Daily torpor is used by small mammals to reduce daily energy expenditure in response to energetic challenges. Optimizing the timing of daily torpor allows mammals to maximize its energetic benefits and, accordingly, torpor typically occurs in the late night and early morning in most species. However, the regulatory mechanisms underlying such temporal regulation have not been elucidated. Direct control by the circadian clock and indirect control through the timing of food intake have both been suggested as possible mechanisms. Here, feeding cycles outside of the circadian range and brain-specific mutations of circadian clock genes ( ; ) were used to separate the roles of the circadian clock and food timing in controlling the timing of daily torpor in mice. These experiments revealed that the timing of daily torpor is transiently inhibited by feeding, while the circadian clock is the major determinant of the timing of torpor. Torpor never occurred during the early part of the circadian active phase, but was preferentially initiated late in the subjective night. Food intake disrupted torpor in the first 4-6 h after feeding by preventing or interrupting torpor bouts. Following interruption, re-initiation of torpor was unlikely until after the next circadian active phase. Overall, these results demonstrate that feeding transiently inhibits torpor while the central circadian clock gates the timing of daily torpor in response to energetic challenges by restricting the initiation of torpor to a specific circadian phase.

Many small mammals, such as the laboratory mouse, utilize the hypometabolic state of torpor in response to caloric restriction. The signals that relay the lack of fuel to initiate a bout of torpor are not known. Because the mouse will only enter a torpid state when calorically challenged, it may be that one of the inputs for initiation into a bout of torpor is the lack of the primary fuel (glucose) used to power brain metabolism in the mouse. Using glucose telemetry in mice, we tested the hypotheses that 1) circulating glucose (GLC), core body temperature (T), and activity are significantly interrelated; and 2) that the level of GLC at the onset of torpor differs from both GLC during arousal from torpor and during feeding when there is no torpor. To test these hypotheses, six C57Bl/6J mice were implanted with glucose telemeters and exposed to different feeding conditions (ad libitum, fasting, limited food intake, and refeeding) to create different levels of GLC and T. We found a strong positive and linear correlation between GLC and T during ad libitum feeding. Furthermore, mice that were calorically restricted entered torpor bouts readily. GLC was low during torpor entry but did not drop precipitously as T did at the onset of a torpor bout. GLC significantly increased during arousal from torpor, indicating the presence of endogenous glucose production. While low GLC itself was not predictive of a bout of torpor, hyperactivity and low GLC preceded the onset of torpor, suggesting that this may be involved in triggering torpor.

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Alternate-day fasting (ADF) is effective for weight loss and increases insulin sensitivity in diet-induced obese rodents. However, the efficacy of ADF in genetic models of obesity has not been comprehensively studied. Mice that are deficient in leptin ( ob/ob mice) are obese, diabetic, and prone to deep bouts of torpor when fasted. We tested the hypotheses that an ADF protocol in ob/ob mice would result in 1) induction of torpor on fasted days, 2) minimal body weight loss if the mice experienced torpor, and 3) no improvement in glucose control in the absence of weight loss. Female ob/ob mice and littermate controls were assigned to 1) an ad libitum regimen or 2) an ADF regimen, consisting of fasting every other day with ad libitum feeding between fasts. Over a 19-day period, littermate control mice on the ADF regimen consumed the same amount of food as littermate control mice on the ad libitum regimen, whereas the ADF ob/ob mice consumed 37% less food than ad libitum ob/ob mice. Fasting days, but not fed days, led to torpor in both genotypes. Fasting days, but not fed days, led to weight loss in both genotypes relative to ad libitum controls. Fasting days, but not fed days, produced enhanced insulin sensitivity in both genotypes and normalized circulating glucose in ob/ob mice. These data demonstrate improved glucose control on fasting days with the use of ADF in a genetic model of obesity in the face of minimal weight loss.