The molecular clock is required for gastric bypass‐induced metabolic effects

Reem Ghaddar; Yuanchao Ye; Yang Song; Jonathan Cedernaes; Daniel Levine; Joseph T Bass; Mohamad Mokadem

doi:10.1096/fasebj.2019.33.1_supplement.lb421

Background Roux‐en‐Y gastric bypass (RYGB) is one the most effective treatments for obesity and type 2 diabetes (T2D). Circadian sleep and feeding behaviors are entrained to the light‐dark cycle by the “central” molecular clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. The molecular clock is also present in cells as “peripheral clocks,” playing a key metabolic role within the liver and other key organs. Circadian rhythm disruption at molecular or environmental levels can alter diurnal food intake patterns in mice and lead to positive energy balance and insulin resistance. We previously showed that improvements in glucose homeostasis after RYGB are due to enhanced hepatic insulin sensitivity and decreased hepatic glucose production, and that weight loss is due to increased energy expenditure in diet‐induced obese (DIO) mice. Aim We aimed to examine the effect of RYGB on molecular clock regulation and test the requirement of a functional molecular clock for an adequate metabolic response of RYGB on weight loss and hepatic glucose regulation. Results Our recent preliminary data show that high‐fat diet (HFD) alters diurnal food intake by increasing calorie consumption during the light cycle when animals are usually asleep. Strikingly, RYGB reverses this HFD‐induced disruption by restoring food consumption to the normal dark period (Figure 1). We also found that the mRNA expression of several clock genes was altered after RYGB within the liver ‐ but not the SCN ‐ of DIO mice (Figure 2). Next, we performed RYGB on mper2luciferase mice (luciferase tagged to the period2 gene as a life reporter). Interestingly, we found that RYGB induces a significant phase shift in the bioluminescence wave of the per2 gene oscillation in the liver (peripheral clock), but not in the SCN (central clock), independent of diet (Figure 3). Finally, we tested the response of the ClockΔ19 mutant mice (deficient in clock core gene) to RYGB and found that RYGB failed to correct the abnormal circadian feeding behavior induced by HFD, and that the ClockΔ19 mice have attenuated weight loss and impaired reduction in hepatic glucose production post‐RYGB (Figure 4). Conclusion This is the first study to show that RYGB reverses disrupted circadian feeding behaviors induced by HFD and regulates the expression of the hepatic clock machinery. It also proved that the molecular clock is essential to the beneficial effects of RYGB on energy balance, diurnal food intake, and hepatic glucose regulation. Deeper understanding of the molecular mechanism of RYGB and the molecular clock can lead to development of less invasive targeted therapies for obesity and T2D that mimic the metabolic mechanism of RYGB, and can alter future clinical decisions to perform bariatric surgeries on patients with obesity who suffer from a disrupted circadian rhythm, as they may have a suboptimal metabolic response to the surgery. Support or Funding Information This study was supported by startup funds from the Internal Medicine Department, University of Iowa, and the American Gastroenterological Association (AGA). This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.

The molecular clock is required for gastric bypass‐induced metabolic effects

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