Stomach ghrelin-secreting cells as food-entrainable circadian clocks

Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13582-7. doi: 10.1073/pnas.0906426106. Epub 2009 Jul 24.


Increases in arousal and activity in anticipation of a meal, termed "food anticipatory activity" (FAA), depend on circadian food-entrainable oscillators (FEOs), whose locations and output signals have long been sought. It is known that ghrelin is secreted in anticipation of a regularly scheduled mealtime. We show here that ghrelin administration increases locomotor activity in nondeprived animals in the absence of food. In mice lacking ghrelin receptors, FAA is significantly reduced. Impressively, the cumulative rise of activity before food presentation closely approximates a Gaussian function (r = 0.99) for both wild-type and ghrelin receptor knockout animals, with the latter having a smaller amplitude. For both groups, once an animal begins its daily anticipatory bout, it keeps running until the usual time of food availability, indicating that ghrelin affects response threshold. Oxyntic cells coexpress ghrelin and the circadian clock proteins PER1 and PER2. The expression of PER1, PER2, and ghrelin is rhythmic in light-dark cycles and in constant darkness with ad libitum food and after 48 h of food deprivation. In behaviorally arrhythmic-clock mutant mice, unlike control animals, there is no evidence of a premeal decrease in oxyntic cell ghrelin. Rhythmic ghrelin and PER expression are synchronized to prior feeding, and not to photic schedules. We conclude that oxyntic gland cells of the stomach contain FEOs, which produce a timed ghrelin output signal that acts widely at both brain and peripheral sites. It is likely that other FEOs also produce humoral signals that modulate FAA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biological Clocks / drug effects
  • Biological Clocks / physiology*
  • Cell Cycle Proteins / metabolism
  • Circadian Rhythm / drug effects
  • Circadian Rhythm / physiology*
  • Feeding Behavior / drug effects
  • Food*
  • Gastric Mucosa / metabolism*
  • Ghrelin / administration & dosage
  • Ghrelin / metabolism*
  • Ghrelin / pharmacology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins / metabolism
  • Period Circadian Proteins
  • Receptors, Ghrelin / deficiency
  • Receptors, Ghrelin / metabolism
  • Stomach / cytology*
  • Stomach / drug effects
  • Time Factors
  • Transcription Factors / metabolism


  • Cell Cycle Proteins
  • Ghrelin
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Per1 protein, mouse
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Receptors, Ghrelin
  • Transcription Factors