Circadian clock controls rhythms in ketogenesis by interfering with PPARα transcriptional network.
Circadian clock controls rhythms in ketogenesis by interfering with PPARα transcriptional network.
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DOI：
10.1073/pnas.2205755119
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发表时间：
2022-10-04
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
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酮体是能量代谢和信号传导的中间体，由于其在健康和疾病中的作用而引起了人们的极大关注。我们对不同饮食的小鼠进行了一项关于酮体和生酮的全天候研究。我们发现，热量限制（一种改善代谢和长寿的饮食干预）诱导血液β-羟基丁酸（βOHB）的高振幅每日节律。血液βOHB节律是由昼夜节律钟和过氧化物酶体增殖物激活受体α转录网络之间的相互作用控制的肝脏中节律性酮生成引起的。这种相互作用导致β-氧化和生酮酶的转录重编程。我们发现，生物钟突变小鼠的重编程受损。生物钟门控的生酮有助于饮食对健康和长寿的影响。酮体是一种富含能量的代谢产物和信号分子，其产生主要受饮食调节。热量限制（CR）是一种饮食干预，可以改善新陈代谢并延长寿命。我们发现，CR诱导血液酮体（β-羟基丁酸[βOHB]）的高振幅每日节律，与肝脏βOHB水平相关。另一种基于周期性禁食的饮食，限时喂养也会导致节律性βOHB，但幅度降低。CR诱导了肝脏中脂肪酸氧化和生酮基因表达的强昼夜节律。转录因子过氧化物酶体增殖物激活受体α（peroxisome-proliferator-activated-receptor α，PPARα）及其转录靶因子肝细胞因子成纤维细胞生长因子21（hepatokine fibroblast growth factor 21，FGF 21）是生酮的主要调节因子。Fgf 21表达和PPARα转录网络在CR肝脏中变得高度节律性，这暗示了昼夜节律钟的参与。生物钟蛋白CLOCK、BMAL 1和隐花色素（cryptochromes，BMAL 1）在机制上干扰了PPARα的转录活性。在昼夜节律钟缺陷的Cry 1，2−/−小鼠中，血液βOHB水平和PPARα靶基因表达的日节律显著受损。这些数据表明，血液βOHB水平受到严格控制，昼夜节律钟是饮食诱导的生酮作用的调节因子。
Ketone bodies, intermediates in energy metabolism and signaling, have attracted significant attention due to their role in health and disease. We performed an around-the-clock study on ketone bodies and ketogenesis with mice on different diets. We found that caloric restriction, a dietary intervention that improves metabolism and longevity, induced high-amplitude daily rhythms in blood β-hydroxybutyrate (βOHB). The blood βOHB rhythms resulted from rhythmic ketogenesis in the liver controlled by the interaction between the circadian clock and peroxisome-proliferator-activated-receptor α transcriptional networks. This interaction resulted in transcriptional reprogramming of beta-oxidation and ketogenesis enzymes. We found that the reprogramming is impaired in circadian clock–mutant mice. The circadian clock–gated ketogenesis contributes to the diet impact on health and longevity. Ketone bodies are energy-rich metabolites and signaling molecules whose production is mainly regulated by diet. Caloric restriction (CR) is a dietary intervention that improves metabolism and extends longevity across the taxa. We found that CR induced high-amplitude daily rhythms in blood ketone bodies (beta-hydroxybutyrate [βOHB]) that correlated with liver βOHB level. Time-restricted feeding, another periodic fasting–based diet, also led to rhythmic βOHB but with reduced amplitude. CR induced strong circadian rhythms in the expression of fatty acid oxidation and ketogenesis genes in the liver. The transcriptional factor peroxisome-proliferator-activated-receptor α (PPARα) and its transcriptional target hepatokine fibroblast growth factor 21 (FGF21) are primary regulators of ketogenesis. Fgf21 expression and the PPARα transcriptional network became highly rhythmic in the CR liver, which implicated the involvement of the circadian clock. Mechanistically, the circadian clock proteins CLOCK, BMAL1, and cryptochromes (CRYs) interfered with PPARα transcriptional activity. Daily rhythms in the blood βOHB level and in the expression of PPARα target genes were significantly impaired in circadian clock–deficient Cry1,2−/− mice. These data suggest that blood βOHB level is tightly controlled and that the circadian clock is a regulator of diet-induced ketogenesis.
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昼夜节律对衰老和寿命的重要性。
影响因子：
16.6
作者：
Acosta-Rodríguez VA;Rijo-Ferreira F;Green CB;Takahashi JS
通讯作者：
Takahashi JS
影响因子：
15.9
作者：
Djouadi, F;Weinheimer, CJ;Kelly, DP
通讯作者：
Kelly, DP
影响因子：
6.3
作者：
Courchesne-Loyer, Alexandre;Croteau, Etienne;Cunnane, Stephen C.
通讯作者：
Cunnane, Stephen C.
昼夜节律的代谢和能量学的融合。
DOI：
10.1126/science.1195027
发表时间：
2010-12-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bass J;Takahashi JS
通讯作者：
Takahashi JS
影响因子：
29
作者：
Badman, Michael K.;Pissios, Pavlos;Maratos-Flier, Eleftheria
通讯作者：
Maratos-Flier, Eleftheria