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 krev   genetika   MeSH
• dieta MeSH
• dietní sacharidy aplikace a dávkování   MeSH
• exprese genu účinky léků   MeSH
• fenofibrát aplikace a dávkování   MeSH
• glykemický clamp MeSH
• hmotnostní úbytek účinky léků   MeSH
• inzulin krev   farmakologie   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 krev   etiologie   patofyziologie   MeSH
• PPAR alfa agonisté   fyziologie   MeSH
• receptory adiponektinu MeSH
• receptory buněčného povrchu genetika   MeSH
• resistin krev   genetika   MeSH
• triglyceridy krev   MeSH
• tuková tkáň chemie   patologie   MeSH
• velikost orgánu účinky léků   MeSH
• ztučnělá játra krev   farmakoterapie   etiologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adiponectin receptor 1, mouse MeSH Prohlížeč
• adiponectin receptor 2, mouse MeSH Prohlížeč
• adiponektin MeSH
• dietní sacharidy MeSH
• fenofibrát MeSH
• inzulin MeSH
• krevní glukóza MeSH
• kyseliny mastné neesterifikované MeSH
• lipidy MeSH
• messenger RNA MeSH
• PPAR alfa MeSH
• receptory adiponektinu MeSH
• receptory buněčného povrchu MeSH
• resistin MeSH
• triglyceridy MeSH

BACKGROUND: The angiotensin receptor blocker telmisartan has unique chemical properties that enable it to partially activate the peroxisome proliferator activated receptor gamma (PPARG) as well as block angiotensin II type 1 receptors. METHODS: To directly test whether some of the metabolic effects of telmisartan require the presence of PPARG, we studied mice in which the gene (Pparg) for PPARG had been deleted in fat or in muscle. RESULTS: We found that knockout of Pparg in fat tissue greatly impaired the ability of telmisartan to increase adiponectin levels and to enhance sensitivity to insulin-stimulated glucose incorporation into adipose tissue lipids. In contrast, muscle-specific Pparg knockout had relatively little or no impact on the ability of telmisartan to increase adiponectin levels or affect glucose metabolism either in fat or muscle. These findings provide compelling evidence that the ability of telmisartan to increase adiponectin levels and stimulate glucose use in adipose tissue may depend on the presence of PPARG in fat. CONCLUSIONS: We conclude that PPARG in adipose tissue is required for at least several of the metabolic actions of telmisartan.

• Klíčová slova
• blood pressure, hypertension, metabolic effects, telmisartan, tissue-specific Pparg knockout mice.,
• MeSH
• benzimidazoly farmakokinetika   MeSH
• benzoáty farmakokinetika   MeSH
• blokátory receptorů AT1 pro angiotensin II farmakokinetika   MeSH
• hypertenze farmakoterapie   metabolismus   MeSH
• inzulinová rezistence MeSH
• krevní glukóza metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• myši knockoutované MeSH
• myši MeSH
• PPAR gama biosyntéza   MeSH
• telmisartan MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• benzimidazoly MeSH
• benzoáty MeSH
• blokátory receptorů AT1 pro angiotensin II MeSH
• krevní glukóza MeSH
• PPAR gama MeSH
• telmisartan MeSH

OBJECTIVE: GDF11 is a member of the TGF-β superfamily that was recently implicated as potential "rejuvenating" factor, which can ameliorate metabolic disorders. The main objective of the presented study was to closely characterize the role of GDF11 signaling in the glucose homeostasis and in the differentiation of white adipose tissue. METHODS: We performed microscopy imaging, biochemical and transcriptomic analyses of adipose tissues of 9 weeks old ob/ob mice and murine and human pre-adipocyte cell lines. RESULTS: Our in vivo experiments employing GDF11 treatment in ob/ob mice showed improved glucose/insulin homeostasis, decreased weight gain and white adipocyte size. Furthermore, GDF11 treatment inhibited adipogenesis in pre-adipocytes by ALK5-SMAD2/3 activation in cooperation with the WNT/β-catenin pathway, whose inhibition resulted in adipogenic differentiation. Lastly, we observed significantly elevated levels of the adipokine hormone adiponectin and increased glucose uptake by mature adipocytes upon GDF11 exposure. CONCLUSION: We show evidence that link GDF11 to adipogenic differentiation, glucose, and insulin homeostasis, which are pointing towards potential beneficial effects of GDF11-based "anti-obesity" therapy.

