Metabolic pathways dynamically regulate tissue development and maintenance. However, the mechanisms that govern the metabolic adaptation of stem or progenitor cells to their local niche are poorly understood. Here, we define the transcription factor PRDM16 as a region-specific regulator of intestinal metabolism and epithelial renewal. PRDM16 is selectively expressed in the upper intestine, with enrichment in crypt-resident progenitor cells. Acute Prdm16 deletion in mice triggered progenitor apoptosis, leading to diminished epithelial differentiation and severe intestinal atrophy. Genomic and metabolic analyses showed that PRDM16 transcriptionally controls fatty acid oxidation (FAO) in crypts. Expression of this PRDM16-driven FAO program was highest in the upper small intestine and declined distally. Accordingly, deletion of Prdm16 or inhibition of FAO selectively impaired the development and maintenance of upper intestinal enteroids, and these effects were rescued by acetate treatment. Collectively, these data reveal that regionally specified metabolic programs regulate intestinal maintenance.

中文翻译：

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PRDM16通过控制区域特定的代谢来维持肠道上皮的稳态。

代谢途径动态调节组织的发育和维持。然而，控制干细胞或祖细胞对其局部生态位的代谢适应的机制了解甚少。在这里，我们将转录因子PRDM16定义为肠道代谢和上皮更新的区域特定调节剂。PRDM16在上消化道中选择性表达，并在隐窝祖细胞中富集。小鼠中急性Prdm16缺失引发祖细胞凋亡，导致上皮分化减少和严重的肠萎缩。基因组和代谢分析表明PRDM16转录控制隐窝中的脂肪酸氧化（FAO）。由PRDM16驱动的FAO计划的表达在上部小肠中最高，而在远端则下降。因此，Prdm16的缺失或对FAO的抑制选择性地损害了上消化道小肠的形成和维持，这些作用通过醋酸盐疗法得以挽救。总体而言，这些数据表明，区域指定的代谢程序可调节肠道维持。