Insulin Signaling in Intestinal Stem and Progenitor Cells as an Important Determinant of Physiological and Metabolic Traits in Drosophila

Abstract

The insulin–IGF-1 signaling (IIS) pathway is conserved throughout multicellular organisms and regulates many traits, including aging, reproduction, feeding, metabolism, stress resistance, and growth. Here, we present evidence of a survival-sustaining role for IIS in a subset of gut cells in Drosophila melanogaster, namely the intestinal stem cells (ISCs) and progenitor cells. Using RNAi to knockdown the insulin receptor, we found that inhibition of IIS in ISCs statistically shortened the lifespan of experimental flies compared with non-knockdown controls, and also shortened their survival under starvation or malnutrition conditions. These flies also showed decreased reproduction and feeding, and had lower amounts of glycogen and glucose in the body. In addition, increased expression was observed for the Drosophila transcripts for the insulin-like peptides dilp2, dilp5, and dilp6. This may reflect increased insulin signaling in peripheral tissues supported by up-regulation of the target of the brain insulin gene (tobi). In contrast, activation of IIS (via knockdown of the insulin pathway inhibitor PTEN) in intestinal stem and progenitor cells decreased fly resistance to malnutrition, potentially by affecting adipokinetic hormone signaling. Finally, Pten knockdown to enhance IIS also activated JAK–STAT signaling in gut tissue by up-regulation of upd2, upd3, and soc36 genes, as well as genes encoding the EGF receptor ligands spitz and vein. These results clearly demonstrate that manipulating insulin levels may be used to modulate various fly traits, which are important determinants of organismal survival.

Insulin-Like Peptides and Cross-Talk With Other Factors in the Regulation of Insect Metabolism

“… Semaniuk et al (2021a) showed that D. melanogaster flies with knockout of different dilps ingested larger amount of carbohydrates. On the other hand, it was demonstrated that in D. melanogaster with the knockdown of insulin receptor in the progenitor and stem cells of the gut, the feeding activity was lowered as well as the glycogen and glucose content in the body ( Strilbytska et al, 2020 ). Recent studies showed that also during starvation, blocking ILP signalling led to reduced feeding, whereas overexpression of ILP genes enhanced this process ( Sudhakar et al, 2020 ).…”

Multiscale analysis reveals that diet-dependent midgut plasticity emerges from alterations in both stem cell niche coupling and enterocyte size

“…However, despite the loss of proliferative cells, these flies were still able to grow their midgut upon switching from HS to HY diets (Figure 6E). In addition to the EGFR pathway, insulin/IGF-like signaling is a master regulator of ISC proliferation, notably in response to diet (Amcheslavsky et al, 2009;Biteau et al, 2010;Choi et al, 2011;O'Brien et al, 2011;Strilbytska et al, 2020;Veenstra et al, 2008). We therefore repressed the insulin pathway by overexpressing a dominant-negative insulin receptor in progenitor cells (esg TS >InR-DN).…”

Drosophila insulin‐like peptides: from expression to functions – a review

“…Overexpression of IIS antagonists (dFOXO and PTEN) in the nervous system and fat body also extended lifespan (Giannakou et al, 2004; Hwangbo et al, 2004; Wessells et al, 2004). However, it was recently discovered that InR knockdown in Drosophila midgut stem cells, which leads to increased expression of dilp2 and dilp5 , caused rapid fly mortality (Strilbytska et al, 2020). Partial depletion of neurosecretory cells, expressing DILP2, DILP3, and DILP5, at both larval (Broughton et al, 2005) and adult stages (Haselton & Fridell, 2010), reduced IIS activity and prolonged lifespan.…”