

“Additionally, we aim to examine the influence of gender and age on the response to single-bout exercise. Ultimately, our objective is to develop population-based guidelines with optimal single-bout exercise prescriptions for mood improvement, serving as an effective strategy to prevent the development of depression.

The study, “Rapid antidepressant effect of single-bout exercise is mediated by adiponectin-induced APPL1 nucleus translocation in anterior cingulate cortex,” was authored by Tong Cheng, Formolo Douglas Affonso, Jiasui Yu, Yunxiao Zhong, Zonghao Ma, Akhlaq Hussain, Formolo Natalia Paludo Silveira, Li Zhang, Kenneth King-yip Cheng, Georg S. Kranz, Kangguang Lin, Gang Chen, Parco Ming-Fai Siu, Jung Sun Yoo, Cora Sau Wan Lai, Aimin Xu, Kwok-Fai So, and Suk-Yu Yau.