Bartok Osnat, Teesalu Mari, Ashwall-Fluss Reut, Pandey Varun, Hanan Mor, Rovenko Bohdana M, Poukkula Minna, Havula Essi, Moussaieff Arieh, Vodala Sadanand, Nahmias Yaakov, Kadener Sebastian, Hietakangas Ville
Biological Chemistry Department, Silberman Institute of Life Sciences The Hebrew University of Jerusalem, Jerusalem, Israel.
Department of Biosciences, University of Helsinki, Helsinki, Finland Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
EMBO J. 2015 Jun 3;34(11):1538-53. doi: 10.15252/embj.201591385. Epub 2015 Apr 27.
Nutrient sensing pathways adjust metabolism and physiological functions in response to food intake. For example, sugar feeding promotes lipogenesis by activating glycolytic and lipogenic genes through the Mondo/ChREBP-Mlx transcription factor complex. Concomitantly, other metabolic routes are inhibited, but the mechanisms of transcriptional repression upon sugar sensing have remained elusive. Here, we characterize cabut (cbt), a transcription factor responsible for the repressive branch of the sugar sensing transcriptional network in Drosophila. We demonstrate that cbt is rapidly induced upon sugar feeding through direct regulation by Mondo-Mlx. We found that CBT represses several metabolic targets in response to sugar feeding, including both isoforms of phosphoenolpyruvate carboxykinase (pepck). Deregulation of pepck1 (CG17725) in mlx mutants underlies imbalance of glycerol and glucose metabolism as well as developmental lethality. Furthermore, we demonstrate that cbt provides a regulatory link between nutrient sensing and the circadian clock. Specifically, we show that a subset of genes regulated by the circadian clock are also targets of CBT. Moreover, perturbation of CBT levels leads to deregulation of the circadian transcriptome and circadian behavioral patterns.
营养感应通路会根据食物摄入情况调整新陈代谢和生理功能。例如，摄入糖分通过Mondo/ChREBP-Mlx转录因子复合体激活糖酵解和脂肪生成基因，从而促进脂肪生成。与此同时，其他代谢途径会受到抑制，但糖分感应时转录抑制的机制仍不清楚。在这里，我们鉴定了cabut（cbt），它是果蝇中负责糖分感应转录网络抑制分支的转录因子。我们证明，通过Mondo-Mlx的直接调控，cbt在摄入糖分后会迅速被诱导。我们发现，CBT会响应糖分摄入抑制几个代谢靶点，包括磷酸烯醇式丙酮酸羧激酶（pepck）的两种同工型。mlx突变体中pepck1（CG17725）的失调是甘油和葡萄糖代谢失衡以及发育致死的原因。此外，我们证明cbt在营养感应和生物钟之间提供了一个调控联系。具体来说，我们表明生物钟调控的一部分基因也是CBT的靶点。此外，CBT水平的扰动会导致生物钟转录组和生物钟行为模式失调。