• MeSH
• adipogeneze * MeSH
• adiponektin metabolismus   MeSH
• beta-katenin * metabolismus   MeSH
• buněčná diferenciace fyziologie   MeSH
• glukosa metabolismus   MeSH
• inzulin metabolismus   MeSH
• kostní morfogenetické proteiny metabolismus   MeSH
• lidé MeSH
• myši MeSH
• protein Smad2 MeSH
• protein Smad3 MeSH
• receptory regulované proteiny Smad MeSH
• růstové diferenciační faktory metabolismus   MeSH
• signální dráha Wnt MeSH
• TGF-beta receptor I. typu MeSH
• transformující růstový faktor beta metabolismus   MeSH
• tukové buňky metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adiponektin MeSH
• beta-katenin * MeSH
• GDF11 protein, human MeSH Prohlížeč
• Gdf11 protein, mouse MeSH Prohlížeč
• glukosa MeSH
• inzulin MeSH
• kostní morfogenetické proteiny MeSH
• protein Smad2 MeSH
• protein Smad3 MeSH
• receptory regulované proteiny Smad MeSH
• růstové diferenciační faktory MeSH
• SMAD2 protein, human MeSH Prohlížeč
• Smad2 protein, mouse MeSH Prohlížeč
• SMAD3 protein, human MeSH Prohlížeč
• Smad3 protein, mouse MeSH Prohlížeč
• TGF-beta receptor I. typu MeSH
• TGFBR1 protein, human MeSH Prohlížeč
• Tgfbr1 protein, mouse MeSH Prohlížeč
• transformující růstový faktor beta MeSH

Obesity with related complications represents a widespread health problem. The etiopathogenesis of obesity is often studied using numerous rodent models. The mouse model of monosodium glutamate (MSG)-induced obesity was exploited as a model of obesity combined with insulin resistance. The aim of this work was to characterize the metabolic status of MSG mice by NMR-based metabolomics in combination with relevant biochemical and hormonal parameters. NMR analysis of urine at 2, 6, and 9 months revealed altered metabolism of nicotinamide and polyamines, attenuated excretion of major urinary proteins, increased levels of phenylacetylglycine and allantoin, and decreased concentrations of methylamine in urine of MSG-treated mice. Altered levels of creatine, citrate, succinate, and acetate were observed at 2 months of age and approached the values of control mice with aging. The development of obesity and insulin resistance in 6-month-old MSG mice was also accompanied by decreased mRNA expressions of adiponectin, lipogenetic and lipolytic enzymes and peroxisome proliferator-activated receptor-gamma in fat while mRNA expressions of lipogenetic enzymes in the liver were enhanced. At the age of 9 months, biochemical parameters of MSG mice were normalized to the values of the controls. This fact pointed to a limited predictive value of biochemical data up to age of 6 months as NMR metabolomics confirmed altered urine metabolic composition even at 9 months.

• Klíčová slova
• Diabetes, Metabolomics, Monosodium glutamate (MSG) induced obesity, Mouse model, NMR, Urine,
• MeSH
• glutamát sodný škodlivé účinky   MeSH
• inzulin metabolismus   MeSH
• játra metabolismus   MeSH
• krevní glukóza metabolismus   MeSH
• lidé MeSH
• metabolismus lipidů MeSH
• metabolomika * MeSH
• moč chemie   MeSH
• myši MeSH
• obezita etiologie   genetika   metabolismus   moč   MeSH
• receptory aktivované proliferátory peroxizomů genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• glutamát sodný MeSH
• inzulin MeSH
• krevní glukóza MeSH
• receptory aktivované proliferátory peroxizomů MeSH

