Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CLOCK transcription factor is a key component of the molecular circadian clock within pacemaker neurons of the hypothalamic suprachiasmatic nucleus. We found that homozygous Clock mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia. Expression of transcripts encoding selected hypothalamic peptides associated with energy balance was attenuated in the Clock mutant mice. These results suggest that the circadian clock gene network plays an important role in mammalian energy balance.
 ...
PMID:Obesity and metabolic syndrome in circadian Clock mutant mice. 1584 77

Recent studies have suggested that the impairment of the circadian molecular clock in peripheral tissues, including adipose tissue, is involved in the development of metabolic syndrome. Although the disorder is often caused by dietary obesity, it remains to be elucidated whether dietary obesity or high-caloric intake per se affects the molecular clock system. To address this issue, this study investigated the effect of high-fat feeding on the rhythmic mRNA expression of clock genes (Clock, Bmal1, Per1, Per2, Cry1, Cry2, and Dbp) in mouse visceral adipose tissue and liver. Mice fed a high-fat diet for 8 wks developed a mild but overt metabolic syndrome of obesity, hyperlipidemia, and hyperglycemia. However, the high-fat feeding had only minimal effects on the rhythmic expression of the clock genes examined in both tissues. On the other hand, daily rhythmicity in the transcript level of cholesterol 7alpha-hydroxylase, a hepatic enzyme controlling circadian cholesterol homeostasis, disappeared in the mice on high-fat chow. These results suggest that high-fat feeding and mild metabolic syndrome scarcely alter the molecular clock system in mouse peripheral tissues, and that physiological circadian rhythms could be affected without altering the system. Further studies are needed to better understand the role of the circadian molecular clock in the development of metabolic syndrome. The first two authors contributed equally to this study.
 ...
PMID:High-fat feeding exerts minimal effects on rhythmic mRNA expression of clock genes in mouse peripheral tissues. 1705 Feb 8

The role of peripheral vs. central circadian rhythms and Clock in the maintenance of metabolic homeostasis and with aging was examined by using Clock(Delta19)+MEL mice. These have preserved suprachiasmatic nucleus and pineal gland rhythmicity but arrhythmic Clock gene expression in the liver and skeletal muscle. Clock(Delta19)+MEL mice showed fasting hypoglycemia in young-adult males, fasting hyperglycemia in older females, and substantially impaired glucose tolerance overall. Clock(Delta19)+MEL mice had substantially reduced plasma insulin and plasma insulin/glucose nocturnally in males and during a glucose tolerance test in females, suggesting impaired insulin secretion. Clock(Delta19)+MEL mice had reduced hepatic expression and loss of rhythmicity of gck, pfkfb3, and pepck mRNA, which is likely to impair glycolysis and gluconeogenesis. Clock(Delta19)+MEL mice also had reduced glut4 mRNA in skeletal muscle, and this may contribute to poor glucose tolerance. Whole body insulin tolerance was enhanced in Clock(Delta19)+MEL mice, however, suggesting enhanced insulin sensitivity. These responses occurred although the Clock(Delta19) mutation did not cause obesity and reduced plasma free fatty acids while increasing plasma adiponectin. These studies on clock-gene disruption in peripheral tissues and metabolic homeostasis provide compelling evidence of a relationship between circadian rhythms and the glucose/insulin and adipoinsular axes. It is, however, premature to declare that clock-gene disruption causes the full metabolic syndrome.
 ...
PMID:Metabolic homeostasis in mice with disrupted Clock gene expression in peripheral tissues. 1768 88

Recent studies have revealed a close relationship between the pathophysiology of metabolic syndrome, which is characterized by obesity and hyperglycemia, and the functioning of internal molecular clocks. In this study, we show that the rhythmic mRNA expression of clock genes (Clock, Bmal1, Cry1, and Dbp) is not attenuated in the liver and visceral adipose tissues of Goto-Kakizaki rats, a model of nonobese, type 2 diabetes, as compared to control Wistar rats. Our results suggest that molecular clock impairment in peripheral tissues of obese diabetic animals may be either caused by obesity-related factor(s), but not hyperglycemia, or be a cause, but not a consequence, of hyperglycemia.
 ...
PMID:Clock gene expression in the liver and adipose tissues of non-obese type 2 diabetic Goto-Kakizaki rats. 1938 96

