281-OR: Time-Restricted Feeding Prevents Deleterious Effects of Diet-Induced Obesity on Circadian Regulation of β-Cell Function and Transcription

by sugaradmin



Introduction and Objective: Disruptions in circadian fasting/feeding cycles contribute to β-cell dysfunction in diabetes. Diet-induced obesity (DIO) (modeled by a high-fat diet) adversely affects circadian glucose homeostasis partly through dysregulation of fasting/feeding cycles. However, its impact on circadian β-cell function and gene expression remains unknown.Methods: To address this, we exposed male/female C57BL/6 mice to chow or DIO for 8 weeks and evaluated behavioral (feeding/activity), physiological (glucose tolerance/insulin secretion), transcriptomic (RNA-seq), and epigenomic (ATAC-seq) circadian rhythms. Additionally, we tested whether normalization of fasting/feeding cycles by time-restricted feeding (tRF) mitigates the effects of DIO.Results: DIO disrupted circadian regulation of fasting/feeding cycles, with the extent of disruption greater in males vs. females (p<0.05). Also, DIO led to the loss of circadian regulation of glucose tolerance and in vivo glucose-stimulated insulin secretion (GSIS) (p<0.05 vs. chow) in males, whereas circadian glucose homeostasis was preserved in female mice. RNA-seq analysis of male islets revealed a ~ 50% reduction in circadian-regulated transcripts under DIO (p<0.05 vs. chow), with attenuated circadian rhythms in key pathways (e.g., Protein processing in ER and cAMP signaling). Importantly, normalization of fasting/feeding cycles in DIO male mice by tRF restored circadian glucose tolerance, GSIS, and islet gene expression (p<0.05 vs. chow). Motif analysis identified transcription factors DBP and NRF1 as mediators of beneficial effects of tRF in DIO islets.Conclusion: Our study demonstrates that 1) DIO perturbs circadian regulation of β cell function and gene expression through dysregulation of fasting/feeding cycles, and 2) highlights notable sex differences in how DIO impacts circadian control of glucose homeostasis and β-cell function.

Disclosure

L. Zhang: None. S.K. Sen: None. T. Nguyen: None. K. Omori: None. A. Bharath: None. A. Matveyenko: None.

Funding

National Institutes of Health (R01DK098468)



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