Circadian Timekeeping Through Nutritional and Metabolic Sensory Networks

Circadian rhythms are predictable biological patterns that recur about every 24 h and, in mammals such as humans, are entrained to daylight by the hypothalamic suprachiasmatic nucleus (SCN). Although light is a potent zeitgeber for the SCN, cells outside of the SCN can synchronize to daily nutrient and metabolic cues. In these tissues, nutrient metabolic processes are regulated by the molecular clock in anticipation of food availability or scarcity. Furthermore, nutrients and metabolic processes themselves may act upon members of the molecular clock to regulate their expression and activity. These interactions maintain synchrony between the SCN and food-entrainable clocks when activity and nutrient intake align. However, the light-entrainable SCN and food-entrainable clocks can become desynchronized, particularly in modern society where humans are commonly exposed to shift work and jet lag. Therefore, the mechanisms for sensing nutrients at specific times of day are critical components of circadian timekeeping and organismal homeostasis. In the following narrative review, we aim to synthesize current evidence on time-of-day-dependent nutrient sensing in mammalian systems, examine how nutrient-derived signals and metabolic processes interact with molecular clock mechanisms across cellular and tissue levels, and evaluate the integration of central and peripheral clocks in regulating gene expression, energy utilization, and organismal homeostasis, including the impacts of feeding cycles and circadian disruption. While previous reviews have discussed circadian nutrient metabolism, this review provides conceptual support for the role of nutrients as time-of-day signaling mechanisms.