Circadian expression of adiponectin and its receptors in human adipose tissue.
ABSTRACT Adiponectin is one of the most clinically relevant cytokines associated with obesity. However, circadian rhythmicity of adiponectin in human adipose tissue (AT) has not been analyzed. To assess whether the mRNA levels of adiponectin and its receptors (ADIPOR1 and ADIPOR2) might show daily circadian rhythms in visceral and sc fat explants obtained from morbid obese women, visceral and sc abdominal AT biopsies (n = 6) were obtained from morbidly obese women (body mass index >or=40 kg/m(2)). Anthropometric variables were measured and fasting plasma glucose, lipid, and lipoprotein concentrations were analyzed. To investigate rhythmic expression pattern, AT explants were cultured during 24 h, and gene expression was analyzed at the following times: 0800, 1400, 2000, and 0200 h, using quantitative real-time PCR. All genes investigated showed a circadian rhythmicity and oscillated accurately and independently of the suprachiasmatic nucleus in both AT explants (P < 0.05). Adiponectin gene expression fluctuated in the same phase as its receptors. Correlation analyses between the genetic circadian oscillation and components of the metabolic syndrome revealed that adiposity and abdominal obesity correlated with a decrease in adiponectin and adiponectin receptors ADIPOR1 and ADIPOR2 amplitude (P < 0.05). Visceral fat showed a trend toward a phase delay and dampening of the mRNA amplitude of adiponectin as compared with sc fat. The mRNA expression of adiponectin and its receptors showed 24-h rhythmicity in human AT from morbidly obese patients.
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ABSTRACT: Adiponectin has been proposed to be a mediator of obesity-associated malignancies and to have direct antineoplastic effects acting via adiponectin receptors AdipoR1 and AdipoR2. We describe herein the expression of AdipoR1 and AdipoR2 in several cancers not previously studied. We used immunohistochemistry to assess expression of adiponectin receptors in archival specimens of renal cell carcinoma (n = 64), hepatocellular carcinoma (n = 123), melanoma (n = 20), cholangiocarcinoma (n = 20), transitional cell carcinoma of the bladder (n = 24), ovarian epithelial carcinoma (n = 63), cervical squamous cell carcinoma (n = 49), and adrenocortical carcinoma (n = 48). To compare expression in malignant versus nonmalignant tissues, we also studied AdipoR1 and AdipoR2 expression in pairs of renal cell carcinoma and adjacent healthy kidney tissue specimens by immunohistochemistry. We also studied mRNA expression in 45 specimens of renal cell carcinoma by real-time polymerase chain reaction. Finally, we utilized Western blotting to confirm the presence of adiponectin receptors and subsequently studied cell signaling pathways of adiponectin in the renal cancer cell line 786-O. Cancers associated with obesity were significantly more likely to express AdipoR1 than cancers not associated with obesity. Of the specimens of renal cell carcinoma, which is strongly associated with obesity, 93.8% expressed AdipoR1 compared to 44.9% of the specimens of cervical cell carcinoma, which is not associated with obesity (p < 0.001). There was no difference in the expression of adiponectin receptors or their mRNA between malignant and benign kidney tissue specimens. Overall, there were no correlations between expression of adiponectin receptors or their mRNA and tumor prognostic factors. Finally, Western blotting confirmed the presence of AdipoR1 in the renal cancer cell line 786-O, and adiponectin activates in vitro several signaling pathways in this cell line. In summary, we report for the first time expression of AdipoR1 and AdipoR2 in the above cancers and that AdipoR1 is more ubiquitously expressed in obesity-associated cancers.Hormones and Cancer 06/2010; 1(3):136-45.
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ABSTRACT: Circadian rhythms (approximately 24h) are widely characterized at molecular level and their generation is acknowledged to originate from oscillations in expression of several clock genes and from regulation of their protein products. While general entrainment of organisms to environmental light-dark cycles is mainly achieved through the master clock of the suprachiasmatic nucleus in mammals, this molecular clockwork is functional in several organs and tissues. Some studies have suggested that disruption of the circadian system (chronodisruption (CD)) may be causal for manifestations of the metabolic syndrome. This review summarizes (1) how molecular clocks coordinate metabolism and their specific role in the adipocyte; (2) the genetic aspects of and scientific evidence for obesity as a chronobiological illness; and (3) CD and its causes and pathological consequences. Finally, ideas about use of chronobiology for the treatment of obesity are discussed.Clinica Chimica Acta - CLIN CHIM ACTA. 01/2012;
Article: Circadian gene variants in cancer.[Show abstract] [Hide abstract]
ABSTRACT: Humans as diurnal beings are active during the day and rest at night. This daily oscillation of behavior and physiology is driven by an endogenous circadian clock not environmental cues. In modern societies, changes in lifestyle have led to a frequent disruption of the endogenous circadian homeostasis leading to increased risk of various diseases including cancer. The clock is operated by the feedback loops of circadian genes and controls daily physiology by coupling cell proliferation and metabolism, DNA damage repair, and apoptosis in peripheral tissues with physical activity, energy homeostasis, immune and neuroendocrine functions at the organismal level. Recent studies have revealed that defects in circadian genes due to targeted gene ablation in animal models or single nucleotide polymorphism, deletion, deregulation and/or epigenetic silencing in humans are closely associated with increased risk of cancer. In addition, disruption of circadian rhythm can disrupt the molecular clock in peripheral tissues in the absence of circadian gene mutations. Circadian disruption has recently been recognized as an independent cancer risk factor. Further study of the mechanism of clock-controlled tumor suppression will have a significant impact on human health by improving the efficiencies of cancer prevention and treatment.Annals of medicine. 06/2014;