Hypothalamic leptin sensitivity and health benefits of time‐restricted feeding are dependent on the time of day in male mice

Abstract

Synchronization between biologic clocks and metabolism is crucial for most species. Here, we examined the ability of leptin, important in the control of energy metabolism, to induce leptin signaling at the molecular as well as the behavioral level throughout the 24‐h day in mice fed either a control or a high‐fat diet (HFD). Furthermore, we investigated the effects of time‐restricted feeding (TRF; a limitation of HFD access to 6 h each day) on energy metabolism during different periods throughout the 24‐h day. In control mice, molecular leptin sensitivity was highest at zeitgeber time (ZT)0 (lights on), declining during the light phase, and increasing during the dark phase. Surprisingly, leptin resistance in HFD‐fed mice was only present from the middle of the dark to the middle of the light period. Specifically, when TRF occurred from ZT21 to ZT3 (when leptin resistance in HFD‐fed mice was most profound), it resulted in a disruption of the daily rhythms of locomotor activity and energy expenditure and in increased plasma insulin levels compared with other TRF periods. These data provide evidence that leptin sensitivity is controlled by the circadian rhythm and that TRF periods may be most efficient when aligned with the leptin‐sensitive period.—Boucsein, A., Rizwan, M. Z., Tups, A. Hypothalamic leptin sensitivity and health benefits of time‐restricted feeding are dependent on the time of day in male mice. FASEB J. 33, 12175–12187 (2019). http://www.fasebj.org

Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice

“…Moreover, the responsiveness of HDKO mice to leptin at ZT 13 suggests that leptin sensitivity was phase-shifted rather than impaired only at ZT 1-4 in HDKO mice. This is consistent with a recent study demonstrating that DIO shifts circadian leptin sensitivity from the beginning of the light phase to the beginning of the dark phase 63 . Both SOCS3 and FABP7 deletions prevent DIO 34,64 , suggesting that their circadian repression by REV-ERBs may be an adaptative mechanism to maintain circadian leptin sensitivity on HFD.…”

Circadian Rhythms of the Hypothalamus: From Function to Physiology

“…Simply delaying feeding time by 4 h elicits a shift in peripheral clocks and increases weight gain in mice fed HFD [ 265 ]. Thus, TRF can actually reverse the deleterious side effects of obesity [ 266 , 267 ]. Even when only adhering to TRF on the weekday and following ad libitum feeding on the weekends in HFD fed mice, the beneficial effects of TRF are still seen [ 266 , 268 ].…”

Central signalling cross‐talk between insulin and leptin in glucose and energy homeostasis

“…In line with this, we found that DIO mice, compared to lean mice, exhibit bouts of increased basal pSTAT3 activation during the 24-hour rhythm. 68 We further demonstrated rhythmic oscillation of basal pSTAT3 activation throughout the day in DIO mice, which was independent of fluctuations in circulating leptin levels. 68 As a result of this circadian fluctuation in basal pSTAT3, dependent on timing, many studies might have missed any physiological regulation of this transcription factor by endogenous leptin because superphysiological doses of leptin lead to an abnormally high level of pSTAT3 activation.…”

“…68 We further demonstrated rhythmic oscillation of basal pSTAT3 activation throughout the day in DIO mice, which was independent of fluctuations in circulating leptin levels. 68 As a result of this circadian fluctuation in basal pSTAT3, dependent on timing, many studies might have missed any physiological regulation of this transcription factor by endogenous leptin because superphysiological doses of leptin lead to an abnormally high level of pSTAT3 activation. Future studies need to determine whether endogenous levels of leptin are able to regulate pSTAT3 levels within their physiological range.…”