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<p>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 <i>RORβ</i>, 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年8月11日

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  • 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,
  • Jun Yao

摘要

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.