Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-1 beta (IL-1 beta) induces anorexia when administered acutely or chronically into the cerebrospinal fluid (CSF) at doses that yield estimated pathophysiological concentrations. Enhanced sensitivity to IL-1 beta-induced anorexia has been observed in animal models of obesity, including the obese (fa/fa) Zucker rat. Obesity is also associated with increased tumor necrosis factor-alpha mRNA expression in adipose tissue. This suggests that obese individuals may have dissimilar sensitivity to cytokine action and differential regulation of cytokine production. In this study, we investigated the regulation of the IL-1 beta system (IL-1 beta, IL-1 receptor type I (IL-1RI) and IL-1 receptor antagonist (IL-1Ra)) in the central nervous system (CNS) in response to the chronic intracerebroventricular (i.c.v.) microinfusion (via osmotic minipumps) of 8 ng IL-1 beta/24 h/72 h-a dose that yields estimated pathophysiological concentrations in the CSF. IL-1 beta, IL-1RI and IL-1Ra mRNAs were determined by sensitive RNase protection assays in brain target regions for IL-1 beta (cerebellum, parieto-frontal cortex, hippocampus, hypothalamus and midbrain). The results show that chronic i.c.v. microinfusion of IL-1 beta increased the IL-1 beta mRNA, IL-1R1 mRNA and IL-1Ra mRNA levels in the hypothalamus > cerebellum in both obese (fa/fa) and lean (Fa/Fa) Zucker rats. IL-1 beta mRNA levels also increased in the cortex, hippocampus and midbrain of obese (fa/fa) rats. The profiles of IL-1 beta mRNA, IL-1RI mRNA and IL-1Ra mRNA in the same hypothalamic samples obtained from obese or lean rats were highly intercorrelated. However, no significant differences in the level of IL-1 beta system mRNAs induction were observed in any brain region between obese and lean rats. On the other hand, levels of rat glyceraldehyde 3-phosphate dehydrogenase mRNA were fairly constant, and heat-inactivated IL-1 beta (8 ng/24 h/72 h) had no effect on IL-1 beta, IL-1RI and IL-1Ra mRNAs levels in any brain region. The data suggest: (1) the operation of an IL-1 beta feedback system (IL-1 beta/IL-1Ra/IL-1RI) in brain regions; (2) that enhanced sensitivity of obese rats to IL-1 beta-induced anorexia is not dependent on changes in the brain IL-1 beta system at the mRNA level; and (3) that the present novel approach can be used to investigate the molecular basis of cytokine action in the CNS.
 ...
PMID:Molecular regulation of the brain interleukin-1 beta system in obese (fa/fa) and lean (Fa/Fa) Zucker rats. 903 35

Pathophysiological and pharmacological concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) in the cerebrospinal fluid (CSF) induce anorexia in normal rats. Obesity in humans and rodents is associated with increased TNF-alpha messenger RNA and protein levels in various cell types. This suggests that obese individuals may have differential regulation of cytokine production and dissimilar responsiveness to cytokines. In the present study, we investigated the effects of the intracerebroventricular (ICV) microinfusion of TNF-alpha (50, 100, and 500 ng/rat), IL-1 beta (1.0, 4.0, and 8.0 ng), and TNF-alpha (100 ng) plus IL-1 beta (1.0 ng) on obese (fa/fa) and lean (Fa/Fa) Zucker rats. The results show that: TNF-alpha and IL-1 beta, and the concomitant administration of TNF-alpha and IL-1 beta decreased the short-term (4 hours), nighttime (12 hours), and total daily food intakes in obese and lean rats; IL-1 beta was more potent relative to TNF-alpha; obese rats showed greater responsiveness to IL-1 beta: 8.0 ng IL-1 beta, for example, decreased the 12-hour food intake by 52% in obese and 22% in lean rats. On the other hand, obese and lean rats did not exhibit a significantly different responsiveness to the anorexia induced by 50, 100, or 500 ng TNF-alpha at the 4-hour period; and the concomitant ICV administration of TNF-alpha and IL-1 beta induced anorexia with additive (4-hour period) or synergistic (12-hour and 24-hour periods) effects in obese rats. The effect of TNF-alpha plus IL-1 beta in lean rats was greater than additive for the 12-hour and 24-hour periods. The difference in suppression of total daily food intake by TNF-alpha plus IL-1 beta in obese (-43%) versus lean (-23%) rats was significantly different (p < 0.01). The results show that obese (fa/fa) and lean (Fa/Fa) Zucker rats have differential responsiveness to the ICV microinfusion of two different classes of cytokines.
 ...
PMID:Differential responsiveness of obese (fa/fa) and lean (Fa/Fa) Zucker rats to cytokine-induced anorexia. 906 14

