Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
Nat Commun. 2023 Sep 26;14(1):5984. doi: 10.1038/s41467-023-41435-y.
Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hypothermia in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in mice. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly blunted in the mice with knockout of PDXK in the preoptic area (POA) of hypothalamus. We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and they may activate medial preoptic area (MPA) neurons in POA to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hypothermia state in mice.
在冬眠/蛰伏期间诱导体温降低使某些哺乳动物能够在极端环境条件下生存。然而，在大多数哺乳动物中，药理学诱导体温降低仍然是一个巨大的挑战。在这里，我们表明一种天然产物 P57 能迅速诱导体温降低并降低小鼠的能量消耗。在机制上，P57 抑制吡哆醛激酶（PDXK）的激酶活性，PDXK 是维生素 B6 的关键代谢酶，催化吡哆醛（PL）的磷酸化，导致下丘脑 PL 的积累，从而导致体温降低。在 PDXK 在下丘脑视前区（POA）敲除的小鼠中，P57 诱导的体温降低明显减弱。我们进一步发现，P57 和 PL 对下丘脑的基因表达调控有一致的影响，它们可能激活 POA 中的中视前区（MPA）神经元，从而诱导体温降低。总之，我们的研究结果表明，P57 通过调节维生素 B6 代谢，具有在治疗性体温降低方面的潜在应用，而 PDXK 作为 P57 在体温调节中一个以前未知的靶点。此外，P57 可能作为一种化学探针，用于探索与小鼠体温降低状态相关的神经元回路。