Adipose tissue has a key role in the development of metabolic syndrome (MS), which includes obesity, type 2 diabetes, dyslipidaemia, hypertension and other disorders. Systemic insulin resistance represents a major factor contributing to the development of MS in obesity. The resistance is precipitated by impaired adipose tissue glucose and lipid metabolism, linked to a low-grade inflammation of adipose tissue and secretion of pro-inflammatory adipokines. Development of MS could be delayed by lifestyle modifications, while both dietary and pharmacological interventions are required for the successful therapy of MS. The n-3 long-chain (LC) PUFA, EPA and DHA, which are abundant in marine fish, act as hypolipidaemic factors, reduce cardiac events and decrease the progression of atherosclerosis. Thus, n-3 LC PUFA represent healthy constituents of diets for patients with MS. In rodents n-3 LC PUFA prevent the development of obesity and impaired glucose tolerance. The effects of n-3 LC PUFA are mediated transcriptionally by AMP-activated protein kinase and by other mechanisms. n-3 LC PUFA activate a metabolic switch toward lipid catabolism and suppression of lipogenesis, i.e. in the liver, adipose tissue and small intestine. This metabolic switch improves dyslipidaemia and reduces ectopic deposition of lipids, resulting in improved insulin signalling. Despite a relatively low accumulation of n-3 LC PUFA in adipose tissue lipids, adipose tissue is specifically linked to the beneficial effects of n-3 LC PUFA, as indicated by (1) the prevention of adipose tissue hyperplasia and hypertrophy, (2) the induction of mitochondrial biogenesis in adipocytes, (3) the induction of adiponectin and (4) the amelioration of adipose tissue inflammation by n-3 LC PUFA.

• MeSH
• adiponektin metabolismus   MeSH
• dietní tuky farmakologie   terapeutické užití   MeSH
• inzulinová rezistence * MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• metabolický syndrom metabolismus   prevence a kontrola   MeSH
• metabolismus lipidů * MeSH
• mitochondrie metabolismus   MeSH
• myši MeSH
• omega-3 mastné kyseliny farmakologie   terapeutické užití   MeSH
• signální transdukce MeSH
• tuková tkáň metabolismus   MeSH
• zánět dietoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• adiponektin MeSH
• dietní tuky MeSH
• omega-3 mastné kyseliny MeSH

OBJECTIVE: Resolution of low-grade inflammation of white adipose tissue (WAT) is one of the keys for amelioration of obesity-associated metabolic dysfunctions. We focused on the identification of adipokines, which could be involved at the early stages of resolution of WAT inflammation. METHODS AND PROCEDURE: Male C57BL/6J mice with obesity induced in response to a 22-week feeding corn oil-based high-fat (cHF) diet were divided into four groups and were fed with, for 2 weeks, control cHF diet or cHF-based diets supplemented with: (i) concentrate of n-3 long-chain polyunsaturated fatty acids, mainly eicosapentaenoic and docosahexaenoic acids (cHF+F); (ii) thiazolidinedione drug rosiglitazone (cHF+TZD); and (iii) both compounds (cHF+F+TZD). RESULTS: The short-term combined intervention exerted additive effect in the amelioration of WAT inflammation in obese mice, namely in the epididymal fat, even in the absence of any changes in either adipocyte volume or fat mass. The combined intervention elicited hypolipidaemic effect and induced adiponectin, whereas the responses to single interventions (cHF+F, cHF+TZD) were less pronounced. In addition, analysis in WAT lysates using protein arrays revealed that the levels of a small set of adipose tissue-related proteins, namely macrophage inflammatory protein 1γ, endoglin, vascular cell adhesion molecule 1 and interleukin 1 receptor antagonist, changed in response to the anti-inflammatory interventions and were strongly reduced in the cHF+F+TZD mice. These results were verified using both the analysis of gene expression and enzyme-linked immunosorbent analysis in WAT lysates. In contrast with adiponectin, which showed changing plasma levels in response to dietary interventions, the levels of the above proteins were affected only in WAT. CONCLUSIONS: We identified several adipose tissue-related proteins, which are locally involved in resolution of low-grade inflammation and remodelling of WAT.

• MeSH
• adipokiny metabolismus   MeSH
• bílá tuková tkáň metabolismus   patologie   MeSH
• dieta s vysokým obsahem tuků MeSH
• dietní tuky MeSH
• ELISA MeSH
• energetický metabolismus MeSH
• imunohistochemie MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• kyseliny dokosahexaenové farmakologie   MeSH
• myši inbrední C57BL MeSH
• myši obézní MeSH
• myši MeSH
• obezita imunologie   patologie   MeSH
• omega-3 mastné kyseliny farmakologie   MeSH
• rosiglitazon MeSH
• thiazolidindiony farmakologie   MeSH
• tukové buňky metabolismus   MeSH
• zánět patologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adipokiny MeSH
• dietní tuky MeSH
• kyseliny dokosahexaenové MeSH
• omega-3 mastné kyseliny MeSH
• rosiglitazon MeSH
• thiazolidindiony MeSH

