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

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Type 1 diabetes management requires restoring glucose control, with beta cell proliferation being a key therapeutic target.
• Understanding beta cell proliferation mechanisms is crucial for identifying novel therapeutic strategies.
• Obesity naturally stimulates beta cell replication in humans and rodents, providing a valuable model for studying these mechanisms.

Purpose of the Study:

• To investigate the molecular mechanisms underlying beta cell proliferation during obesity.
• To identify specific transcriptional programs and signaling pathways involved in beta cell expansion in an obese model.

Main Methods:

• Utilized single-cell transcriptomics on islets from female Lepr (Leptin receptor) knockout (KO) mice, which develop obesity and beta cell expansion.
• Analyzed gene expression patterns to identify distinct beta cell populations and their associated cellular processes.

Main Results:

• Identified specific beta cell populations in Lepr KO mice undergoing unfolded protein response (UPR), stress resolution, and cell cycle progression.
• Observed that UPR in Lepr KO beta cells upregulated chaperone proteins, ribosomal biogenesis, and cell cycle genes.
• Found enrichment of X-box binding protein 1 (Xbp1) and Myc target genes within these upregulated transcriptional programs.

Conclusions:

• A coordinated transcriptional mechanism involving Xbp1 and Myc is suggested to mediate the alleviation of UPR and stimulation of beta cell proliferation in obese female mice.
• These findings highlight potential therapeutic targets for enhancing beta cell regeneration in conditions like type 1 diabetes.