Abstract
BackgroundIn our 24-hour society, an increasing number of people are required to be awake and active at night. As a result, the circadian rhythm of feeding is seriously compromised. To mimic this, we subjected mice to restricted feeding (RF), a paradigm in which food availability is limited to short and unusual times of day. RF induces a food-anticipatory increase in the levels of the hunger hormone ghrelin. We aimed to investigate whether ghrelin triggers the changes in body weight and gastric emptying that occur during RF. Moreover, the effect of genetic deletion of the core clock gene Bmal1 on these physiological adaptations was studied.MethodsWild-type, ghrelin receptor knockout and Bmal1 knockout mice were fed ad libitum or put on RF with a normal or high-fat diet (HFD). Plasma ghrelin levels were measured by radioimmunoassay. Gastric contractility was studied in vitro in muscle strips and in vivo (13C breath test). Cytokine mRNA expression was quantified and infiltration of immune cells was assessed histologically.ResultsThe food-anticipatory increase in plasma ghrelin levels induced by RF with normal chow was abolished in HFD-fed mice. During RF, body weight restoration was facilitated by ghrelin and Bmal1. RF altered cytokine mRNA expression levels and triggered contractility changes resulting in an accelerated gastric emptying, independent from ghrelin signaling. During RF with a HFD, Bmal1 enhanced neutrophil recruitment to the stomach, increased gastric IL-1α expression and promoted gastric contractility changes.ConclusionsThis is the first study demonstrating that ghrelin and Bmal1 regulate the extent of body weight restoration during RF, whereas Bmal1 controls the type of inflammatory infiltrate and contractility changes in the stomach. Disrupting the circadian rhythm of feeding induces a variety of diet-dependent metabolic, immune and gastrointestinal alterations, which may explain the higher prevalence of obesity and immune-related gastrointestinal disorders among shift workers.
Highlights
The amount or type of food we ingest, and the timing of food consumption seems to play a crucial role in the development of obesity and associated metabolic disorders [1]
This study aimed to examine whether ghrelin might serve as an output signal of the food-entrainable oscillators (FEOs) that triggers physiological adaptations to alterations in the circadian rhythm of feeding induced by restricted feeding (RF)
We found that Bmal1 determines the extent of body weight restoration during RF, and defines the type of infiltrating immune cells and influences the changes in contractility prior to food availability during RF with a high-fat diet
Summary
The amount or type of food we ingest, and the timing of food consumption seems to play a crucial role in the development of obesity and associated metabolic disorders [1]. In our 24-hour society, people are voluntarily shifting their normal activity patterns to unusual times of day, for instance by shift working or frequent time zone traveling As a result, they are seriously compromising their circadian system, an evolutionary conserved timekeeping mechanism that generates daily behavioral rhythms that allow organisms to actively anticipate and adapt to predictable environmental changes, thereby increasing the likelihood of survival [2]. They are seriously compromising their circadian system, an evolutionary conserved timekeeping mechanism that generates daily behavioral rhythms that allow organisms to actively anticipate and adapt to predictable environmental changes, thereby increasing the likelihood of survival [2] In mammals, this timing system is comprised, in a hierarchical way, of a hypothalamic master clock and peripheral oscillators in numerous body cells. The effect of genetic deletion of the core clock gene Bmal on these physiological adaptations was studied
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