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

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2021 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 10086769
- **Project number:** 5I01BX004774-02
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Mohamad Mokadem
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086769

## Citation

> US National Institutes of Health, RePORTER application 10086769, Regulation of glucose homeostasis via the molecular clock machinery and the hepatic vagus nerve after Roux-en-Y gastric bypass (5I01BX004774-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10086769. Licensed CC0.

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