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Title: An approximation to the temporal order in endogenous circadian rhythms of genes implicated in human adipose tissue metabolism

Author
item GARAULET, MARTA - Universidad De Murcia
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item GOMEZ-ABELLAN, PURIFICACION - Universidad De Murcia
item MARTINEZ, JOSE - University Of Navarra
item MADRID, JUAN - Universidad De Murcia

Submitted to: Journal of Cellular Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/5/2010
Publication Date: 8/1/2011
Citation: Garaulet, M., Ordovas, J.M., Gomez-Abellan, P., Martinez, J.A., Madrid, J.A. 2011. An approximation to the temporal order in endogenous circadian rhythms of genes implicated in human adipose tissue metabolism. Journal of Cellular Physiology. 226(8):2075-2080.

Interpretive Summary: A circadian rhythm is any biological process that displays an endogenous change during a 24 hour period. These rhythms are driven by a circadian clock, and there are many health problems (i.e., obesity, cardiovascular diseases, neurological disorders) associated with disturbances of the human circadian rhythm. These disturbances may be driven by environmental as well as by genetic factors. Visceral fat (that surrounding internal organs) (VAT) and subcutaneous abdominal fat (that under the skin) (SAT) exhibit varied risk properties for chronic diseases. Regarding the effect of obesity on circadian patterns, it is known that human adipose tissue (AT) shows circadian rhythmicity but an integrated study of the factors involved in its regulation has not been reported. Therefore, our objective was to provide an overall view of the internal temporal order of circadian rhythms in human AT including genes implicated in metabolic processes such as energy intake and expenditure, insulin resistance, adipocyte differentiation, dyslipidemia, and body fat distribution. VAT and SAT biopsies (n=6) were obtained from severely obese women (BMI greater than or equal to 40 kg/m2). To investigate rhythmic expression patterns, AT explants were cultured during 24-h and gene expression was analyzed at the following times: 08:00, 14:00, 20:00, 02:00 h, using quantitative real-time PCR. Several genes involved in risk for chronic diseases such as Clock genes, glucocorticoid metabolism-related genes, leptin, adiponectin and their receptors were studied. Significant differences in the rhythm of gene expression were found between VAT and SAT. Particularly interesting were the relationships between adiponectin, leptin, and glucocorticoid metabolism-related genes circadian profiles. For example, in SAT, leptin showed maximum expression at night whereas adiponectin was at its peak in mid-morning. In contrast, in VAT, leptin expression occurred in the evening and adiponectin was also delayed. The type fat-specific (VAT vs. SAT) patterns demonstrated for these metabolic regulators have implications for energy intake, insulin sensitivity and overall metabolic homeostasis, and may therefore shed some light on the different metabolic risks associated with VAT and SAT.

Technical Abstract: Although it is well established that human adipose tissue (AT) shows circadian rhythmicity, published studies have been discussed as if tissues or systems showed only one or few circadian rhythms at a time. To provide an overall view of the internal temporal order of circadian rhythms in human AT including genes implicated in metabolic processes such as energy intake and expenditure, insulin resistance, adipocyte differentiation, dyslipidemia, and body fat distribution. Visceral and subcutaneous abdominal AT biopsies (n=6) were obtained from morbid obese women (BMI greater than or equal to 40 kg/m(2) ). To investigate rhythmic expression pattern, AT explants were cultured during 24-h and gene expression was analyzed at the following times: 08:00, 14:00, 20:00, 02:00 h using quantitative real-time PCR. Clock genes, glucocorticoid metabolism-related genes, leptin, adiponectin and their receptors were studied. Significant differences were found both in achrophases and relative-amplitude among genes (P less than 0.05). Amplitude of most genes rhythms was high ( more than 30%). When interpreting the phase map of gene expression in both depots, data indicated that circadian rhythmicity of the genes studied followed a predictable physiological pattern, particularly for subcutaneous AT. Interesting are the relationships between adiponectin, leptin, and glucocorticoid metabolism-related genes circadian profiles. Their metabolic significance is discussed. Visceral AT behaved in a different way than subcutaneous for most of the genes studied. For every gene, protein mRNA levels fluctuated during the day in synchrony with its receptors. We have provided an overall view of the internal temporal order of circadian rhythms in human adipose tissue.