Chronic Timed Sleep Restriction Attenuates LepRb-Mediated Signaling Pathways and Circadian Clock Gene Expression in the Rat Hypothalamus.

Qi Sun,Wei Wei,Ren Lin,Deliang Wen,Dan Wu,Yang Liu,Lihong Jia

doi:10.3389/fnins.2020.00909

Abstract

The sleep duration of adolescents has continued to decline over the past 20 years. Sleep insufficiency is one of the most important risk factors for obesity, but the mechanisms underlying the association are unclear. Therefore, the hypothalamic-regulated mechanisms of appetite and the circadian clock gene expression were examined in sleep-restricted rats. Rats aged 7 weeks were randomly divided into two groups: the control group and sleep restriction group (7 rats/group) rats were sleep-restricted for 4 weeks. Body weight gain and amount of food/water consumption were quantified. The expression of genes or proteins which regulated appetite and energy metabolism via leptin receptor signaling and the circadian clock in the hypothalamus were assessed. Chronic sleep restriction induced increased food intake and weight gain in adolescent and young adult rats from the second week of initiation of sleep restriction. Phosphorylation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) was decreased, although levels of circulating leptin or leptin receptor expression were unaltered. Furthermore, insulin receptor substrate (IRS)/phosphoinositide 3-kinase (PI3K)/AKT/mTOR and forkhead box O1 (FoxO1) signaling pathways were also compromised. Moreover, core circadian clock genes were also decreased in the sleep restriction group compared with the control. Chronic timed sleep restriction induced hyperphagic behaviors, attenuated leptin receptor-mediated signaling pathways, and depleted the expression of circadian clock gene in the hypothalamus of adolescent and young adult rats.

Highlights

Insufficient sleep in children and adolescents is highly prevalent worldwide
We first demonstrated that the weight gain and daily food intake of chronically sleep-restricted rats increased during their natural sleep course
We found that Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3)/POMC signaling downstream of the leptin receptor in the hypothalamus was compromised after chronic sleep restriction, the leptin levels in the serum and LepRb protein expression remained unaltered

Summary

Introduction

Insufficient sleep in children and adolescents is highly prevalent worldwide. It is reported that 72.7% of high school students and 57.8% of middle school students in the United States do not get enough sleep (Wheaton et al, 2018). Longitudinal studies have provided evidence that children who sleep for a shorter duration are more likely to have a higher body mass index when they are adults (Landhuis et al, 2008). Our previous study reported that shorter sleep durations might increase the risk of being overweight or obese in different age groups of students (Sun et al, 2018). Several studies have reported that sleep curtailment might affect children’s self-control when making food choices, resulting in increased intake of unhealthy foods and increased risk of overeating (Hjorth et al, 2014; Hibi et al, 2017; Martinez et al, 2017). The effect of sleep curtailment on the regulation of appetite in the hypothalamus and the mechanisms underlying this are not fully understood and need further exploration

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Conclusion