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Open Access Highly Accessed Research article

Diurnal variation of the human adipose transcriptome and the link to metabolic disease

Andrey Loboda1, Walter K Kraft2, Bernard Fine1, Jeffrey Joseph3, Michael Nebozhyn1, Chunsheng Zhang1, Yudong He1, Xia Yang1, Christopher Wright1, Mark Morris1, Ira Chalikonda1, Mark Ferguson1, Valur Emilsson1, Amy Leonardson1, John Lamb1, Hongyue Dai1, Eric Schadt1, Howard E Greenberg2 and Pek Yee Lum1*

Author affiliations

1 Rosetta Inpharmatics, LLC (A wholly-owned subsidiary of Merck & Co., Inc.), 401 Terry Ave N., Seattle, WA 98109, USA

2 Thomas Jefferson University, Department of Pharmacology and Experimental Therapeutics, Philadelphia, PA 19107, USA

3 Thomas Jefferson University, Department of Anesthesiology, Philadelphia, PA 19107, USA

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Citation and License

BMC Medical Genomics 2009, 2:7  doi:10.1186/1755-8794-2-7

Published: 9 February 2009

Abstract

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.

Conclusion

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.