title: Role of the clock gene Bmal1 and the gastric ghrelin-secreting cell in the circadian regulation of the ghrelin-GOAT system.
abstract: As adequate food intake is crucial to survival, organisms have evolved endogenous circadian clocks to generate optimal temporal patterns of food-related behavior and physiology. The gastric ghrelin-secreting cell is thought to be part of this network of peripheral food-entrainable oscillators (FEOs), regulating the circadian release of this orexigenic peptide. This study aimed to determine the role of the core clock gene Bmal1 and the gastric ghrelin-secreting cell as an FEO in the circadian rhythmicity of ghrelin expression and secretion in vivo and in vitro. Bmal1-deficient mice not only lacked circadian rhythmicity in plasma ghrelin levels and food intake, but also showed decreased gastric mRNA expression of ghrelin and ghrelin O-acyltransferase (GOAT), the ghrelin activating enzyme. Furthermore, in the absence of the hypothalamic master clock, food-related stimuli entrained the molecular clock of gastric ghrelinoma cells to regulate the rhythmic release of ghrelin. Divergent responses in octanoyl and total ghrelin release towards different food cues were observed, suggesting that the FEO also regulates the circadian rhythmicity of GOAT. Collectively, these findings indicate that circadian rhythmicity of ghrelin signaling requires Bmal1 and is driven by a food-responsive clock in the gastric ghrelin-secreting cell that not only regulates ghrelin, but also GOAT activity.
authors.affiliation: Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Laermans
authors.affiliation: Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Vancleef
authors.affiliation: Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Tack
authors.affiliation: Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium.
authors.forename: I
authors.initials: I
authors.lastname: Depoortere
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics*; D000217:Acyltransferases / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000502:physiology*; D003463:Cues; D004435:Eating; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism*; D017353:Gene Deletion; D015870:Gene Expression; D054439:Ghrelin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013270:Stomach / Q000166:cytology*
chemical_list: D056930:ARNTL Transcription Factors; D054439:Ghrelin; D008565:Membrane Proteins; D012333:RNA, Messenger; D000217:Acyltransferases; C526983:Mboat4 protein, mouse