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Systemic organ wasting induced by localized expression of the secreted insulin/IGF antagonist ImpL2
Young Kwon1, Wei Song1, Ilia A Droujinine1
1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Organ wasting, related to changes in nutrition and metabolic activity of cells and tissues, is observed under conditions of starvation and in the context of diseases, including cancers. We have developed a model for organ wasting in adult Drosophila, whereby overproliferation induced by activation of Yorkie, the Yap1 oncogene ortholog, in intestinal stem cells leads to wasting of the ovary, fat body, and muscle. These organ-wasting phenotypes are associated with a reduction in systemic insulin/IGF signaling due to increased expression of the secreted insulin/IGF antagonist ImpL2 from the overproliferating gut. Strikingly, expression of rate-limiting glycolytic enzymes and central components of the insulin/IGF pathway is upregulated with activation of Yorkie in the gut, which may provide a mechanism for this overproliferating tissue to evade the effect of ImpL2. Altogether, our study provides insights into the mechanisms underlying organ-wasting phenotypes in Drosophila and how overproliferating tissues adapt to global changes in metabolism.
Insights
Overproliferation in Drosophila gut stem cells causes organ wasting by increasing insulin/IGF antagonist ImpL2. The gut adapts by upregulating glycolysis and insulin/IGF pathway components to evade ImpL2 effects.
Area of Science:
- Cell Biology
- Genetics
- Metabolism
Background:
- Organ wasting is linked to metabolic changes during starvation and diseases like cancer.
- The Yap1 oncogene ortholog, Yorkie, plays a role in cell proliferation.
Purpose of the Study:
- To develop a Drosophila model for studying organ wasting.
- To investigate the mechanisms by which gut overproliferation causes systemic organ wasting.
- To understand how overproliferating tissues adapt to metabolic changes.
Main Methods:
- Induction of Yorkie overproliferation in adult Drosophila intestinal stem cells.
- Analysis of organ wasting phenotypes (ovary, fat body, muscle).
- Measurement of systemic insulin/IGF signaling and ImpL2 expression.
- Assessment of glycolytic enzyme and insulin/IGF pathway component expression in the gut.
Main Results:
- Yorkie activation in gut stem cells induced ovary, fat body, and muscle wasting.
- Organ wasting correlated with increased gut ImpL2 expression, reducing systemic insulin/IGF signaling.
- Overproliferating gut tissues upregulated glycolytic enzymes and insulin/IGF pathway components.
- This upregulation may allow the gut to evade the effects of ImpL2.
Conclusions:
- Drosophila model effectively demonstrates organ wasting driven by gut overproliferation.
- Systemic insulin/IGF signaling reduction is a key mechanism in Yorkie-induced organ wasting.
- Overproliferating gut exhibits adaptive metabolic changes to counteract systemic signals.
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