Regulation of glucose homeostasis via the molecular clock machinery and the hepatic vagus nerve after Roux-en-Y gastric bypass

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This application describes a structured research plan targeted to explore the role of the molecular “clock” – which is responsible for maintaining endogenous circadian rhythm - in the mechanism of glucose regulation after gastric bypass. It is estimated that ~ 30 million Americans have diabetes (mainly type 2) which has been tightly associated with insulin resistance and obesity. Furthermore, 1 in every 3 Americans is currently obese and by the year 2020 it’s estimated that ~ 75% will be either overweight or obese. Bariatric surgery proved to be very effective in reducing body weight and reversing most of the obesity associated co-morbidities (such as diabetes) with effects lasting as long as 20 years. Emerging evidence suggests that Roux-en-Y gastric bypass (RYGB) induces its metabolic effects by modulating neuronal-hormonal pathways between the gut and energy regulating centers within the brain. We developed a mouse model of RYGB that can recapitulate most of the human findings and this model can be used to further dissect the underlying mechanism of this surgery. In this proposal, we show that RYGB reverses the disruption caused by high fat diet (HFD) on diurnal food intake behavior. It causes an increase in the percentage of food intake consumed during the dark cycle (physiologic feeding time) back to that observed in healthy lean animals. RYGB also corrects the HFD- induced alteration in hepatic clock gene oscillation as well as the paraventricular nucleus of the hypothalamus. The improvement in glucose metabolism after RYGB was shown to be primarily due to reduction in hepatic glucose production and amelioration of hepatic insulin sensitivity. The molecular clock machinery (within the liver and certain areas of the brain) plays a key role in lipid, carbohydrate, and xenobiotic metabolism in synchrony with the fasting/feeding cycle. Here, we show that RYGB induces an attenuated response to weight loss and glucose improvement in clock∆19 mutant mice (deficient in the Clock gene) compared to wild-type controls. In addition, we acquired new data showing that selective forebrain deletion of Bmal1 (another core clock gene) disrupts normal circadian feeding and results in abnormal hepatic glucose production independent of weight. Interestingly, selective hepatic vagotomy corrects this metabolic abnormality. This data suggest that the molecular clock play a role in the gluco-regulatory effects of RYGB in a pathway involving the hepatic vagus nerve. Aim#1 will test if the effects of RYGB on glucose homeostasis require a functional central (i.e hypothalamic) and peripheral (i.e. hepatic) molecular clock. Aim#2 will test if RYGB reprograms central clock gene expression to regulate glucose metabolism via a mechanism involving the hepatic vagus. Identifying pathways used by RYGB to induce its metabolic benefits will hopefully assist in future development of less invasive therapies for obesity and type 2 diabetes.