What Does The Pancreas Have To Do With Mood? Insulin's Surprising Connection To Bipolar Disorder Discovered

Researchers have discovered that the RORβ gene, linked to bipolar disorder, can affect both the pancreas and the brain. In laboratory models and mice, excess levels of this gene reduced insulin release during the day, causing hyperactivity in the hippocampus and depressive symptoms. At night, the process reversed: insulin increased, the hippocampus became less active, and symptoms of mania emerged. This mechanism reveals a feedback loop between the pancreas and the brain, regulated by the day-night cycle, which may explain the mood swings in bipolar disorder and open up new avenues for treatment.

Bipolar disorder is a mental health condition characterized by intense and recurring mood swings, ranging from episodes of deep depression to phases of mania or hypomania, marked by excessive energy, impulsivity, and euphoria.

These fluctuations go far beyond the common emotional fluctuations of everyday life and can significantly affect a person's personal, professional, and social life. Although its causes are multifactorial, involving genetics, brain function, environmental factors, and possibly metabolic processes, recent scientific advances have revealed new connections that help us better understand this complex condition.

Recent research has shown that many people with psychiatric disorders, especially bipolar disorder, also experience metabolic alterations, such as difficulties with glucose control or insulin secretion. This association was already well documented, but until now, the precise biological link between metabolic symptoms and mood swings was not understood.

A groundbreaking study published in Nature and conducted by researchers at Tsinghua University in China has provided new insights by revealing a surprising link between the pancreas and the brain, regulated by the circadian rhythm, the biological cycle of light and dark throughout the day.

To investigate this connection, scientists used induced pluripotent stem cells from individuals with bipolar disorder and managed to generate pancreatic islets in the laboratory, structures responsible for insulin production.

These islets presented a striking defect: they released less insulin than expected. This problem was associated with an increased expression of the RORβ gene, already known as a genetic risk factor for bipolar disorder.

The researchers then modeled the condition in mice. They genetically engineered animals to overexpress the RORβ gene specifically in pancreatic β cells, the cells responsible for insulin production.

The results were striking: during the light phase of the day, these mice exhibited depression-like behaviors, and during the dark phase, they developed manic behaviors. This strikingly mirrors the mood cycles typical of bipolar disorder in humans.

At the cellular level, the mechanisms were clear. During the light phase, overexpression of RORβ reduced insulin release from the pancreatic islets. This drop in insulin was directly associated with hyperactivity in the hippocampus, a brain region essential for regulating mood, memory, and stress response.

This hyperactivity in the hippocampus was not just an immediate effect; it had a delayed impact that manifested itself in the dark phase. During this period, insulin release increased, hippocampal activity decreased, and manic-like behaviors emerged.

This pattern revealed a previously unknown mechanism: a feedback loop between the pancreas and hippocampus that functions bidirectionally and is regulated by the circadian rhythm. In other words, metabolic changes in the pancreas affect brain activity, and these brain changes, in turn, modify pancreatic function, creating a cycle that may explain the mood swings of bipolar disorder.

The findings not only offer a biological explanation for the coexistence of metabolic alterations and psychiatric symptoms, but also broaden the understanding of bipolar disorder.

This condition may not be solely a brain disease, but rather a systemic disorder in which body and mind are deeply connected. This paves the way for new treatment strategies, such as interventions that target pancreatic function, insulin regulation, or the adjustment of circadian rhythms through medication, light therapy, or even dietary habits.

Although further human studies are needed to confirm this mechanism, the integrative model proposed by the researchers already represents an important advance. It helps understand how genetic, metabolic, and brain factors combine to generate the mood cycles characteristic of bipolar disorder and points to new possibilities for therapies that treat the body and brain together.

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A pancreas–hippocampus feedback mechanism regulates circadian changes in depression-related behaviors

Yao-Nan Liu, Qiu-Wen Wang, Xin-Yu She, Li-Jun Li, Bing Wang, Ruilan Yang, Qian Li, Si-Yao Lu, Ying-Han Wang, Wei Shen, Chong-Lei Fu, Dan Li, Lan Yi, Chun-Xue Wang, Wei Shi, Xin Cheng, Liping Cao, Shuangli Mi, and Jun Yao

Nature Neuroscience, 11 August 2025

https://doi.org/10.1038/s41593-025-02040-y

Abstract: 

Individuals with neuropsychiatric disorders often show metabolic symptoms. However, the mechanisms underlying this co-occurrence remain unclear. Here we show that induced pluripotent stem cell-derived pancreatic islets from individuals with bipolar disorder have insulin secretion deficits caused by increased expression of RORβ, a susceptibility gene for bipolar disorder. Enhancing RORβ expression in mouse pancreatic β cells induced depression-related behaviors in the light phase and mania-like behaviors in the dark phase. Pancreatic RORβ overexpression in the light phase reduced insulin release from islets, inducing hippocampal hyperactivity and depression-like behaviors. Furthermore, this hippocampal hyperactivity in the light phase had the delayed effect of promoting insulin release in the dark phase, resulting in mania-like behaviors and hippocampal neuronal hypoactivity. Our results in mice point to a pancreas–hippocampus feedback mechanism by which metabolic and circadian factors cooperate to generate behavioral fluctuations and which may play a role in bipolar disorder.