Nature Communications (Oct 2024)

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

  • Cristiane dos 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,
  • Rafael Arrojo e Drigo

DOI
https://doi.org/10.1038/s41467-024-53127-2
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 22

Abstract

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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.