Stem Cell Intrinsic Hexosamine Metabolism Regulates Intestinal Adaptation to Nutrient Content

Abstract

SummaryThe intestine is an organ with an exceptionally high rate of cell turnover, and perturbations in this process can lead to severe diseases such as cancer or intestinal atrophy. Nutrition has a profound impact on intestinal volume and cellular architecture. However, how intestinal homeostasis is maintained in fluctuating dietary conditions remains insufficiently understood. By utilizing the Drosophila midgut model, we reveal a novel stem cell intrinsic mechanism coupling cellular metabolism with stem cell extrinsic growth signal. Our results show that intestinal stem cells (ISCs) employ the hexosamine biosynthesis pathway (HBP) to monitor nutritional status. Elevated activity of HBP promotes Warburg effect-like metabolic reprogramming required for adjusting the ISC division rate according to nutrient content. Furthermore, HBP activity is an essential facilitator for insulin signaling-induced ISC proliferation. In conclusion, ISC intrinsic hexosamine synthesis regulates metabolic pathway activities and defines the stem cell responsiveness to niche-derived growth signals.

Axin proteolysis by Iduna is required for the regulation of stem cell proliferation and intestinal homeostasis in Drosophila

“…To exclude the possibility that Iduna mutant flies raised on regular diet had reduced nutrient uptake, we monitored fly feeding by an Acid Blue 9 colorimetric assay (Mattila et al, 2018). We noticed no decrease in food intake in Iduna mutants kept on regular diet at 24-25°C compared with controls ( Fig.…”

For Intestinal Homeostasis, You Are What You Eat

“…Finally, the authors show that dietary GlcNAc, or gfat2 expression, is sufficient to rescue the reduced clone size seen under conditions of reduced insulin signaling. Taken together, these findings from Mattila et al (2018) lead to the model that the HBP is required in ISCs for a metabolic switch toward glycolytic metabolism to support the biosynthetic pathways needed for intestinal growth in response to nutrient signaling. The mechanisms by which the HBP promotes glycolytic metabolism, however, remain unclear.…”

“…In contrast to the effects of dietary carbohydrates reported by Mattila et al (2018), Obniski et al (2018) focus on the role of lipids on cell fate specification in the ISC lineage. They show that young adults raised on a lipid-depleted diet have reduced numbers of the differentiated secretory cell type in the fly intestine, enteroendocrine cells (EEs).…”

“…Similarly, S-adenosyl methionine, derived from dietary methionine, can promote intestinal stem cell (ISC) proliferation and maintain intestinal homeostasis (Obata et al, 2018). In this issue of Developmental Cell, Mattila et al (2018) and Obniski et al (2018) provide important new insights into the mechanisms by which dietary nutrients can affect intestinal cellular responses in Drosophila .…”

“…Mattila et al (2018) start with the remarkable observation that dietary N-acetyl-D-glucosamine (GlcNAc), an intermediate metabolite of the hexosamine biosynthesis pathway (HBP), is sufficient to reverse the intestinal growth defects normally seen under nutrient-deprived conditions. To understand the mechanisms by which dietary GlcNAc has these effects, the authors perform clonal analysis using mutants for gfat2, which encodes a rate-limiting enzyme in the HBP pathway.…”