Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure.
Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure.
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DOI：
10.1016/j.cmet.2022.03.005
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发表时间：
2022-04-05
期刊：
影响因子：
29
通讯作者：
Morita, Masahiro
中科院分区：
文献类型：
--
作者：
Katsumura, Sakie;Siddiqui, Nadeem;Goldsmith, Michael Rock;Cheah, Jaime H.;Fujikawa, Teppei;Minegishi, Genki;Yamagata, Atsushi;Yabuki, Yukako;Kobayashi, Kaoru;Shirouzu, Mikako;Inagaki, Takeshi;Huang, Tim H. -M.;Musi, Nicolas;Topisirovic, Ivan;Larsson, Ola;Morita, Masahiro
肝细胞因子是肝脏分泌的蛋白质，介导器官间的通讯，以维持食物摄入和能量消耗之间的代谢平衡。然而，肝细胞因子水平在刺激后迅速调节的分子机制在很大程度上是未知的。在这里，我们揭示了hocT6L去腺苷酶在对刺激做出反应后关闭了肝细胞因子的表达（例如，运动和食物）来协调能量摄入和消耗。从机制上讲，hocT6L抑制稳定了肝脏Gdf15和Fgf21 mRNA，增加了相应的血清蛋白水平。GDF15的上调刺激后脑抑制食欲，而增加的FGF21影响肝脏和脂肪组织诱导能量消耗和脂质消耗。尽管肝细胞因子治疗代谢紊乱的潜力，但它们的给药疗法一直具有挑战性。通过小分子筛选，我们发现了一种可增强GDF 15和FGF 21肝因子水平的α T6 L抑制剂，从而显着改善饮食诱导的代谢综合征。因此，我们的发现为治疗代谢综合征的前所未有的策略奠定了基础。Katsumura等人证明，在多重刺激后，介导器官间通讯的GDF 15和FGF 21肝细胞因子的表达被肝hocT6L去腺苷酶关闭。小鼠肝脏hocT6L抑制通过脑和外周组织调节食物摄入和能量消耗，从而改善饮食诱导的肥胖和代谢紊乱。
Hepatokines, secretory proteins from the liver, mediate inter-organ communication to maintain a metabolic balance between food intake and energy expenditure. However, molecular mechanisms by which hepatokine levels are rapidly adjusted following stimuli are largely unknown. Here, we unravel CNOT6L deadenylase switches off hepatokine expression after responding to the stimuli (e.g., exercise and food) to orchestrate energy intake and expenditure. Mechanistically, CNOT6L inhibition stabilizes hepatic Gdf15 and Fgf21 mRNAs, increasing corresponding serum protein levels. The resulting up-regulation of GDF15 stimulates the hindbrain to suppress appetite, while increased FGF21 affects the liver and adipose tissues to induce energy expenditure and lipid consumption. Despite the potential of hepatokines to treat metabolic disorders, their administration therapies have been challenging. Using small-molecule screening, we identified a CNOT6L inhibitor enhancing GDF15 and FGF21 hepatokine levels, which dramatically improves diet-induced metabolic syndrome. Our discovery, therefore, lays the foundation for an unprecedented strategy to treat metabolic syndrome. Katsumura et al. demonstrate that expression of GDF15 and FGF21 hepatokines that mediate inter-organ communication is switched off by hepatic CNOT6L deadenylase following multiple stimuli. Hepatic CNOT6L inhibition in mice modulates food intake and energy expenditure through the brain and peripheral tissues, thereby ameliorating diet-induced obesity and metabolic disorders.
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