Systemic organ wasting induced by localized expression of the secreted insulin/IGF antagonist ImpL2

Young Kwon; Wei Song; Ilia A Droujinine; Yanhui Hu; John M Asara; Norbert Perrimon

doi:10.1016/j.devcel.2015.02.012

Systemic organ wasting induced by localized expression of the secreted insulin/IGF antagonist ImpL2

Dev Cell. 2015 Apr 6;33(1):36-46. doi: 10.1016/j.devcel.2015.02.012.

Authors

Young Kwon¹, Wei Song², Ilia A Droujinine², Yanhui Hu², John M Asara³, Norbert Perrimon⁴

Affiliations

¹ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: ykwon@genetics.med.harvard.edu.
² Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
³ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
⁴ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: perrimon@receptor.med.harvard.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Genetically Modified / genetics
Animals, Genetically Modified / growth & development
Animals, Genetically Modified / metabolism
Biomarkers / metabolism
Blotting, Western
Cells, Cultured
Drosophila Proteins / genetics
Drosophila Proteins / metabolism*
Drosophila melanogaster / genetics
Drosophila melanogaster / growth & development
Drosophila melanogaster / metabolism
Fat Body / cytology
Fat Body / metabolism
Female
Gastrointestinal Tract / cytology
Gastrointestinal Tract / metabolism*
Gene Expression Profiling
Hemolymph / metabolism
Hyperglycemia / metabolism
Hyperglycemia / pathology
Insulin / chemistry*
Insulin / metabolism
Insulin Secretion
Insulin-Like Growth Factor I / antagonists & inhibitors*
Insulin-Like Growth Factor I / metabolism
Male
Metabolomics
Muscle, Skeletal / cytology
Muscle, Skeletal / metabolism
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Oligonucleotide Array Sequence Analysis
Ovary / cytology
Ovary / metabolism
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Stem Cells / cytology
Stem Cells / metabolism*
Trans-Activators / genetics
Trans-Activators / metabolism*
Wasting Syndrome / metabolism*
Wasting Syndrome / pathology
YAP-Signaling Proteins

Substances

Biomarkers
Drosophila Proteins
Insulin
Nuclear Proteins
RNA, Messenger
Trans-Activators
YAP-Signaling Proteins
Yki protein, Drosophila
Insulin-Like Growth Factor I

Associated data

GEO/GSE65325

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding