Impaired function of the suprachiasmatic nucleus rescues the loss of body temperature homeostasis caused by time-restricted feeding

Abstract

The suprachiasmatic nucleus (SCN) is the master circadian pacemaker that drives body temperature rhythm. Time-restricted feeding (TRF) has potential as a preventative or therapeutic approach against many diseases. The potential side effects of TRF remain unknown. Here we show that daily 4-h TRF treatment in mice can severely impair body temperature homeostasis and can result in lethality. Nearly half of the mice died at 21°C, and all mice died at 18°C during 4-h TRF. This effect was modulated by the circadian clock and was associated with severe hypothermia due to loss of body temperature homeostasis. Remarkably, disrupting the circadian clock by SCN lesions or constant light rescued lethality during TRF. Analysis of circadian gene expression in the dorsomedial hypothalamus (DMH) demonstrated that TRF reprograms rhythmic transcriptome in DMH and suppresses expression of genes, such as Ccr5 and Calcrl, which are involved in thermoregulation. Together, our results demonstrated a potent effect of TRF on body temperature homeostasis and the role of SCN function in this process. Our results further suggested that circadian arrhythmicity can have potential beneficial effects under certain stress conditions.

Circadian Clock-Controlled Checkpoints in the Pathogenesis of Complex Disease

“…Time-restricted feeding in mice has been shown to impair the body temperature homeostasis (Zhang et al, 2020c). Circadian gene expression analysis in the dorsomedial hypothalamus revealed that rhythmically reprogramming of thermoregulation gene expression is involved in the impairment of body temperature regulation (Zhang et al, 2020c). Integrative cistromic and transcriptomic analysis Myeloid cells adhere to atherosclerotic lesions in a rhythmic manner with a peak between ZT17-ZT1 because of the diurnal expression of the CCL2-CCR2 axis.…”

“…Complete loss of circadian behavior was found in forebrain/SCN-specific Bmal1 knockout mice, and the related circadian rhythms in peripheral tissues was differentially affected by light/dark cycles and feeding ( Izumo et al, 2014 ). Time-restricted feeding in mice has been shown to impair the body temperature homeostasis ( Zhang et al, 2020c ). Circadian gene expression analysis in the dorsomedial hypothalamus revealed that rhythmically reprogramming of thermoregulation gene expression is involved in the impairment of body temperature regulation ( Zhang et al, 2020c ).…”

Protocol for setup and circadian analysis of inverted feeding in mice

“…Zhang et al. reported that 4-h NRF regimen in mice severely impairs body temperature homeostasis at 21°C and below ( Zhang et al., 2020 ). Simply reversing the biphasic dietary intake pattern by 12 h does not mimic the effects of inverted feeding as suggested by a recent study ( Xie et al., 2020 ).…”

“…Light intensity might affect the entrainment of peripheral clocks by inverted feeding. We and others use 200 lux of LED light intensity in time-restricted feeding studies ( Xin et al., 2021 ; Zhang et al., 2020 ). When we unintentionally analyzed food entrainment in male mice under 500 lux of LED light intensity, DRF male mice showed dampened rhythmicity of circadian clock transcripts in heart and kidney ( Xin et al., 2021 ).…”

Time-restricted feeding near dawn entrains long-term behavioral changes through the suprachiasmatic nucleus

“…The fact that mice given a 4-hour time-restricted feeding (TRF) at 21°C causes death, viewed alongside the observation that this phenotype can be rescued by impairing SCN function (Zhang et al, 2020), clearly suggests that the SCN somehow respond to TRF induced hunger-link food stimulation and regulate neuronal plasticity to modulate adaptive behaviors. The available evidence suggests that cyclic adenosine monophosphate (cAMP) is both an output of the SCN and an integral component of the SCN, regulating transcriptional cycles (Hastings et al, 2019; O’Neill et al, 2008).…”