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<p>The vagus nerve (VN) is a major component of the parasympathetic nervous system that regulates glucose and energy homeostasis. However, the specific molecular signaling pathways within the VN that regulates this&#xa0;homeostasis remain unclear. Here, we show that vagal neuron-specific deletion of <i>phosphatase and tensin homolog (Pten)</i>, the endogenous negative regulator of PI3K, led to increased vagal output. Intriguingly, dopaminergic signaling genes were upregulated, correlating with elevated sympathetic nerve density and increased norepinephrine levels in adipose tissue of vagal&#xa0;<i>Pten</i>-deficient mice. These mice were also protected against high-fat diet-induced obesity, insulin resistance, and systemic inflammation. To investigate insulin-specific PI3K signaling within the VN, we generated mice with vagal neuron-specific <i>insulin receptor</i> deletion that resulted in exacerbation of metabolic defects, which was rescued by concomitant <i>Pten</i> deletion. In summary, we show that insulin-PI3K-PTEN axis within vagal neurons is essential in optimizing the autonomic output that determines peripheral inflammatory and metabolic homeostasis.</p>

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PTEN regulates vagal-insulin signaling to optimize autonomic output determining peripheral inflammatory and metabolic homeostasis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月10日

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  • Yu Zhe Li,
  • Joe Eun Son,
  • Nathaniel Vo,
  • Catherine Bellisimo,
  • Ju Hee Lee,
  • Joshua Rapps,
  • Evan Pollock-Tahiri,
  • Martha Ghebreselassie,
  • Chuck T. Chen,
  • Richard P. Bazinet,
  • Filio Billia,
  • Akira Suzuki,
  • Chi-Chung Hui,
  • Tak W. Mak,
  • Hoon-Ki Sung,
  • Paul Yoo,
  • Minna Woo

摘要

The vagus nerve (VN) is a major component of the parasympathetic nervous system that regulates glucose and energy homeostasis. However, the specific molecular signaling pathways within the VN that regulates this homeostasis remain unclear. Here, we show that vagal neuron-specific deletion of phosphatase and tensin homolog (Pten), the endogenous negative regulator of PI3K, led to increased vagal output. Intriguingly, dopaminergic signaling genes were upregulated, correlating with elevated sympathetic nerve density and increased norepinephrine levels in adipose tissue of vagal Pten-deficient mice. These mice were also protected against high-fat diet-induced obesity, insulin resistance, and systemic inflammation. To investigate insulin-specific PI3K signaling within the VN, we generated mice with vagal neuron-specific insulin receptor deletion that resulted in exacerbation of metabolic defects, which was rescued by concomitant Pten deletion. In summary, we show that insulin-PI3K-PTEN axis within vagal neurons is essential in optimizing the autonomic output that determines peripheral inflammatory and metabolic homeostasis.