Abstract
Studying circadian rhythms in most human tissues is hampered by difficulty in collecting serial samples. Here we reveal circadian rhythms in the transcriptome and metabolic pathways of human white adipose tissue. Subcutaneous adipose tissue was taken from seven healthy males under highly controlled ‘constant routine’ conditions. Five biopsies per participant were taken at six-hourly intervals for microarray analysis and in silico integrative metabolic modelling. We identified 837 transcripts exhibiting circadian expression profiles (2% of 41619 transcript targeting probes on the array), with clear separation of transcripts peaking in the morning (258 probes) and evening (579 probes). There was only partial overlap of our rhythmic transcripts with published animal adipose and human blood transcriptome data. Morning-peaking transcripts associated with regulation of gene expression, nitrogen compound metabolism, and nucleic acid biology; evening-peaking transcripts associated with organic acid metabolism, cofactor metabolism and redox activity. In silico pathway analysis further indicated circadian regulation of lipid and nucleic acid metabolism; it also predicted circadian variation in key metabolic pathways such as the citric acid cycle and branched chain amino acid degradation. In summary, in vivo circadian rhythms exist in multiple adipose metabolic pathways, including those involved in lipid metabolism, and core aspects of cellular biochemistry.
Highlights
Many aspects of mammalian metabolism exhibit daily variation driven in part by an endogenous circadian timing system[1]
In this study seven healthy male participants underwent restricted sleep-wake and meal times before entering the laboratory, to maximise circadian synchronisation. They maintained this sleep and feeding schedule for three days in the laboratory before undergoing a 37-hour constant routine, during which five six-hourly subcutaneous adipose tissue biopsies were taken per participant
Unsupervised clustering performed on the 837 circadian transcripts revealed 3 distinct clusters (Fig. 1A)
Summary
Many aspects of mammalian metabolism exhibit daily variation driven in part by an endogenous circadian timing system[1] This system is comprised of a central ‘master’ clock in the hypothalamic suprachiasmatic nuclei and an integrated network of circadian clocks present in all major tissues within the body[2]. In addition to defining internal biological time, clock proteins bind to response elements in output genes[8,9] Many of these output genes themselves encode transcription factors and the circadian clock can temporally regulate a large part of the transcriptome[10,11]. Www.nature.com/scientificreports in understanding of circadian rhythmicity in animal tissues, there is very little information on molecular rhythms in humans. Resulting rhythms are driven primarily by the endogenous circadian system
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