Brain insulin resistance links the failure of energy metabolism with cognitive decline in both type 2 Diabetes Mellitus (T2D) and Alzheimer's disease (AD), although the molecular changes preceding overt brain insulin resistance remain unexplored. Abnormal biliverdin reductase-A (BVR-A) levels were observed in both T2D and AD and were associated with insulin resistance. Here, we demonstrate that reduced BVR-A levels alter insulin signaling and mitochondrial bioenergetics in the brain. Loss of BVR-A leads to IRS1 hyper-activation but dysregulates Akt-GSK3β complex in response to insulin, hindering the accumulation of pGSK3β into the mitochondria. This event impairs oxidative phosphorylation and fosters the activation of the mitochondrial Unfolded Protein Response (UPRmt). Remarkably, we unveil that BVR-A is required to shuttle pGSK3β into the mitochondria. Our data sheds light on the intricate interplay between insulin signaling and mitochondrial metabolism in the brain unraveling potential targets for mitigating the development of brain insulin resistance and neurodegeneration.

中文翻译：

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胆绿素还原酶-A 通过 GSK3β 磷酸化将胰岛素信号传导与线粒体代谢整合


大脑胰岛素抵抗将能量代谢失败与 2 型糖尿病 (T2D) 和阿尔茨海默氏病 (AD) 的认知能力下降联系起来，尽管明显的大脑胰岛素抵抗之前的分子变化仍未被探索。在 T2D 和 AD 中均观察到胆绿素还原酶 A (BVR-A) 水平异常，并且与胰岛素抵抗相关。在这里，我们证明 BVR-A 水平降低会改变大脑中的胰岛素信号传导和线粒体生物能学。 BVR-A 的缺失会导致 IRS1 过度激活，但会导致 Akt-GSK3β 复合物对胰岛素的反应失调，从而阻碍 pGSK3β 在线粒体中的积累。该事件会损害氧化磷酸化并促进线粒体未折叠蛋白反应 (UPRmt) 的激活。值得注意的是，我们发现 BVR-A 是将 pGSK3β 运送到线粒体中所必需的。我们的数据揭示了大脑中胰岛素信号传导和线粒体代谢之间复杂的相互作用，揭示了减轻大脑胰岛素抵抗和神经退行性疾病发展的潜在目标。