Diurnal variation of the human adipose transcriptome and the link to metabolic disease.
BACKGROUND
Circadian (diurnal) rhythm is an integral part of the physiology of the body; specifically, sleep, feeding behavior and metabolism are tightly linked to the light-dark cycle dictated by earth's rotation.


METHODS
The present study examines the effect of diurnal rhythm on gene expression in the subcutaneous adipose tissue of overweight to mildly obese, healthy individuals. In this well-controlled clinical study, adipose biopsies were taken in the morning, afternoon and evening from individuals in three study arms: treatment with the weight loss drug sibutramine/fasted, placebo/fed and placebo/fasted.


RESULTS
The results indicated that diurnal rhythm was the most significant driver of gene expression variation in the human adipose tissue, with at least 25% of the genes having had significant changes in their expression levels during the course of the day. The mRNA expression levels of core clock genes at a specific time of day were consistent across multiple subjects on different days in all three arms, indicating robust diurnal regulation irrespective of potential confounding factors. The genes essential for energy metabolism and tissue physiology were part of the diurnal signature. We hypothesize that the diurnal transition of the expression of energy metabolism genes reflects the shift in the adipose tissue from an energy-expending state in the morning to an energy-storing state in the evening. Consistent with this hypothesis, the diurnal transition was delayed by fasting and treatment with sibutramine. Finally, an in silico comparison of the diurnal signature with data from the publicly-available Connectivity Map demonstrated a significant association with transcripts that were repressed by mTOR inhibitors, suggesting a possible link between mTOR signaling, diurnal gene expression and metabolic regulation.


CONCLUSIONS
Diurnal rhythm plays an important role in the physiology and regulation of energy metabolism in the adipose tissue and should be considered in the selection of novel targets for the treatment of obesity and other metabolic disorders.
Loboda
Andrey
A
Rosetta Inpharmatics, LLC (A wholly-owned subsidiary of Merck & Co,, Inc,), 401 Terry Ave N,, Seattle, WA 98109, USA. andrey_loboda@merck.com
Kraft
Walter K
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Fine
Bernard
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Joseph
Jeffrey
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Nebozhyn
Michael
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Zhang
Chunsheng
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He
Yudong
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Yang
Xia
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Wright
Christopher
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Morris
Mark
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Chalikonda
Ira
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Ferguson
Mark
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Emilsson
Valur
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Leonardson
Amy
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Lamb
John
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Dai
Hongyue
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Schadt
Eric
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Greenberg
Howard E
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Lum
Pek Yee
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