Obezita je závažné metabolické ochorenie, ktoré ohrozuje pacienta zvýšeným výskytom metabolických, kardiovaskulárnych, nádorových1–3) ako aj ďalších pridružených, zvlášť autoimunitných ochorení, čím sa výrazne zvyšuje morbidita i mortalita pacientov a znižuje sa kvalita života4). Nerovnováha medzi lipolýzou a lipogenézou vyúsťuje do mnohých súvisiacich metabolických porúch na rôznych regulačných úrovniach transkripcie, translácie a/alebo aktivity enzýmov. Jednou z intenzívne študovaných oblastí v rámci regulácie lipogenézy, ktorú často sprevádza zápal, je receptor aktivovaný peroxizómovým proliferátorom (PPAR), konkrétne jeho izomér PPAR-γ. PPAR-γ je ligandom aktivovaný transkripčný faktor patriaci do rodiny jadrových receptorov. Je prednostne prítomný v diferencovaných makrofágoch a v tukovom tkanive5, 6), kde má dôležitú funkciu v diferenciácii adipocytov a riadenia zápalového procesu v zmysle inhibície expresie génov prozápalových cytokínov. Inhibícia PPAR-γ zápalovými cytokínmi ako napr. TNF-α môže predstavovať molekulový mechanizmus lipidových porúch, a tým prispievať k patogenéze rôznych ochorení, ako sú napr. zápal, inzulínová rezistencia alebo ateroskleróza, kde spoločnou črtou sú poruchy v metabolizme lipidov. Pôsobenie špecifických agonistov PPAR-γ mení uvoľňovanie signálnych molekúl z tukového tkaniva, čo má ďalekosiahle metabolické následky na iné tkanivá. Zohráva tak významnú úlohu pri inhibícii zápalu a rozvoja inzulínovej rezistencie.
Obesity is a serious metabolic disease that threatens patients with increasing incidence of the metabolic, cardiovascular, cancer1–3) and other associated, especially autoimmune diseases. It increases significantly the morbidity and mortality of patients and reduces quality of their life. The imbalance between lipolysis and lipogenesis results in a number of metabolic related disorders at the different regulatory levels of transcription, translation, and/or activity of enzymes. One of the extensively studied areas in regulating lipogenesis, often accompanied by inflammation, is a peroxisome proliferator activated receptors (PPARs), especially its isomer PPAR-γ. PPAR-γ is a ligand-activated transcription factor belonging to the family of nuclear receptors. It is mostly presented in differentiated macrophages and adipose tissue5, 6). It has an important function of adipocyte differentiation and inflammation management in terms of gene expression inhibition of pro-inflammatory cytokines. PPAR-γ inhibition of inflammatory cytokines such as TNF-α may present the molecular mechanism of lipid disorders, thus contributing to the pathogenesis of various diseases, e.g. inflammation, insulin resistance and atherosclerosis, for which the lipid metabolism disorders are a common feature. Under the action of specific agonists, PPAR-γ alter the release of signal molecules from adipose tissue, which has far-reaching metabolic consequences in other tissues. It plays an important role in the inhibition of inflammation and the development of insulin resistance.
- MeSH
- adipokiny metabolismus MeSH
- lidé MeSH
- metabolismus lipidů * fyziologie genetika MeSH
- obezita komplikace MeSH
- PPAR alfa fyziologie metabolismus MeSH
- PPAR beta fyziologie metabolismus MeSH
- PPAR gama * fyziologie metabolismus MeSH
- tuková tkáň fyziologie metabolismus MeSH
- zánět MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
The aim of our study was to measure serum concentrations of fibroblast growth factor 19 (FGF-19) in patients with obesity (OB), obesity and type 2 diabetes mellitus (T2DM) and healthy subjects (C) at baseline and after selected interventions. We measured serum FGF-19 levels and other biochemical and hormonal parameters in 29 OB and 19 T2DM females and 30 sex- and age-matched control subjects. The interventions were acute hyperinsulinemia during isoglycemic-hyperinsulinemic clamp (n=11 for T2DM and 10 for C), very-low calorie diet (VLCD, n=12 for OB) and 3 months treatment with PPAR-alpha agonist fenofibrate (n=11 for T2DM). Baseline serum FGF-19 levels were significantly lower in OB relative to C group (132.1+/-12.7 vs. 202.2+/-16.7 pg/ml, p<0.05), while no significant difference was observed between T2DM and OB or control group. Acute hyperinsulinemia tended to decrease FGF-19 levels in both healthy and T2DM subjects. Three weeks of VLCD in OB group had no significant effect on FGF-19, whereas three months of fenofibrate treatment markedly reduced FGF-19 levels in T2DM patients (194.58+/-26.2 vs. 107.47+/-25.0 pg/ml, p<0.05). We conclude that FGF-19 levels in our study were at least partially dependent upon nutritional status, but were not related to parameters of glucose metabolism or insulin sensitivity.
