The food-entrainable oscillator (FEO) is a mysterious circadian clock because its anatomical location(s) and molecular timekeeping mechanism are unknown. Food anticipatory activity (FAA), which is defined as the output of the FEO, emerges during temporally restricted feeding. FAA disappears immediately during ad libitum feeding and reappears during subsequent fasting. A free-running FAA rhythm has been observed only in rare circumstances when food was provided with a period outside the range of entrainment. Therefore, it is difficult to study the circadian properties of the FEO. Numerous studies have attempted to identify the critical molecular components of the FEO using mutant and genetically engineered mouse models. Herein we critically review the experimental protocols and findings of these studies in mouse models. Several themes emerge from these studies. First, there is little consistency in restricted feeding protocols between studies. Moreover, the protocols were sometimes not optimal, resulting in erroneous conclusions that FAA was absent in some mouse models. Second, circadian genes are not necessary for FEO timekeeping. Thus, another noncanonical timekeeping mechanism must exist in the FEO. Third, studies of mouse models have shown that signaling pathways involved in circadian timekeeping, reward (dopaminergic), and feeding and energy homeostasis can modulate, but are not necessary for, the expression of FAA. In sum, the approaches to date have been largely unsuccessful in discovering the timekeeping mechanism of the FEO. Moving forward, we propose the use of standardized and optimized experimental protocols that focus on identifying genes that alter the period of FAA in mutant and engineered mouse models. This approach is likely to permit discovery of molecular components of the FEO timekeeping mechanism.
|Number of pages||17|
|Journal||Journal of Biological Rhythms|
|State||Published - Oct 1 2018|
Bibliographical noteFunding Information:
We believe we have reviewed all FAA studies in mutant and genetically engineered mice herein. If we have overlooked a study, we apologize and would like to be notified of said study. We would like to thank the reviewers of this manuscript for their insightful suggestions. J.S.P is supported by National Institutes of Health (NIH) grants DK098321, P20 GM103527 (Junior Investigator), DK107851, and the University of Kentucky. S.Y. is supported by NIH grant R21 NS099809.
© 2018 The Author(s).
- food anticipatory activity
- food entrainment
- restricted feeding
ASJC Scopus subject areas
- Physiology (medical)