To analyze in severely obese women the circadian expression of the clock genes hPer2, hBmal1, and hCry1 in explants from subcutaneous (SAT) and visceral (VAT) adipose tissue (AT), in order to elucidate whether this circadian clockwork can oscillate accurately and independently of the suprachiasmatic nucleus (SCN) and if glucocorticoid metabolism-related genes such as glucocorticoid receptor (hGr) and 11beta-hydroxysteroid dehydrogenase 1 (h11 beta Hsd1) and the transcription factor peroxisome proliferator activated receptor gamma (hPPAR gamma) are part of the clock controlled genes. AT biopsies were obtained from morbid obese patients (BMI > or =40 kg/m(2)) (n = 7). Anthropometric variables were measured and fasting plasma lipids and lipoprotein concentrations were analyzed. In order to carry out rhythmic expression analysis, AT explants were cultured during 24 h and gene expression was performed at the following times (T): 0, 6, 12, and 18 h, with quantitative real-time PCR. Clock genes oscillated accurately and independently of the SCN in AT explants. Their intrinsic oscillatory mechanism regulated the timing of other genes such as hPPAR gamma and glucocorticoid-related genes. Circadian patterns differed between VAT and SAT. Correlation analyses between the genetic circadian oscillation and components of the metabolic syndrome (MetS) revealed that subjects with a higher sagittal diameter showed an increased circadian variability in hPer2 expression (r = 0.91; P = 0.031) and hBmal1 (r = 0.90; P = 0.040). Data demonstrate the presence of peripheral circadian oscillators in human AT independently of the central circadian control mechanism. This knowledge paves the way for a better understanding of the circadian contribution to medical conditions such as obesity and MetS.
 ...
PMID:Circadian rhythm of clock genes in human adipose explants. 1947 85

The association between obesity, other cardiovascular risk factors, and cognitive function in a Canadian First Nations population was investigated using a cross-sectional design. Eligible individuals were aged >/=18 years, without a history of stroke, nonpregnant, with First Nations status, and who had undergone cognitive function assessment by the Clock Drawing Test (CDT) and Trail Making Test Parts A and B. Parts A and B were combined into an Executive Function Score (TMT-exec). Hypertension, a previous history of cardiovascular disease, dyslipidemia, metabolic syndrome, insulin resistance, and the presence and duration of diabetes were examined in addition to obesity. In the case of TMT-exec only, obese individuals were at an approximately fourfold increased risk for lowered cognitive performance compared to those who were not obese in multivariable models (odds ratio (OR): 3.77, 95% confidence interval (CI): 1.46-9.72) whereas there was no effect for overweight individuals compared to those with a normal weight in unadjusted analysis. Those having an increased waist circumference also had 5 times the risk compared to those without an increased waist circumference (OR: 5.41, 95% CI: 1.83-15.99). Adjusted for age, sex, and insulin resistance, individuals having the metabolic syndrome were at an approximately fourfold increased risk compared to those without the metabolic syndrome (OR: 3.67, 95% CI: 1.34-10.07). No other cardiovascular risk factors were associated. Obesity and metabolic syndrome were associated with lowered cognitive performance. These results highlight the importance of studying the health effects of obesity beyond traditional disease endpoints, even in a relatively youthful population.
 ...
PMID:Obesity and lowered cognitive performance in a Canadian First Nations population. 1947 88

In all living organisms, one of the most indispensable biological functions is the circadian clock (suprachiasmatic nuclei; SCN), which acts like a multifunction timer to regulate homeostatic systems such as sleep and activity, hormone levels, appetite, and other bodily functions with 24h cycles. Circadian rhythms regulate diverse physiologic processes, including homeostatic functions of steroid hormones and their receptors. Perturbations of these rhythms are associated with pathogenic conditions such as depression, diabetes and cancer. Clock genes are identified as the genes that ultimately control a vast array of circadian rhythms in physiology and behavior. Clock gene regulates several diseases such as cancer, metabolic syndrome and sleep etc. CLOCK mutation affects the expression of rhythmic genes in wild-type (WT) tissue, but also affects that of non-rhythmic genes. On the other hand, the change of the drug pharmacodynamic and pharmacokinetic (PK/PD) parameters are influenced by not only inter-individual variability but also intra-individual variabilities of medications. Identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. The mechanisms underlying chronopharmacological findings should be clarified from viewpoint of clock genes. On the other hand, several drugs have an effect on molecular clock. Thus, the knowledge of intra- and inter-individual variability of molecular clock should be applied for the clinical practice. Therefore, we introduce the regulatory system of biological rhythm from viewpoints of clock genes and the possibility of pharmacotherapy based on the intra- and inter-individual variability of clock genes.
 ...
PMID:Chronopharmacological strategies: Intra- and inter-individual variability of molecular clock. 2063 41

