Raptor levels are critical for 13-cell adaptation to a high-fat diet in male mice

Objective: The essential role of raptor/mTORC1 signaling in 13-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 13-cells to insulin resistant state.Method: Here, we use mice with heterozygous deletion of raptor in 13-cells (braHet) to assess whether reduced mTORC1 function is critical for 13cell function in normal conditions or during 13-cell adaptation to high-fat diet (HFD).Results: Deletion of a raptor allele in 13-cells showed no differences at the metabolic level, islets morphology, or 13-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 13-cell genes like Ins1, MafA, Ucn3, Glut2, Glp1r, and specially PDX1 suggesting an improper 13-cell adaptation to HFD.Conclusion: This study identifies that raptor levels play a key role in maintaining PDX1 levels and 13-cell function during the adaptation of 13-cell to HFD. Finally, we identified that Raptor levels regulate PDX1 levels and 13-cell function during 13-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 13-cell function in conditions of insulin resistance in male mice. & COPY; 2023 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).