DMHPpp1r17 neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication,Cell Metabolism

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DMHPpp1r17 neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication
Cell Metabolism ( IF 27.7 ) Pub Date : 2024-01-08 , DOI: 10.1016/j.cmet.2023.12.011
Kyohei Tokizane ₁ , Cynthia S Brace ₁ , Shin-Ichiro Imai ₂

Affiliation

Recent studies have shown that the hypothalamus functions as a control center of aging in mammals that counteracts age-associated physiological decline through inter-tissue communications. We have identified a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMH neurons), that regulates aging and longevity in mice. DMH neurons regulate physical activity and WAT function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), through sympathetic nervous stimulation. Within DMH neurons, the phosphorylation and subsequent nuclear-cytoplasmic translocation of Ppp1r17, regulated by cGMP-dependent protein kinase G (PKG; ), affect gene expression regulating synaptic function, causing synaptic transmission dysfunction and impaired WAT function. Both DMH-specific knockdown, which suppresses age-associated Ppp1r17 translocation, and the chemogenetic activation of DMH neurons significantly ameliorate age-associated dysfunction in WAT, increase physical activity, and extend lifespan. Thus, these findings clearly demonstrate the importance of the inter-tissue communication between the hypothalamus and WAT in mammalian aging and longevity control.

中文翻译：

DMHPpp1r17神经元通过下丘脑-脂肪组织间通讯调节小鼠的衰老和寿命

最近的研究表明，下丘脑作为哺乳动物衰老的控制中心，通过组织间通讯抵消与年龄相关的生理衰退。我们在下丘脑背内侧 (DMH) 中发现了一个关键的神经元亚群，以 Ppp1r17 表达（DMH 神经元）为标志，可调节小鼠的衰老和寿命。 DMH 神经元通过交感神经刺激调节身体活动和 WAT 功能，包括细胞外烟酰胺磷酸核糖转移酶 (eNAMPT) 的分泌。在 DMH 神经元内，Ppp1r17 的磷酸化和随后的核细胞质易位受 cGMP 依赖性蛋白激酶 G (PKG；) 的调节，影响调节突触功能的基因表达，导致突触传递功能障碍和 WAT 功能受损。 DMH 特异性敲低（抑制与年龄相关的 Ppp1r17 易位）和 DMH 神经元的化学遗传学激活均显着改善与年龄相关的 WAT 功能障碍，增加体力活动并延长寿命。因此，这些发现清楚地证明了下丘脑和 WAT 之间的组织间通讯在哺乳动物衰老和长寿控制中的重要性。

更新日期：2024-01-08

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