Mechanical stress regulates insulin sensitivity through integrin-dependent control of insulin receptor localization

Jung Kim, David Bilder, Thomas P. Neufeld

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Insulin resistance, the failure to activate insulin signaling in the presence of ligand, leads to metabolic diseases, including type 2 diabetes. Physical activity and mechanical stress have been shown to protect against insulin resistance, but the molecular mechanisms remain unclear. Here, we address this relationship in the Drosophila larval fat body, an insulin-sensitive organ analogous to vertebrate adipose tissue and livers. We found that insulin signaling in Drosophila fat body cells is abolished in the absence of physical activity and mechanical stress even when excess insulin is present. Physical movement is required for insulin sensitivity in both intact larvae and fat bodies cultured ex vivo. Interestingly, the insulin receptor and other downstream components are recruited to the plasma membrane in response to mechanical stress, and this membrane localization is rapidly lost upon disruption of larval or tissue movement. Sensing of mechanical stimuli is mediated in part by integrins, whose activation is necessary and sufficient for mechanical stress-dependent insulin signaling. Insulin resistance develops naturally during the transition from the active larval stage to the immotile pupal stage, suggesting that regulation of insulin sensitivity by mechanical stress may help coordinate developmental programming with metabolism.

Original languageEnglish (US)
Pages (from-to)156-164
Number of pages9
JournalGenes and Development
Volume32
Issue number2
DOIs
StatePublished - Jan 15 2018

Bibliographical note

Funding Information:
We thank Dr. Lynn Cooley, Dr. Ernst Hafen, Dr. Stefan Luschnig, and Dr. Guy Tanentzapf for generous gifts of flies. We appreciate the helpful discussion provided by Dr. MyungJun Kim and Dr. Hiroshi Nakato. We also thank the Vienna Drosophila RNAi Center, the Bloomington Drosophila Stock Center, and the Developmental Studies Hybridoma bank at the University of Iowa for providing fly stocks and antibodies. This work was supported by National Institutes of Health (NIH) grant R01GM62509 to T.P.N., and NIH grant R01GM111111 to D.B.

Publisher Copyright:
© 2018 Kim et al.

Keywords

  • Drosophila
  • Insulin receptor tracking
  • Insulin sensitivity
  • Integrin signaling
  • Mechanical stress
  • Target of rapamycin (TOR)

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