Tumor necrosis factor-alpha (TNF alpha) can decrease adipose tissue mass, but in obesity, adipose tissue hypertrophy persists despite increased TNF alpha expression. The hormonal milieu of obesity may antagonize the adipostat effects of TNF alpha. We examined the effects of insulin and the synthetic glucocorticoid, dexamethasone (Dex), on TNF alpha-induced apoptosis and gene expression in human adipocytes and preadipocytes. Using RT multiplex PCR, the expression of the proapoptotic genes interleukin-1 beta (IL-1 beta)-converting enzyme (ICE) and TNF alpha and the antiapoptotic genes bcl-2, nuclear factor-kappa B (NF kappa B), and NF kappa B inhibitory subunit, I kappa B, were examined. The expression and release of IL-1 beta, a postulated downstream effector of ICE-mediated apoptosis, were also determined. TNF alpha increased the messenger ribonucleic acid levels of ICE, TNF alpha, IL-1 beta, bcl-2, and NF kappa B in preadipocytes and adipocytes (P < 0.01). Dex inhibited TNFalpha-induced messenger ribonucleic acid expression of ICE, TNF alpha, and IL-1 beta (P < 0.01), but not that of bcl-2 and NF kappa B. TNF alpha stimulated IL-1 beta release from preadipocytes and adipocytes up to 20-fold, but the effect was abrogated by Dex. Apoptosis induced by TNF alpha was reduced to control levels (P < 0.01) by Dex. Insulin had no significant effect on TNF alpha-induced apoptosis and gene expression. In obesity, glucocorticoids may reduce TNF alpha actions in adipose tissue by inhibiting TNF alpha-induced apoptosis, IL-1 beta release, and TNF alpha expression.
 ...
PMID:Dexamethasone inhibits tumor necrosis factor-alpha-induced apoptosis and interleukin-1 beta release in human subcutaneous adipocytes and preadipocytes. 1139 93

