Snail family transcription factors are expressed in various stem cell types, but their function in maintaining stem cell identity is unclear. In the adult Drosophila midgut, the Snail homolog Esg is expressed in intestinal stem cells (ISCs) and their transient undifferentiated daughters, termed enteroblasts (EB). We demonstrate here that loss of esg in these progenitor cells causes their rapid differentiation into enterocytes (EC) or entero-endocrine cells (EE). Conversely, forced expression of Esg in intestinal progenitor cells blocks differentiation, locking ISCs in a stem cell state. Cell type-specific transcriptome analysis combined with Dam-ID binding studies identified Esg as a major repressor of differentiation genes in stem and progenitor cells. One critical target of Esg was found to be the POU-domain transcription factor, Pdm1, which is normally expressed specifically in differentiated ECs. Ectopic expression of Pdm1 in progenitor cells was sufficient to drive their differentiation into ECs. Hence, Esg is a critical stem cell determinant that maintains stemness by repressing differentiation-promoting factors, such as Pdm1.

ObjectiveDietary protein dilution (PD) has been associated with metabolic advantages such as improved glucose homeostasis and increased energy expenditure. This phenotype involves liver-induced release of FGF21 in response to amino acid insufficiency; however, it has remained unclear whether dietary dilution of specific amino acids (AAs) is also required. Circulating branched chain amino acids (BCAAs) are sensitive to protein intake, elevated in the serum of obese humans and mice and thought to promote insulin resistance. We tested whether replenishment of dietary BCAAs to an AA-diluted (AAD) diet is sufficient to reverse the glucoregulatory benefits of dietary PD.MethodsWe conducted AA profiling of serum from healthy humans and lean and high fat-fed or New Zealand obese (NZO) mice following dietary PD. We fed wildtype and NZO mice one of three amino acid defined diets: control, total AAD, or the same diet with complete levels of BCAAs (AAD + BCAA). We quantified serum AAs and characterized mice in terms of metabolic efficiency, body composition, glucose homeostasis, serum FGF21, and tissue markers of the integrated stress response (ISR) and mTORC1 signaling.ResultsSerum BCAAs, while elevated in serum from hyperphagic NZO, were consistently reduced by dietary PD in humans and murine models. Repletion of dietary BCAAs modestly attenuated insulin sensitivity and metabolic efficiency in wildtype mice but did not restore hyperglycemia in NZO mice. While hepatic markers of the ISR such as P-eIF2α and FGF21 were unabated by dietary BCAA repletion, hepatic and peripheral mTORC1 signaling were fully or partially restored, independent of changes in circulating glucose or insulin.ConclusionsRepletion of BCAAs in dietary PD is sufficient to oppose changes in somatic mTORC1 signaling but does not reverse the hepatic ISR nor induce insulin resistance in type 2 diabetes during dietary PD.