Characteristics of Circadian Gene Expressions in Mice White Adipose Tissue and 3T3-L1 Adipocytes

Abstract

Most, if not all, of physiological and behavioral processes exhibit circadian rhythms. Recently, molecular clocks similar to those operating in the suprachiasmatic nucleus (SCN) neurons have been found in several peripheral tissues. Among peripheral tissues, several recent studies have revealed that white adipose tissues secrete a number of biologically active molecules such as leptin, resistin, adiponectin, etc. Importantly, the levels of these cytokine-like molecules are associated with development of lifestyle-related diseases such as diabetic mellitus, cardiovascular diseases, and obesity. In this study, we attempted to characterize circadian gene expression in adipose tissue. Here, we show that the expression of several clock genes exhibits daily oscillation in mice white adipocytes. Circadian expression of adipocytes-related genes such as peroxisome proliferator-activated receptor (PPAR) γ2 was also observed. Interestingly, expression pattern of some clock genes in adipocytes is distinct from that in stromal-vascular fractions containing preadipocytes. In addition to these in vivo studies, we demonstrated that serum-or dexamethasone-shock induced the cyclic gene expression of clock genes in cultured adipocytes. Consequently, we are led to conclude that adipocytes contain the machineries necessary for circadian oscillation similar to that found in SCN. We then examined that whether the pharmacological effects of PPARγ2 ligand depend on the time of administration. Consist with its receptor levels, the pharmacological effects of PPARγ ligand administered during a dark period were more efficient than those during a light period in mice. These results suggest that chronotherapy targeted for adipocyte functions could be effective in improving of the symptoms of hyperlipidemia and other related diseases.

Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, regulates adipogenesis

“…First, BMAL1 is highly induced during adipogenesis (ref. 8 and this study). Second, BMAL1-deficient mice lack diurnal variation in triglyceride level (17).…”

“…Epididymal white adipose tissue was excised from mice and fractionated into an adipocyte and a stromal-vascular fractions as described in ref. 8. Briefly, freshly excised fat pads from C57BL͞6J mice were rinsed in PBS, minced, and digested for 45 min at 37°C in Krebs-Ringer bicarbonate, pH 7.4, with 4% BSA and 1.5 mg͞ml type I collagenase (Worthington).…”

“…Therefore, molecular clock may play important roles in the regulation of metabolic activity in adipocytes. In a previous study, we reported that white adipose tissue contains functional molecular clock and that expression of several adipocytokines, including leptin, and plasminogen activator inhibitor-1 display circadian rhythm (8). The diurnal rhythm in the level of these molecules suggests that the molecular clock is at least partly associated with the onset of metabolic syndrome.…”

Characterization of the Molecular Clock in Mouse Peritoneal Macrophages

“…4). [7][8][9][10][11][12] The presence of molecular clock system in macrophage suggests that macrophages functions display circadian rhythm. As shown in Fig.…”

“…[7][8][9][10][11][12] The molecular clock is composed of transcriptional feedback loops in organisms ranging from cyanobacteria to humans. Two transcription factors, the brain and muscle Arnt-like protein-1 (BMAL1; also referred to as MOP3 or Arnt3) and CLOCK, play central roles in the regulation of circadian rhythms.…”