The Mysterious Food-Entrainable Oscillator: Insights from Mutant and Engineered Mouse Models

Jul 24, 2018Journal of biological rhythms

Understanding the Food-Driven Body Clock Using Genetically Modified Mice

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Abstract

Food anticipatory activity (FAA) disappears during ad libitum feeding and reappears during subsequent fasting.

The food-entrainable oscillator (FEO) is linked to circadian rhythms but its anatomical location and molecular mechanism remain unknown.
Inconsistent feeding protocols across studies have led to erroneous conclusions regarding the absence of FAA in certain mouse models.
Circadian genes are not required for the timekeeping of the FEO, suggesting an alternative timekeeping mechanism.
Dopaminergic signaling pathways, along with those regulating feeding and energy, can influence the expression of FAA but are not essential for it.
Current research methods have not successfully identified the timekeeping mechanism of the FEO, indicating a need for improved experimental protocols.

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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.

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The Mysterious Food-Entrainable Oscillator: Insights from Mutant and Engineered Mouse Models

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