Glucocorticoids, the end-products of the hypothalamic-pituitary- adrenal (HPA) axis, influence the functions of virtually all organs and tissues through the nuclear glucocorticoid receptor (GR). Circulating levels of glucocorticoids fluctuate naturally in a circadian fashion under the strong influence of the hypothalamic suprachiasmatic nucleus (SCN) circadian CLOCK system, and regulate the transcriptional activity of the GR in the brain and peripheral target tissues. We recently reported that the basic helix-loop- helix transcription factor Clock, which is a histone acetyltransferase and a central component of the self-oscillating transcription factor loop that generates circadian rhythms, represses GR transcriptional activity by acetylating lysine residues within the 'lysine cluster' located in the hinge region of the receptor. This Clock-mediated repression of GR transcriptional activity oscillates in inverse phase to the HPA axis, acting as a target tissue counter-regulatory mechanism to the diurnally fluctuating circulating glucocorticoids. Interestingly, mild evening elevations of corti-sol, as occurs in chronic stress situations, and frequent uncoupling of the SCN CLOCK-directed HPA axis from the daily oscillation of target tissue sensitivity to glucocorticoids, as happens in trans-time zone travel and night shift work, produce functional hypercortisolism and, hence, multiple components of the metabolic syndrome with resultant cardiovascular complications.
 ...
PMID:Circadian CLOCK-mediated regulation of target-tissue sensitivity to glucocorticoids: implications for cardiometabolic diseases. 2116 65

Many pathophysiological circumstances vary during 24 h periods. Many physiologic processes undergo biological rhythms, including the sleep-wake rhythm and metabolism. Disruptive effect in the 24 h variations can manifest as the emergence or exacerbation of pathological conditions. So, chronotherapeutics is gaining increasing interest in experimental biology, medicine, pharmacy, and drug delivery. This science and the plethora of information should be used intelligently for optimizing the effectiveness and safety of the drug, relying on the timing of drug intake. These chronopharmacological findings are affected by not only the pharmacodynamics but also pharmacokinetics of drugs. The mammalian circadian pacemaker is located in the suprachiasmatic nucleus. The molecular mechanisms are associated with Clock genes that control the circadian rhythms in physiology, pathology, and behavior. Clock controls several diseases such as metabolic syndrome, cancer, and so on. CLOCK mutation influences the expression of both rhythmic and nonrhythmic genes in wild-type tissues. These genotypic changes lead to phenotypic changes, affecting the drug pharmacokinetic and pharmacodynamic parameters. This review is intended to elaborate system regulating biological rhythms and the applicability in pharmaceutics from viewpoints of the intraindividual and interindividual variabilities of Clock genes.
 ...
PMID:Molecular basis of chronopharmaceutics. 2165 20

Deficiency of fatty acid translocase Cd36 has been shown to have a major role in the pathogenesis of metabolic syndrome in the spontaneously hypertensive rat (SHR). We have tested the hypothesis that the effects of Cd36 mutation on the features of metabolic syndrome are contextually dependent on genomic background. We have derived two new congenic strains by introgression of limited chromosome 4 regions of SHR origin, both including the defective Cd36 gene, into the genetic background of a highly inbred model of insulin resistance and dyslipidemia, polydactylous (PD) rat strain. We subjected standard diet-fed adult males of PD and the congenic PD.SHR4 strains to metabolic, morphometric and transcriptomic profiling. We observed significantly improved glucose tolerance and lower fasting insulin levels in PD.SHR4 congenics than in PD. One of the PD.SHR4 strains showed lower triglyceride concentrations across major lipoprotein fractions combined with higher levels of low-density lipoprotein cholesterol compared with the PD progenitor. The hepatic transcriptome assessment revealed a network of genes differentially expressed between PD and PD.SHR4 with significant enrichment by members of the circadian rhythmicity pathway (Arntl (Bmal1), Clock, Nfil3, Per2 and Per3). In summary, the introduction of the chromosome 4 region of SHR origin including defective Cd36 into the PD genetic background resulted in disconnected shifts of metabolic profile along with distinct changes in hepatic transcriptome. The synthesis of the current results with those obtained in other Cd36-deficient strains indicates that the eventual metabolic effect of a deleterious mutation such as that of SHR-derived Cd36 is not absolute, but rather a function of complex interactions between environmental and genomic background, upon which it operates.
 ...
PMID:CD36-deficient congenic strains show improved glucose tolerance and distinct shifts in metabolic and transcriptomic profiles. 2247 11


1 2 Next >>