Control of Region-Specific Intestinal Metabolism and Maintenance by PRDM16

Abstract

Distinct metabolic programs regulate intestinal stem cell renewal and differentiation. However, the mechanisms that rewire metabolism during differentiation are poorly defined. It is also unclear whether progenitors in different intestinal regions utilize specialized metabolic programs. Here, we identify the transcription factor PRDM16 as a critical region-specific regulator of small intestinal metabolism and progenitor differentiation. Acute deletion of Prdm16 in mice causes severe intestinal atrophy, apoptosis, and an accumulation of poorly differentiated cells. Genomic and metabolic studies show that PRDM16 controls the levels of fatty acid oxidation (FAO) within the stem cell niche. Notably, PRDM16 levels and FAO are highest in the upper small intestine and decline distally. Accordingly, deletion of Prdm16 or inhibition of FAO selectively impairs the differentiation of upper-intestinal enteroid cultures. Collectively, these data reveal that PRDM16 specifies a region-specific FAO metabolic switch in intestinal progenitor cells to maintain tissue homeostasis.