Glucocorticoids are regulated at the prereceptor level by 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), which interconverts inactive cortisone and active cortisol. In a previous study, we noted that patients with hypothalamic obesity had an increased ratio of cortisol/cortisone metabolites, suggesting enhanced 11 beta-HSD-1 activity. In this in vitro study, we tested the hypothesis that adipose 11 beta-HSD-1 is regulated by the hypothalamus via circulating hormones, sympathetic nervous system innervation, and/or cytokines. Preadipocytes were retrieved from sc fat from healthy nonobese individuals and differentiated in vitro to mature adipocytes. Cells were incubated with several potential effectors, and the activity of 11 beta-HSD-1 was assayed by measuring conversion of added 500 nM cortisone to cortisol. Expression of 11 beta-HSD-1 mRNA was determined by real-time PCR, whereas lipolytic effects were determined by measuring glycerol concentration in the culture medium. CRH down-regulated 11 beta-HSD-1 activity with maximal effect at 10(-9)M (65 +/- 10% of control; P < 0.001) and caused a reduction in lipolysis. Likewise, ACTH down-regulated 11 beta-HSD-1 activity with maximal effect at 10(-9) M (65 +/- 20%; P < 0.05) and reduced medium glycerol. Neither CRH nor ACTH affected 11 beta-HSD-1 mRNA expression. TNF alpha up-regulated 11 beta-HSD-1 activity maximally at 0.6 x 10(-9) M (140 +/- 20%; P < 0.001); the same cytokine increased 11 beta-HSD-1 mRNA levels to 3-fold of control (P < 0.05) and increased medium glycerol levels to 165 +/- 14% of control (P < 0.01). IL-1 beta also up-regulated 11 beta-HSD-1 activity maximally at 0.6 x 10(-9) M (160 +/- 33%; P < 0.001) and caused an increase in glycerol levels (159 +/- 11% of control; P < 0.001). Of the adrenergic agonists, salbutamol up-regulated 11 beta-HSD-1 activity maximally at 10(-7) M (162 +/- 46%; P < 0.02), and clonidine down-regulated it at 10(-7) M (82 +/- 15%; P < 0.005). We conclude that possible distinct hypothalamic mediators regulating adipose tissue 11 beta-HSD-1 might include down-regulation of 11 beta-HSD-1 activity by CRH, ACTH, and alpha 2 sympathetic stimulation, and up-regulation of the enzyme by beta 2 sympathetic stimulation and by the cytokines TNFalpha and IL-1 beta.
 ...
PMID:Modulation of 11 beta-hydroxysteroid dehydrogenase type 1 in mature human subcutaneous adipocytes by hypothalamic messengers. 1251 81

The present studies examined the effect of obesity in humans on the release of transforming growth factor beta1 (TGF-beta1) by human adipose tissue. The regulation of TGF-beta1 release by adipose tissue as well as the question of whether its release is due to the adipocytes or the nonfat cells in adipose tissue was also examined. There was a statistically significant (r=0.50) correlation between the body mass index of the fat donors and the subsequent release of TGF-beta1 release by subcutaneous adipose tissue. There was also a positive correlation between total TGF-beta1 release by adipose tissue explants and body fat content (r=0.69). The question of whether tumor necrosis factor alpha (TNF-alpha) and/or interleukin 1 beta (IL-1 beta) regulate the release of TGF-beta1 was investigated by incubation of adipose tissue explants with a soluble human TNF-alpha receptor (etanercept) and a neutralizing antihuman IL-1 beta antibody. The release of TGF-beta1 over 48 hours by adipose tissue explants was significantly enhanced in the presence of both the inhibitor of TNF-alpha and of IL-1 beta. It is of interest, in view of the elevated circulating insulin in blood of morbidly obese women, that the release of TGF-beta1 by adipose tissue was enhanced in the presence of insulin. The question of whether the release of TGF-beta1 by human adipose tissue explants was primarily due to adipocytes, as is the case for leptin, or the nonfat cells present in human adipose tissue, as is the case for IL-8 and prostaglandin E(2), was examined. The release of TGF-beta1 was primarily by the nonfat cells of human adipose tissue because release by adipocytes was less than 10% of that by the nonfat cells of adipose tissue.
 ...
PMID:Transforming growth factor beta1 release by human adipose tissue is enhanced in obesity. 1625 47

