Insulin resistance in cavefish as an adaptation to a nutrient-limited environment

Misty R. Riddle, Ariel C. Aspiras, Karin Gaudenz, Robert Peuß, Jenny Y. Sung, Brian Martineau, Megan Peavey, Andrew C. Box, Julius A. Tabin, Suzanne McGaugh, Richard Borowsky, Clifford J. Tabin, Nicolas Rohner

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Periodic food shortages are a major challenge faced by organisms in natural habitats. Cave-dwelling animals must withstand long periods of nutrient deprivation, as - in the absence of photosynthesis - caves depend on external energy sources such as seasonal floods. Here we show that cave-adapted populations of the Mexican tetra, Astyanax mexicanus, have dysregulated blood glucose homeostasis and are insulin-resistant compared to river-adapted populations. We found that multiple cave populations carry a mutation in the insulin receptor that leads to decreased insulin binding in vitro and contributes to hyperglycaemia. Hybrid fish from surface-cave crosses carrying this mutation weigh more than non-carriers, and zebrafish genetically engineered to carry the mutation have increased body weight and insulin resistance. Higher body weight may be advantageous in caves as a strategy to cope with an infrequent food supply. In humans, the identical mutation in the insulin receptor leads to a severe form of insulin resistance and reduced lifespan. However, cavefish have a similar lifespan to surface fish and do not accumulate the advanced glycation end-products in the blood that are typically associated with the progression of diabetes-associated pathologies. Our findings suggest that diminished insulin signalling is beneficial in a nutrient-limited environment and that cavefish may have acquired compensatory mechanisms that enable them to circumvent the typical negative effects associated with failure to regulate blood glucose levels.

Original languageEnglish (US)
Pages (from-to)647-651
Number of pages5
JournalNature
Volume555
Issue number7698
DOIs
StatePublished - Mar 29 2018

Bibliographical note

Funding Information:
Acknowledgements We thank Y. Chinchore and C. Sengel for technical advice; X. Gao for bioinformatics support; Z. Zakibe for photographs of the fish; the Aquatics facility at Stowers for fish maintenance and support; the cell culture core at Stowers for cell line maintenance and advice; the molecular biology core at Stowers for design, execution and validation of the CRISPR constructs; the proteomics core; M. Levy for advice and computational modelling of the insulin receptor; A. Herman for help with the genome scan; the Microscopy Resources on the North Quad (MicRoN) core at Harvard Medical School; M. Miller for illustration; and S. Williams, F. Damen, S. Xiong, E. Kingsley and K. Fox for feedback on the manuscript text. This work was supported by a grant from the NIH to C.J.T. (HD089934) and institutional funding to N.R. M.R.R. was supported by a National Research Service Award (DK108495) and R.P. was supported by a grant from the Deutsche Forschungsgemeinschaft (PE 2807/1-1).

Publisher Copyright:
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

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