Islet single-cell transcriptomic profiling during obesity-induced beta cell expansion in female mice

Targeting beta cell proliferation is an appealing approach to restore glucose control in type 1 diabetes. However, the underlying mechanisms of beta cell proliferation remain incompletely understood, limiting identification of new therapeutic targets. Obesity is a naturally occurring process that potently induces human and rodent beta cell replication, representing an ideal model to study mechanisms of beta cell proliferation. We showed previously acute whole-body Lepr gene deletion in adult mice induces obesity and massive beta cell expansion. Here, using single-cell transcriptomics with female Lepr KO islets, we identified distinct populations of beta cells undergoing unfolded protein response (UPR), stress resolution, and cell cycle progression. Lepr KO beta cells undergoing UPR markedly increased chaperone protein, ribosomal biogenesis, and cell cycle transcriptional programs that were enriched for Xbp1 and Myc target genes. Our findings suggest a coordinated transcriptional mechanism involving Xbp1 and Myc to alleviate UPR and stimulate beta cell proliferation in obese female mice.