Obesity is a low grade inflammatory state associated with premature cardiovascular morbidity and mortality. Along with traditional risk factors the measurement of endothelial function, insulin resistance, inflammation and arterial stiffness may contribute to the assessment of cardiovascular risk. We conducted a randomised placebo controlled trial to assess the effects of 12 weeks treatment with a PPAR alpha agonist (fenofibrate) and a PPAR gamma agonist (pioglitazone) on these parameters in obese glucose tolerant men. Arterial stiffness was measured using augmentation index and pulse wave velocity (PWV). E-selectin, VCAM-1 and ICAM-1 were used as markers of endothelial function. Insulin sensitivity improved with pioglitazone treatment (p=0.001) and, in keeping with this, adiponectin increased by 85.2% (p<0.001). Pro-inflammatory cytokine levels (TNFalpha, IL-6 and IL-1 beta) fell with both treatments (p<0.01 for TNFalpha and IL-1 beta, p<0.001 for IL-6). VCAM-1 and ICAM-1 were reduced with both treatments (p<0.001 for VCAM-1, p<0.05 for ICAM-1) and E-selectin improved with pioglitazone treatment (p=0.05). Both treatments resulted in a fall in augmentation index. PWV fell by 17.4% with fenofibrate treatment (p<0.001) and 16.3% with pioglitazone treatment (p<0.001). Pioglitazone and fenofibrate treatment of obese, glucose tolerant men reduces inflammation, improves markers of endothelial function and reduces arterial stiffness. These results suggest that treatment with PPAR agonists has potential to reduce the incidence of premature cardiovascular disease associated with obesity.
 ...
PMID:Fenofibrate and pioglitazone improve endothelial function and reduce arterial stiffness in obese glucose tolerant men. 1714 61

In adipose tissue metabolism, cytokines were major regulators. mRNA expression studies show that adipocytes can synthesize both tumor necrosis factor-alpha and several interleukins (ILs), notably IL-1 beta (IL-1beta) and IL-6. In particular, IL-1beta expression is under strong genetic control. We examined the relationship among obesity, polymorphism of the IL-1beta at position +3953 in exon 5, and Sasang constitution. In a group of 181 healthy females with a marked variation in body mass index (BMI), we determined the genotype of IL-1beta by polymerase chain reaction-restriction fragment length polymorphism assays. A significant decrease was found for the IL-1beta T allele in the overweight group (BMI 25 approximately 29 kg/m(2)) compared with the lean group with a BMI < 25 kg/m(2) (P = .049, odds ratio [OR] = 0.296). Carriers of T allele in the heterozygous or homozygous form did not show a significant difference in physical and clinical characteristics. In addition, in Taeumin female subjects, the frequency of IL-1beta T allele was apparently decreased in the overweight group (BMI 25 approximately 29 kg/m(2)) compared with the lean group with a BMI < 25 kg/m(2) (P = .007, OR = 0.152). In overweight women, we found an association between the +3953 C/T polymorphism in the IL-1beta gene and BMI. In addition, we found an association among IL-1beta polymorphism, obesity, and Sasang constitution.
 ...
PMID:Interleukin-1 beta gene polymorphism and traditional constitution in obese women. 1846 25

The adipokine tissue inhibitor of metalloproteinase (TIMP)-1 is upregulated when weight is gained and promotes adipose tissue development. In the present study, the effect of insulin resistance-inducing and proinflammatory interleukin (IL)-1 beta on TIMP-1 gene expression and secretion was investigated in 3T3-L1 adipocytes. Interestingly, protein secretion and mRNA production of TIMP-1 were significantly stimulated by IL-1 beta. Thus, IL-1 beta induced TIMP-1 secretion in a dose-dependent manner with maximal 3.5-fold upregulation seen at 0.67 ng/ml IL-1 beta relative to untreated cells. Furthermore, TIMP-1 mRNA synthesis was significantly stimulated by IL-1 beta in a dose-dependent fashion with 2.5-fold induction seen at IL-1 beta concentrations as low as 0.02 ng/ml and maximal 8.1-fold upregulation found at 20 ng/ml effector. Induction of TIMP-1 mRNA was also time dependent with maximal 9.6-fold upregulation detectable after 8 h of IL-1 beta treatment. Signaling studies suggested that janus kinase 2 is involved in IL-1 beta-induced TIMP-1 mRNA expression. Taken together, our results demonstrate that the TIMP-1 expression is selectively upregulated by proinflammatory IL-1 beta, supporting a direct association between insulin resistance, inflammation, and adipose tissue development in obesity.
 ...
PMID:Tissue inhibitor of metalloproteinase-1 mRNA production and protein secretion are induced by interleukin-1 beta in 3T3-L1 adipocytes. 1857 71

