Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the Akita mouse
- The Hadassah-Hebrew University Medical Center, Israel
- The Hebrew University-Hadassah Medical School, Israel
- Miller School of Medicine, University of Miami, United States
Abstract
Unresolved ER stress followed by cell death is recognized as the main cause of a multitude of pathologies including neonatal diabetes. A systematic analysis of the mechanisms of β-cell loss and dysfunction in Akita mice, in which a mutation in the proinsulin gene causes a severe form of permanent neonatal diabetes, showed no increase in β-cell apoptosis throughout life. Surprisingly, we found that the main mechanism leading to β-cell dysfunction is marked impairment of β-cell growth during the early postnatal life due to transient inhibition of mTORC1, which governs postnatal β-cell growth and differentiation. Importantly, restoration of mTORC1 activity in neonate β-cells was sufficient to rescue postnatal β-cell growth, and to improve diabetes. We propose a scenario for the development of permanent neonatal diabetes, possibly also common forms of diabetes, where early-life events inducing ER stress affect β-cell mass expansion due to mTOR inhibition.
Data availability
The RNA-seq data is available through NCBI. The accession number is: GSE114927
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RNAseq analysis of whole islets from pre-weaning wild type and Akita miceGene Expression Omnibus, GSE114927.
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RNA profiling of P16ink4a-expressing pancreatic beta-cellsGene Expression Omnibus, GSE76992.
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Identification of Nkx6.1 regulated genes in mature pancreatic isletsGene Expression Omnibus, GSE40470.
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Chromatin immunoprecipitation of mouse MIN6 pancreatic beta cells to identify Pdx1 targetsArrayExpress Archive of Functional Genomics Data, E-MTAB-134.
Article and author information
Author details
Funding
Israel Science Foundation (ISF-347/12)
- Gil Leibowitz
Israel Science Foundation (ISF-1563/14)
- Gil Leibowitz
Israel Science Foundation (2323/17)
- Gil Leibowitz
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the Hebrew University. All of the animals were handled according to approved institutional animal care and use committee of the Hebrew University. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Hebrew University (Permit Number: MD-17-15065-4). Every effort was made to minimize animal suffering.
Copyright
© 2018, Riahi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the Akita mouse
eLife 7:e38472.
https://doi.org/10.7554/eLife.38472
Further reading
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- Stem Cells and Regenerative Medicine
Exploring how proliferation and maturation of beta-cells can be impaired after birth will shed light on the origins of various forms of diabetes.
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- Cell Biology
Dietary protein absorption in neonatal mammals and fishes relies on the function of a specialized and conserved population of highly absorptive lysosome-rich enterocytes (LREs). The gut microbiome has been shown to enhance absorption of nutrients, such as lipids, by intestinal epithelial cells. However, whether protein absorption is also affected by the gut microbiome is poorly understood. Here, we investigate connections between protein absorption and microbes in the zebrafish gut. Using live microscopy-based quantitative assays, we find that microbes slow the pace of protein uptake and degradation in LREs. While microbes do not affect the number of absorbing LRE cells, microbes lower the expression of endocytic and protein digestion machinery in LREs. Using transgene-assisted cell isolation and single cell RNA-sequencing, we characterize all intestinal cells that take up dietary protein. We find that microbes affect expression of bacteria-sensing and metabolic pathways in LREs, and that some secretory cell types also take up protein and share components of protein uptake and digestion machinery with LREs. Using custom-formulated diets, we investigated the influence of diet and LRE activity on the gut microbiome. Impaired protein uptake activity in LREs, along with a protein-deficient diet, alters the microbial community and leads to an increased abundance of bacterial genera that have the capacity to reduce protein uptake in LREs. Together, these results reveal that diet-dependent reciprocal interactions between LREs and the gut microbiome regulate protein absorption.
