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Rhythmic Messenger Ribonucleic Acid Expression of Clock Genes and Adipocytokines in Mouse Visceral Adipose Tissue

Division of Clinical Pharmacology (H.A., H.Y., Y.H., Y.O., S.T., A.F.), Department of Pharmacology, Jichi Medical School, Tochigi 329-0498, Japan; and Department of Diabetes and Digestive Disease (T.T., S.K.), Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8641, Japan

Address all correspondence and requests for reprints to: Dr. Akio Fujimura, Department of Pharmacology, Jichi Medical School, Tochigi 329-0498, Japan. E-mail: akiofuji{at}jichi.ac.jp.

Various peripheral tissues show circadian rhythmicity, which is generated at the cellular level by their own core oscillators that are composed of transcriptional/translational feedback loops involving a set of clock genes. Although the circulating levels of some adipocytokines, i.e. bioactive substances secreted by adipocytes, are on a 24-h rhythmic cycle, it remains to be elucidated whether the clock gene system works in adipose tissue. To address this issue, we investigated the daily mRNA expression profiles of the clock genes and adipocytokines in mouse perigonadal adipose tissues. In C57BL/6J mice, all transcript levels of the clock genes (Bmal1, Per1, Per2, Cry1, Cry2, and Dbp) and adipocytokines (adiponectin, resistin, and visfatin) clearly showed 24-h rhythms. On the other hand, the rhythmic expression of these genes was mildly attenuated in obese KK mice and greatly attenuated in more obese, diabetic KK-A^y mice. Obese diabetes also diminished the rhythmic expression of the clock genes in the liver. Interestingly, a 2-wk treatment of KK and KK-A^y mice with pioglitazone impaired the 24-h rhythmicity of the mRNA expression of the clock genes and adipocytokines despite the antidiabetic effect of the drug. In contrast, pioglitazone improved the attenuated rhythmicity in the liver. These findings suggest that the intracellular clock gene system acts in visceral adipose tissues as well as liver and is influenced by the conditions of obesity/type 2 diabetes and pioglitazone treatment.

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