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

• Published in: Nature communications 2024-10, Vol.15 (1), p.9063-22, Article 9063
• Main Authors: dos Santos, Cristiane, Cambraia, Amanda, Shrestha, Shristi, Cutler, Melanie, Cottam, Matthew, Perkins, Guy, Lev-Ram, Varda, Roy, Birbickram, Acree, Christopher, Kim, Keun-Young, Deerinck, Thomas, Dean, Danielle, Cartailler, Jean Philippe, MacDonald, Patrick E., Hetzer, Martin, Ellisman, Mark, Arrojo e Drigo, Rafael
• Format: Article
• Language: English
• Subjects: 101/58; 13/51; 14; 14/19; 14/28; 14/32; 14/63; 45; 45/91; 631/443/319/1557; 631/443/7; 631/80/2373/2238; Aging; Animals; Beta cells; Caloric Restriction; Cell Proliferation; Diabetes mellitus; Diet, High-Fat - adverse effects; Dietary restrictions; Energy metabolism; Gene Regulatory Networks; High fat diet; Homeostasis; Humanities and Social Sciences; Image resolution; Insulin; Insulin - metabolism; Insulin Resistance; Insulin-Secreting Cells - metabolism; Longevity; Longevity - physiology; Male; Metabolomics; Mice; Mice, Inbred C57BL; Mitochondria - metabolism; Mitophagy; multidisciplinary; Network analysis; Nutrient deficiency; Protein structure; Science; Science (multidisciplinary); Structure-function relationships; Transcription factors; Transcriptomics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-53127-2

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. Caloric restriction (CR) can extend the organism life- and health-span. Here, the authors show that mild caloric restriction enhances insulin sensititivy to promote beta cell health and longevity, through an optimization of energy metabolism and homeostasis pathways.