Abstract
BackgroundCircadian (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.MethodsThe 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.ResultsThe 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.ConclusionDiurnal 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.
Highlights
Circadian rhythm is an integral part of the physiology of the body; sleep, feeding behavior and metabolism are tightly linked to the light-dark cycle dictated by earth's rotation
The expression levels of the core clock genes and the diurnal output genes showed little day-to-day variation during the duration of the study, despite the adipose biopsies being taken from multiple subjects in a trial that lasted over a period of time
The results offer new insights into the physiology of adipose tissue in relation to the diurnal cycle, underscoring the importance of diurnal rhythm for basic physiology of the adipose tissue and energy metabolism in the body
Summary
Circadian (diurnal) rhythm is an integral part of the physiology of the body; sleep, feeding behavior and metabolism are tightly linked to the light-dark cycle dictated by earth's rotation. Circadian (diurnal) rhythms are part of the daily lives of many living organisms, from photosynthetic prokaryotes to higher eukaryotes [1,2] These oscillations likely evolved to ensure temporal coordination of physiological and behavioral processes, both for adapting to predictable daily environmental changes and orchestrating cellular machinery necessary for life. First described in the suprachiasmatic nucleus, circadian clocks have been identified in many peripheral tissues, including adipose, heart, kidney and vasculature [4,5,6]. These peripheral clocks are regulated by central circadian clock machinery and circulating serum markers of circadian function [7,8]. Many genes in peripheral tissues show oscillatory behavior that is responsive to restricted feeding or other perturbations [9]
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