The Polycystic ovary syndrome (PCOS) is the most frequent endocrine disorder in premenopausal women and is associated with features of the insulin resistance syndrome, altered glucose homeostasis, and central obesity. Inflammation appears to be a link between obesity and insulin resistance, because adipose tissue is one major source of proinflammatory cytokines. Since peroxisome proliferator-activated receptor (PPAR)gamma affects adipocyte differentiation as well as insulin sensitivity, we investigated whether the levels of proinflammatory factors in PCOS patients are related to sequence variations of the PPAR gamma gene. Proinflammatory cytokine levels, i.e. IL-1 beta, IL-6, IL-7, IL-8, IL-17 and TNFalpha, were evaluated in PCOS patients (n=21) in comparison to obese controls (n=120). Next to this the complete coding sequence of the PPAR gamma gene was investigated by resequencing all probands. We show that the levels of IL-8 and IL-17 were unchanged, IL-1 beta, IL-6 and TNFalpha were elevated and the level of IL-7 was decreased in PCOS patients compared to obese controls. Sequence analyses of the PPAR gamma gene indicated that neither the common polymorphisms P12A or H478 H, nor novel polymorphisms (E79Q, V32G, -39 T>C, c.480 +33 t > g,) or unique sequence variations (S22S, A23A, T41A, S226C, K272 T, I484I, c.819 +24 a>c) detected in this investigation revealed evidence for a direct association of PPAR gamma with altered IL-7, IL-1beta, IL-6 and TNFalpha levels in PCOS patients. So, alterations in inflammatory serum markers appear to be a feature of PCOS per se, and are independent of PPAR gamma variants.
 ...
PMID:Increased low grade inflammatory serum markers in patients with Polycystic ovary syndrome (PCOS) and their relationship to PPARgamma gene variants. 1868 73

The objective of this study was to determine whether single nucleotide polymorphisms (SNPs) in the Interleukin-1 (IL-1) gene family are associated with central obesity and metabolic syndrome in a coronary heart disease population. The IL-1 alpha C-889T (rs1800587) and IL-1 beta +3954 (rs1143634) SNPs were studied in a Western Australian coronary heart disease (CHD) population (N = 556). Subjects who were TT homozygous at either SNP had larger waist circumference (IL-1 alpha: 1.8 cm greater, P = 0.04; IL-1 beta: 4 cm greater, P = 0.0004) compared with major allele homozygotes. Individuals with two copies of the IL-1 alpha:IL-1 beta T:T haplotype had greater waist circumference (4.7 cm greater, P = 0.0001) compared to other haplotypes. There was a significant interaction between the IL-1 beta SNP and BMI level on waist circumference (P = 0.01). When the cohort was stratified by median BMI, TT carriers for IL-1 beta with above median BMI had greater waist circumference (6.1 cm greater, P = 0.007) compared to baseline carriers, whilst no significant association was seen in the below median group. Similarly, when the cohort was stratified by median fibrinogen level (IL-1 alpha interaction P = 0.01; IL-1 beta interaction P = 0.04), TT carriers for both SNPs in the above median fibrinogen group had greater waist circumference (IL-1 alpha 2.7 cm greater, P = 0.007; IL-1 beta 3.3 cm greater, P = 0.003) compared with major allele homozygotes. This association was not seen in the below median group. Also, we found a trend of increased metabolic syndrome for IL-1 beta TT homozygotes (P = 0.07). In conclusion, our findings suggest that in a CHD population IL-1 gene polymorphisms may be involved in increased central obesity, and the genetic influences are more evident among patients who have a higher level of obesity or inflammatory markers.
 ...
PMID:Association of Interleukin-1 gene polymorphisms with central obesity and metabolic syndrome in a coronary heart disease population. 1871 98


1 2 3 Next >>