Introduction and Objective: Lifestyle-related circadian disruption, including night-shift work, increases susceptibility to obesity and type 2 diabetes. However, the long-term effects of maternal circadian misalignment during pregnancy on metabolic health of adult offspring remain unclear. We investigated whether gestational circadian disruption, modeled using a short-day (SD) light cycle, programs offspring for metabolic dysfunction.Methods: Pregnant C57BL/6J mice were exposed to an 8h light/8h dark (SD) cycle from embryonic day 1 to birth. Control dams remained on a standard 12h/12h cycle. After delivery, all offspring were returned to a 12h/12h cycle and maintained on normal chow unless specified. Metabolic assessments included body weight, random blood glucose, glucose and insulin tolerance, tissue insulin signaling, and hepatic gluconeogenesis. A subset of offspring was challenged with a high-fat diet to evaluate susceptibility to metabolic stress.Results: Under normal chow conditions, male but not female SD offspring exhibited increased body weight. Both sexes showed elevated random blood glucose, impaired glucose tolerance, and insulin resistance. These defects were accompanied by reduced insulin-stimulated AKT activation in skeletal muscle, adipose tissue, and liver. Interestingly, the SD offspring also demonstrated enhanced hepatic gluconeogenesis, and upregulation of liver Pck1 and G6pc, indicating increased hepatic glucose output. Under high-fat diet, SD offspring showed persistent glucose intolerance, insulin resistance, and impaired insulin signaling.Conclusion: Gestational circadian disruption predisposes offspring to obesity in a sex-specific manner and increases the risk of glucose intolerance and insulin resistance in both sexes. Findings underscore maternal gestational circadian health as a key determinant of offspring metabolic risk.
M.I. Oraebosi: None. M. Schupp: None. H. Lin: None. S. Jo: None. E. Alejandro: None. R. Cao: None.
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