Raptor levels are critical for β-cell adaptation to a high-fat diet in male mice

• Published in: Molecular metabolism (Germany) Vol. 75; p. 101769
• Main Authors: Blandino-Rosano, Manuel, Louzada, Ruy Andrade, Werneck-De-Castro, Joao Pedro, Lubaczeuski, Camila, Almaça, Joana, Rüegg, Markus A., Hall, Michael N., Leibowitz, Gil, Bernal-Mizrachi, Ernesto
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.09.2023; Elsevier
• Subjects: Animals; Beta-cell; Diet, High-Fat - adverse effects; FOXA2; High-fat diet; Insulin - metabolism; Insulin Resistance; Insulin-Secreting Cells - metabolism; Islet; Male; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mice; Original; PDX1; Raptor; PDX1; Beta-cell; Islet; High-fat diet; Raptor; FOXA2
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2023.101769

The essential role of raptor/mTORC1 signaling in β-cell survival and insulin processing has been recently demonstrated using raptor knock-out models. Our aim was to evaluate the role of mTORC1 function in adaptation of β-cells to insulin resistant state. Here, we use mice with heterozygous deletion of raptor in β-cells (βraHet) to assess whether reduced mTORC1 function is critical for β-cell function in normal conditions or during β-cell adaptation to high-fat diet (HFD). Deletion of a raptor allele in β-cells showed no differences at the metabolic level, islets morphology, or β-cell function in mice fed regular chow. Surprisingly, deletion of only one allele of raptor increases apoptosis without altering proliferation rate and is sufficient to impair insulin secretion when fed a HFD. This is accompanied by reduced levels of critical β-cell genes like Ins1, MafA, Ucn3, Glut2, Glp1r, and specially PDX1 suggesting an improper β-cell adaptation to HFD. This study identifies that raptor levels play a key role in maintaining PDX1 levels and β-cell function during the adaptation of β-cell to HFD. Finally, we identified that Raptor levels regulate PDX1 levels and β-cell function during β-cell adaptation to HFD by reduction of the mTORC1-mediated negative feedback and activation of the AKT/FOXA2/PDX1 axis. We suggest that Raptor levels are critical to maintaining PDX1 levels and β-cell function in conditions of insulin resistance in male mice. •The mTOR signaling pathway is deregulated in human diseases such as cancer and diabetes.•The role of partial mTORC1 reduction in β-cells during β-cell adaptation to insulin resistance remains unanswered.•Heterozygous raptor deletion in β-cells impaired HFD adaptation by reducing critical β-cell gene expression.•Raptor levels are critical for maintenance of PDX1 levels and β-cell function.•AKT/FOXA2/PDX1 axis plays a role in β-cell adaptation to HFD.