Korenfeld Noga, Charni-Natan Meital, Bruse Justine, Goldberg Dana, Marciano-Anaki Dorin, Rotaro Dan, Gorbonos Tali, Radushkevitz-Frishman Talia, Polizzi Arnaud, Nasereddin Abed, Gover Ofer, Bar-Shimon Meirav, Fougerat Anne, Guillou Hervé, Goldstein Ido
Institute of Biochemistry, Food Science and Nutrition. The Robert H. Smith Faculty of Agriculture, Food and Environment. The Hebrew University of Jerusalem. 229 Herzl Street, Rehovot 7610001, Israel.
Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP- PURPAN, UMR 1331, UPS, Université de Toulouse, 180 Chemin de Tournefeuille, 31027 Toulouse, France.
Nucleic Acids Res. 2025 Jan 7;53(1). doi: 10.1093/nar/gkae1161.
Mammals withstand frequent and prolonged fasting periods due to hepatic production of glucose and ketone bodies. Because the fasting response is transcriptionally regulated, we asked whether enhancer dynamics impose a transcriptional program during recurrent fasting and whether this generates effects distinct from a single fasting bout. We found that mice undergoing alternate-day fasting (ADF) respond profoundly differently to a following fasting bout compared to mice first experiencing fasting. Hundreds of genes enabling ketogenesis are 'sensitized' (i.e. induced more strongly by fasting following ADF). Liver enhancers regulating these genes are also sensitized and harbor increased binding of PPARα, the main ketogenic transcription factor. ADF leads to augmented ketogenesis compared to a single fasting bout in wild-type, but not hepatocyte-specific PPARα-deficient mice. Thus, we found that past fasting events are 'remembered' in hepatocytes, sensitizing their enhancers to the next fasting bout and augment ketogenesis. Our findings shed light on transcriptional regulation mediating adaptation to repeated signals.
由于肝脏能够产生葡萄糖和酮体，哺乳动物能够耐受频繁且持续时间较长的禁食期。因为禁食反应受转录调控，所以我们探究增强子动态变化在反复禁食过程中是否会施加一个转录程序，以及这是否会产生与单次禁食发作不同的效应。我们发现，与首次经历禁食的小鼠相比，隔日禁食（ADF）的小鼠对随后的禁食发作反应截然不同。数百个促进生酮作用的基因被“致敏”（即，在ADF后的禁食中诱导作用更强）。调控这些基因的肝脏增强子也被致敏，并且主要生酮转录因子PPARα的结合增加。与单次禁食发作相比，ADF在野生型小鼠中会导致生酮作用增强，但在肝细胞特异性PPARα缺陷小鼠中则不会。因此，我们发现肝细胞会“记住”过去的禁食事件，使其增强子对下一次禁食发作敏感，并增强生酮作用。我们的研究结果揭示了介导对重复信号适应的转录调控机制。