- MeSH
- akutní nemoc MeSH
- biologické markery krev MeSH
- diabetes mellitus 2. typu krev terapie MeSH
- dospělí MeSH
- fenofibrát farmakologie terapeutické užití MeSH
- fibroblastové růstové faktory krev MeSH
- hyperinzulinismus krev terapie MeSH
- inzulinová rezistence MeSH
- kalorická restrikce metody MeSH
- krevní glukóza metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- obezita krev MeSH
- PPAR alfa agonisté fyziologie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
- srovnávací studie MeSH
Silymarin is widely used in supportive therapy of liver diseases. It has been shown lately that silymarin has beneficial effects on some risk factors of atherosclerosis owing to its hypolipidemic properties. PPARalpha plays a key role in lipid metabolism and homeostasis as its target genes are involved in catabolism of fatty acids by beta-oxidation (e.g. acyl-CoA oxidase) and by omega-oxidation (e.g. cytochrome P4504A). Here we studied the possibility that hypolipidemic effects of silymarin may be mediated by PPARalpha. Rats fed with a high-cholesterol diet with either silymarin or fenofibrate (as a positive control both for PPARalpha expression as well as for lipid determination) were used. The effects of silymarin on expression of PPARalpha both at the mRNA (including selected target genes) as well as the protein level were determined. In parallel, the levels of cholesterol and triacylglycerols were determined. Our results confirmed the hypolipidemic effects of silymarin and demonstrated that these effects are probably not mediated by PPARalpha because of unchanged mRNA levels of PPARalpha target genes. Furthermore, this work shows for the first time that cholesterol itself inhibits expression of CYP4A mRNA.
- MeSH
- exprese genu účinky léků MeSH
- financování organizované MeSH
- hypolipidemika farmakologie metabolismus MeSH
- krysa rodu rattus MeSH
- potkani Wistar MeSH
- PPAR alfa biosyntéza fyziologie genetika MeSH
- silymarin fyziologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
We studied the effect of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activation on serum concentrations and tissue expression of resistin, adiponectin, and adiponectin receptor-1 and -2 (AdipoR1 and AdipoR2) mRNA in normal mice and mice with insulin resistance induced by lipogenic, simple-carbohydrate diet (LD). Sixteen weeks of LD feeding induced obesity with liver steatosis and increased insulin levels but did not significantly affect circulating adiponectin or resistin. Treatment with PPAR-alpha agonist fenofibrate decreased body weight and fat pad weight and ameliorated liver steatosis in LD-fed mice with concomitant reduction in blood glucose, free fatty acid, triglyceride, serum insulin levels, and homeostasis model assessment index values. Euglycemic-hyperinsulinemic clamp demonstrated the development of whole-body and liver insulin resistance in LD-fed mice, which were both normalized by fenofibrate. Fenofibrate treatment markedly increased circulating resistin levels on both diets and adiponectin levels in chow-fed mice only. Fat adiponectin mRNA expression was not affected by fenofibrate treatment. Resistin mRNA expression increased in subcutaneous but not gonadal fat after fenofibrate treatment. In addition to fat, a significant amount of adiponectin mRNA was also expressed in the muscle. This expression markedly increased after fenofibrate treatment in chow- but not in LD-fed mice. Adipose tissue expression of AdipoR1 mRNA was significantly reduced in LD-fed mice and increased after fenofibrate treatment. In conclusion, PPAR-alpha activation ameliorated the development of insulin resistance in LD-fed mice despite a major increase in serum resistin levels. This effect could be partially explained by increased AdipoR1 expression in adipose tissue after fenofibrate treatment.
- MeSH
- adiponektin genetika krev MeSH
- dieta MeSH
- dietní sacharidy aplikace a dávkování MeSH
- exprese genu účinky léků MeSH
- fenofibrát aplikace a dávkování MeSH
- financování organizované MeSH
- glykemický clamp MeSH
- hmotnostní úbytek účinky léků MeSH
- inzulin farmakologie krev MeSH
- inzulinová rezistence MeSH
- játra chemie účinky léků MeSH
- kosterní svaly chemie MeSH
- krevní glukóza analýza MeSH
- kyseliny mastné neesterifikované analýza MeSH
- lipidy biosyntéza MeSH
- messenger RNA analýza MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- obezita etiologie krev patofyziologie MeSH
- PPAR alfa agonisté fyziologie MeSH
- receptory adiponektinu MeSH
- receptory buněčného povrchu genetika MeSH
- resistin genetika krev MeSH
- triglyceridy krev MeSH
- tuková tkáň chemie patologie MeSH
- velikost orgánu účinky léků MeSH
- ztučnělá játra etiologie farmakoterapie krev MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- MeSH
- diabetes mellitus 2. typu epidemiologie etiologie MeSH
- finanční podpora výzkumu jako téma MeSH
- hlodavci metabolismus MeSH
- inzulinová rezistence fyziologie MeSH
- játra enzymologie metabolismus MeSH
- lidé MeSH
- obezita enzymologie metabolismus patofyziologie MeSH
- PPAR alfa agonisté fyziologie metabolismus MeSH
- svaly enzymologie metabolismus MeSH
- tuková tkáň enzymologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
- MeSH
- diabetes mellitus farmakoterapie patofyziologie MeSH
- experimenty na zvířatech MeSH
- hlodavci MeSH
- hypolipidemika klasifikace terapeutické užití MeSH
- lidé MeSH
- lipidy škodlivé účinky MeSH
- metabolismus lipidů MeSH
- PPAR alfa agonisté fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- klinické zkoušky MeSH
