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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 a 4-hour TRF stimulus 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-hour TRF. Moreover, this effect was modulated by the circadian clock and was associated with severe hypothermia due to loss of body temperature homeostasis, which is different from "torpor", an adaptive response under food deprivation. Disrupting the circadian clock by the SCN lesions or a non-invasive method (constant light) which disrupts circadian clock 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. We demonstrate a side effect of 4-hour TRF on the homeostasis of body temperature and a rescue function by impairing the SCN function. Altogether, our results suggested that constructing a circadian arrhythmicity may have a beneficial effect on the host response to an acute stress.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC7455017 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Zhang Zhihui Z Zhai Qiaocheng Q Gu Yue Y Zhang Tao T Huang Zhengyun Z Liu Zhiwei Z Liu Yi Y Xu Ying Y

Science bulletin 20200319 15

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 a 4-hour TRF stimulus 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-hour TRF. Moreover, this effect was ...[more]

PMID: 32864176

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Project description:BackgroundThe prevalence of obesity has increased dramatically worldwide. The obesity epidemic begs for novel concepts and therapeutic targets that cohesively address "food-abuse" disorders. We demonstrate a molecular link between impairment of a central kinase (Akt) involved in insulin signaling induced by exposure to a high-fat (HF) diet and dysregulation of higher order circuitry involved in feeding. Dopamine (DA) rich brain structures, such as striatum, provide motivation stimuli for feeding. In these central circuitries, DA dysfunction is posited to contribute to obesity pathogenesis. We identified a mechanistic link between metabolic dysregulation and the maladaptive behaviors that potentiate weight gain. Insulin, a hormone in the periphery, also acts centrally to regulate both homeostatic and reward-based HF feeding. It regulates DA homeostasis, in part, by controlling a key element in DA clearance, the DA transporter (DAT). Upon HF feeding, nigro-striatal neurons rapidly develop insulin signaling deficiencies, causing increased HF calorie intake.Methodology/principal findingsWe show that consumption of fat-rich food impairs striatal activation of the insulin-activated signaling kinase, Akt. HF-induced Akt impairment, in turn, reduces DAT cell surface expression and function, thereby decreasing DA homeostasis and amphetamine (AMPH)-induced DA efflux. In addition, HF-mediated dysregulation of Akt signaling impairs DA-related behaviors such as (AMPH)-induced locomotion and increased caloric intake. We restored nigro-striatal Akt phosphorylation using recombinant viral vector expression technology. We observed a rescue of DAT expression in HF fed rats, which was associated with a return of locomotor responses to AMPH and normalization of HF diet-induced hyperphagia.Conclusions/significanceAcquired disruption of brain insulin action may confer risk for and/or underlie "food-abuse" disorders and the recalcitrance of obesity. This molecular model, thus, explains how even short-term exposure to "the fast food lifestyle" creates a cycle of disordered eating that cements pathological changes in DA signaling leading to weight gain and obesity.

Project description:The circadian misalignment of the gut microbiota caused by unusual eating times in adult animals is related to disease development. However, whether the composition and diurnal rhythm of gut microbiota can be optimized by synchronizing the window period of eating with natural eating habits to reduce the risk of diarrhea remains unclear, especially in growing animals. In this study, 108 5-week-old weaned rabbits (nocturnal animals) were randomly subjected to daytime feeding (DF) and night-restricted feeding (NRF). At age 12 weeks, six rabbits were selected from each group, and caecum and cecal contents, as well as serum samples were collected at 4-h intervals during 24 h. Overall, NRF was found to reduce the risk of diarrhea in growing rabbits, improved the diurnal rhythm and abundance of beneficial microorganisms, along with the production of beneficial metabolites, whereas reduced the abundance of potential pathogens (Synergistes, Desulfovibrio, and Alistipes). Moreover, NRF improved diurnal rhythm of tryptophan hydroxylase isoform 1 and serotonin. Furthermore, NRF strengthened the diurnal amplitude of body core temperature, and promoted the diurnal expression of intestinal clock genes (BMAL1, CLOCK, REV-ERBα, and PER1), and genes related to the regulation of the intestinal barrier (CLAUDIN-1), and intestinal epithelial cell self-proliferation and renewal (BMI1). In vitro simulation experiments further revealed that synchronization of microbial-driven serotonin rhythm and eating activity-driven body temperature oscillations, which are important zeitgebers, could promote the diurnal expression of clock genes and CLAUDIN-1 in rabbit intestinal epithelial cells (RIEC), and enhance RIEC proliferation. This is the first study to reveal that NRF reprograms the diurnal rhythm of the gut microbiome, promotes the diurnal expression of clock genes and tight junction genes via synchronization of microbial-driven serotonin rhythm and eating activity-driven body temperature oscillations, thereby improving intestinal health and reducing the risk of diarrhea in growing rabbits. Collectively, these results provide a new perspective for the healthy feeding and management of growing animals.

Project description:The suprachiasmatic nucleus (SCN), locus of a circadian clock, is a small nucleus of approximately 20,000 neurons that oscillate with a period of about 24 hours. While individual neurons produce circadian oscillations even when dispersed in culture, the coherence and robustness of oscillation of the SCN as a whole is dependent on its circuitry. Surprisingly, the individual neurons of the intact SCN do not all oscillate in phase with each other. To understand the oscillatory dynamics across the intact nucleus, we develop a model of the relation of the phase of neurons to their PER2 expression at a particular subjective time (CT1900) using time series data from SCN slice preparations. Next, we use the model, which produces a surprisingly good fit in the SCN slice data, to estimate oscillator phase at a single time point (CT1900) in snapshot data from PER2 expression measurements in intact, unsliced SCN-wide tissue. To monitor temporal changes in phase in time series data, we use PER2::LUC imaging in an ex vivo SCN slice preparation. To study phase in the intact SCN at a fixed time point we use data generated by PER2 staining and a tissue clearing protocol. Because PER2 expression, as measured in the time series slices and the snapshot intact SCN are not directly comparable, the model estimated from time series slices to the snapshot intact SCN data requires a calibrating constant. The results indicate that our model provides a surprisingly good fit to the SCN slice data and is therefore a meaningful method for estimating phase in the intact SCN snapshot data, permitting the study of virtual interventions such as virtual tissue slicing. We next compare oscillation in circuits in the SCN-wide tissue to those that have been disrupted by virtual slicing using a Kuramoto model to simulate the dynamics. The results support prior evidence that the damage done by coronal slicing has the most disruptive impact on SCN oscillation, while horizontal slicing has the least damage. The results point to the importance of connectivity along the caudal-to-rostral axis and indicate that SCN circuit organization depends on the caudal-to-rostral flow of information. In summary, the construction of this model is a major finding of the paper. Our modeling allows us to perform the previously impossible analysis of oscillatory dynamics in static data in an intact SCN captured at a single time point.

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

Publications

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

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