Gastric Bypass reprograms hepatic clock machinery and improves glucose flux independent of weight

Abstract

Background: The molecular clock machinery regulates several homeostatic rhythms, including but not limited to glucose homeostasis. We previously demonstrated that Roux-en Y Gastric Bypass (RYGB) has a weight-independent effect on glucose metabolism, and transiently reduces food intake. In this study we investigate the effects of RYGB on diurnal eating behavior as well as its effects on the molecular clock, and its requirement for the metabolic effects of this bariatric procedure in obese mice. Results: We find that RYGB reverses the high fat diet-induced disruption in diurnal eating pattern during the early post-surgery phase of food reduction (Figure1). “Dark-cycle” pair-feeding experiments improved glucose tolerance to the level of bypass-operated animals during the physiologic “fasting” phase (Zeitgeber ZT2), but not the “feeding” phase (ZT14)(Figure 2). Using a clock gene reporter mouse model ( mPer2 luciferase), we reveal that RYGB induces a liver-specific phase shift in peripheral clock oscillation with no changes to the central clock activity within the suprachiasmatic nucleus (SCN) (Figure 3). In addition, we show that weight loss effects are attenuated in obese ClockΔ19 mutant mice post-RYGB (Figure 4) that also fails to improve glucose metabolism after surgery (Figure 5), specifically early hepatic glucose production (Figure 6). Conclusion: RYGB reprograms the peripheral clock within the liver early after surgery to alter diurnal eating behavior and regulate hepatic glucose flux. US Veterans Merit Award (#I01 BX004774) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.