Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice

Cristiane Santos, Amanda Cambraia, Shristi Shrestha, Melanie Cutler, Matthew Cottam, Guy Perkins, Varda Lev-Ram, Birbickram Roy, Christopher Acree, Keun-Young Kim, Thomas Deerinck, Danielle Dean, Jean Philippe Cartailler, Patrick E. MacDonald, Martin Hetzer, Mark Ellisman and Rafael Arrojo e Drigo ()
Additional contact information
Cristiane Santos: Nashville
Amanda Cambraia: Nashville
Shristi Shrestha: Nashville
Melanie Cutler: Nashville
Matthew Cottam: Nashville
Guy Perkins: University of California San Diego
Varda Lev-Ram: University of California San Diego
Birbickram Roy: University of Alberta
Christopher Acree: Nashville
Keun-Young Kim: University of California San Diego
Thomas Deerinck: University of California San Diego
Danielle Dean: Nashville
Jean Philippe Cartailler: Nashville
Patrick E. MacDonald: University of Alberta
Martin Hetzer: Institute of Science and Technology Austria (ISTA)
Mark Ellisman: University of California San Diego
Rafael Arrojo e Drigo: Nashville

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract Caloric restriction (CR) can extend the organism life- and health-span by improving glucose homeostasis. How CR affects the structure-function of pancreatic beta cells remains unknown. We used single nucleus transcriptomics to show that CR increases the expression of genes for beta cell identity, protein processing, and organelle homeostasis. Gene regulatory network analysis reveal that CR activates transcription factors important for beta cell identity and homeostasis, while imaging metabolomics demonstrates that beta cells upon CR are more energetically competent. In fact, high-resolution microscopy show that CR reduces beta cell mitophagy to increase mitochondria mass and the potential for ATP generation. However, CR beta cells have impaired adaptive proliferation in response to high fat diet feeding. Finally, we show that long-term CR delays the onset of beta cell aging hallmarks and promotes cell longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cell structure-function during aging and diabetes.

Date: 2024
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DOI: 10.1038/s41467-024-53127-2

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