An Ultradian Feeding Schedule in Rats Affects Metabolic Gene Expression in Liver, Brown Adipose Tissue and Skeletal Muscle with Only Mild Effects on Circadian Clocks.

Paul De Goede,Andries Kalsbeek,Etienne Challet,Vincent-Joseph Poirel,Ewout Foppen,Yan Su,Satish Sen

doi:10.3390/ijms19103171

Abstract

Restricted feeding is well known to affect expression profiles of both clock and metabolic genes. However, it is unknown whether these changes in metabolic gene expression result from changes in the molecular clock or in feeding behavior. Here we eliminated the daily rhythm in feeding behavior by providing 6 meals evenly distributed over the light/dark-cycle. Animals on this 6-meals-a-day feeding schedule retained the normal day/night difference in physiological parameters including body temperature and locomotor activity. The daily rhythm in respiratory exchange ratio (RER), however, was significantly phase-shifted through increased utilization of carbohydrates during the light phase and increased lipid oxidation during the dark phase. This 6-meals-a-day feeding schedule did not have a major impact on the clock gene expression rhythms in the master clock, but did have mild effects on peripheral clocks. In contrast, genes involved in glucose and lipid metabolism showed differential expression. In conclusion, eliminating the daily rhythm in feeding behavior in rats does not affect the master clock and only mildly affects peripheral clocks, but disturbs metabolic rhythms in liver, skeletal muscle and brown adipose tissue in a tissue-dependent manner. Thereby, a clear daily rhythm in feeding behavior strongly regulates timing of peripheral metabolism, separately from circadian clocks.

Highlights

Recurring biological events in the mammalian behavioral system such as the sleep-wake, feeding-fasting and rest-activity cycles are under the control of the master or central clock, located in the suprachiasmatic nucleus (SCN) in the anterior hypothalamus of the brain
The daily rhythm produced by this molecular clock mechanism has a period of approx. 24 h and is entrained to the exact 24-h rhythm of the outside world by environmental light perceived by the retina and reaching the SCN via the retino-hypothalamic tract (RHT)
Many studies have investigated the effects of time restricted feeding (TRF) on energy metabolism by focusing on gene expression in liver, skeletal muscle, brown adipose tissue (BAT) and white adipose tissue (WAT) [31,32,35]. Since in these studies clock gene expression profiles were strongly affected by time-restricted feeding (TRF), it was not possible to determine whether the changes in the expression profiles of metabolic genes were driven by the altered rhythms in feeding behavior itself or the altered rhythms in clock gene expression

Summary

Introduction

Recurring biological events in the mammalian behavioral system such as the sleep-wake, feeding-fasting and rest-activity cycles are under the control of the master or central clock, located in the suprachiasmatic nucleus (SCN) in the anterior hypothalamus of the brain. The SCN clock output controls and coordinates other secondary clocks in the brain and peripheral clocks present in virtually every other tissue in the body through neural, humoral and behavioral rhythms, and regulates bodily rhythms in metabolism [1,2,3,4]. The positive limb of this molecular clock consists of the core clock elements BMAL1 and CLOCK Heterodimerization of these core clock elements drives transcription of the Period (Per, Per, and Per3) and Cryptochrome genes (Cry and Cry2) [8,9,10,11]. The molecular clock uses clock-controlled genes such as Dbp, as well as other transcription factors, as an output to regulate a wide variety of cellular processes, of which many involve metabolic processes [18,19]. The biological clock plays a major role in energy metabolism, at a whole-body level, and at a tissue/cellular level

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