PRDM16 Maintains Homeostasis of the Intestinal Epithelium by Controlling Region-Specific Metabolism

• Published in: Cell stem cell Vol. 25; no. 6; pp. 830 - 845.e8
• Main Authors: Stine, Rachel R., Sakers, Alexander P., TeSlaa, Tara, Kissig, Megan, Stine, Zachary E., Kwon, Chan Wook, Cheng, Lan, Lim, Hee-Woong, Kaestner, Klaus H., Rabinowitz, Joshua D., Seale, Patrick
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.12.2019
• Subjects: apoptosis; differentiation; duodenum; fatty acid oxidation; intestinal stem cell; intestine; metabolism; PRDM16; transit amplifying cell; transit amplifying cell; intestine; intestinal stem cell; differentiation; PRDM16; apoptosis; metabolism; fatty acid oxidation; duodenum
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2019.08.017

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. [Display omitted] •PRDM16 regulates small intestinal epithelial renewal via promoting fatty acid oxidation•PRDM16 and FAO levels are highest in the upper small intestine and decline distally•FAO is required for the growth and differentiation of upper intestinal progenitors•Intestinal region-specific metabolic programs regulate epithelial renewal Metabolic program expression and dependency vary along the length of the small intestine. PRDM16 transcriptionally regulates fatty acid oxidation (FAO), which is highest in the upper small intestine. Loss of Prdm16 reduces FAO, leading to apoptosis and diminished epithelial differentiation of progenitor cells in the upper intestine.