title: Shifting the circadian rhythm of feeding in mice induces gastrointestinal, metabolic and immune alterations which are influenced by ghrelin and the core clock gene Bmal1.
abstract: BACKGROUND
  In 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.
  
  
  METHODS
  Wild-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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  This 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.
authors.affiliation: Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Jorien
authors.initials: J
authors.lastname: Laermans
authors.affiliation: Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Broers
authors.affiliation: Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Kelly
authors.initials: K
authors.lastname: Beckers
authors.affiliation: Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Laurien
authors.initials: L
authors.lastname: Vancleef
authors.affiliation: Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: Steensels
authors.affiliation: Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Theo
authors.initials: T
authors.lastname: Thijs
authors.affiliation: Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Tack
authors.affiliation: Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Inge
authors.initials: I
authors.lastname: Depoortere
mesh_terms: D056930:ARNTL Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000222:Adaptation, Physiological; D000818:Animals; D001835:Body Weight / Q000502:physiology*; D002940:Circadian Rhythm; D016207:Cytokines / Q000235:genetics; D059305:Diet, High-Fat; D005247:Feeding Behavior / Q000502:physiology*; D005746:Gastric Emptying / Q000502:physiology*; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D054439:Ghrelin / Q000097:blood / Q000378:metabolism*; D007109:Immunity / Q000502:physiology*; D051379:Mice; D020556:Neutrophil Infiltration / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; D016207:Cytokines; D054439:Ghrelin; D009195:Peroxidase