Introduction and Objective: The molecular clock regulates energy balance and glucose metabolism. Roux-en-Y gastric bypass (RYGB) modulates these processes, but the underlying neural and hepatic mechanisms remain unclear. Prior findings show that RYGB in CLOCK-deficient mice blunts weight loss, fails to improve glucose homeostasis, and alters hepatic clock-gene rhythms independent of body weight. Because parasympathetic input—particularly motor vagal fibers—is required for RYGB-enhanced glucose control, this study tested the role of hepatic vagal innervation and the liver clock in postoperative glucose regulation.Methods: Using mPer2-Luciferase reporter mice, we performed RYGB or sham surgery with or without selective hepatic vagal denervation (DEN). In vivo 24-hour bioluminescence imaging assessed hepatic clock oscillations. Glucose kinetics were quantified via hyperinsulinemic-euglycemic clamps. Parallel experiments used Alb-Bmal1 knockout mice to test clock necessity.Results: RYGB elevated hepatic Per2 activity across the diurnal cycle versus shams. Vagal denervation did not alter this activation but partially restored rhythmicity, reducing elevated Per2 levels at ZT3 and ZT15. RYGB increased whole-body glucose disappearance (Rd) and hepatic uptake under basal and clamped conditions, effects abolished by DEN. Alb-Bmal1 knockouts retained normal RYGB-induced improvements in hepatic glucose flux.Conclusion: Hepatic vagal innervation is dispensable for RYGB-induced activation of liver clock genes but required for enhanced glucose clearance and hepatic uptake. The intrinsic hepatic clock is not essential for RYGB-mediated glucose improvements, indicating a vagus-dependent, clock-independent mechanism linking bariatric surgery to improved glucose homeostasis.
M. Mokadem: Research Support; Current; Novo Nordisk.
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