Two-meal caloric restriction induces 12-hour rhythms and improves glucose homeostasis.

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Glucose metabolism is tightly regulated and disrupting glucose homeostasis is a hallmark of many diseases. Caloric restriction (CR), periodic fasting, and circadian rhythms are interlinked with glucose metabolism. Here, we directly investigated if CR depends on periodic fasting and circadian rhythms to improve glucose metabolism. CR was implemented as two‐meals per day (2M‐CR), provided at 12‐hour intervals, and compared with one meal per day CR, mealtime (MT), and ad libitum (AL) feeding. The 2M‐CR impacted the circadian rhythms in blood glucose, metabolic signaling, circadian clock, and glucose metabolism gene expression. 2M‐CR significantly reduced around the clock blood glucose and improved glucose tolerance. Twenty‐four‐hour rhythms in mTOR signaling and gene expression observed under AL, MT, and CR, became 12‐hour rhythms in 2M‐CR. The 12‐hour rhythms in behavior, gene expression, and signaling persisted in fasted mice, implicating some internal regulation. The study highlights that the reduction in caloric intake rather than meal frequency and duration of fasting is essential for metabolic reprograming and improvement in glucose metabolism and provides evidence on food‐entrained molecular pacemaker, which can be uncoupled from the light‐entrained circadian clock and rhythms.