AIMS/HYPOTHESIS: Fatty acids of marine origin, i.e. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) act as hypolipidaemics, but they do not improve glycaemic control in obese and diabetic patients. Thiazolidinediones like rosiglitazone are specific activators of peroxisome proliferator-activated receptor gamma, which improve whole-body insulin sensitivity. We hypothesised that a combined treatment with a DHA and EPA concentrate (DHA/EPA) and rosiglitazone would correct, by complementary additive mechanisms, impairments of lipid and glucose homeostasis in obesity. METHODS: Male C57BL/6 mice were fed a corn oil-based high-fat diet. The effects of DHA/EPA (replacing 15% dietary lipids), rosiglitazone (10 mg/kg diet) or a combination of both on body weight, adiposity, metabolic markers and adiponectin in plasma, as well as on liver and muscle gene expression and metabolism were analysed. Euglycaemic-hyperinsulinaemic clamps were used to characterise the changes in insulin sensitivity. The effects of the treatments were also analysed in dietary obese mice with impaired glucose tolerance (IGT). RESULTS: DHA/EPA and rosiglitazone exerted additive effects in prevention of obesity, adipocyte hypertrophy, low-grade adipose tissue inflammation, dyslipidaemia and insulin resistance, while inducing adiponectin, suppressing hepatic lipogenesis and decreasing muscle ceramide concentration. The improvement in glucose tolerance reflected a synergistic stimulatory effect of the combined treatment on muscle glycogen synthesis and its sensitivity to insulin. The combination treatment also reversed dietary obesity, dyslipidaemia and IGT. CONCLUSIONS/INTERPRETATION: DHA/EPA and rosiglitazone can be used as complementary therapies to counteract dyslipidaemia and insulin resistance. The combination treatment may reduce dose requirements and hence the incidence of adverse side effects of thiazolidinedione therapy.

• MeSH
• dietní tuky farmakologie   MeSH
• glykogen biosyntéza   MeSH
• hypoglykemika farmakologie   MeSH
• inzulin fyziologie   MeSH
• kosterní svaly účinky léků   metabolismus   MeSH
• kukuřičný olej farmakologie   MeSH
• kyselina eikosapentaenová farmakologie   MeSH
• kyseliny dokosahexaenové farmakologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• omega-3 mastné kyseliny farmakologie   MeSH
• porucha glukózové tolerance metabolismus   MeSH
• rosiglitazon MeSH
• thiazolidindiony farmakologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dietní tuky MeSH
• glykogen MeSH
• hypoglykemika MeSH
• inzulin MeSH
• kukuřičný olej MeSH
• kyselina eikosapentaenová MeSH
• kyseliny dokosahexaenové MeSH
• omega-3 mastné kyseliny MeSH
• rosiglitazon MeSH
• thiazolidindiony MeSH

OBJECTIVE: We previously demonstrated that the handle-region peptide, a prorenin/renin receptor [(P)RR] blocker, reduces body weight and fat mass and may improve insulin sensitivity in high-fat fed mice. We hypothesized that knocking out the adipose tissue (P)RR gene would prevent weight gain and insulin resistance. METHODS: An adipose tissue-specific (P)RR knockout (KO) mouse was created by Cre-loxP technology using AP2-Cre recombinase mice. Because the (P)RR gene is located on the X chromosome, hemizygous males were complete KO and had a more pronounced phenotype on a normal diet (ND) diet compared to heterozygous KO females. Therefore, we challenged the female mice with a high-fat diet (HFD) to uncover certain phenotypes. Mice were maintained on either diet for 9 weeks. RESULTS: KO mice had lower body weights compared to wild-types (WT). Only hemizygous male KO mice presented with lower total fat mass, higher total lean mass as well as smaller adipocytes compared to WT mice. Although food intake was similar between genotypes, locomotor activity during the active period was increased in both male and female KO mice. Interestingly, only male KO mice had increased O2 consumption and CO2 production during the entire 24-hour period, suggesting an increased basal metabolic rate. Although glycemia during a glucose tolerance test was similar, KO males as well as HFD-fed females had lower plasma insulin and C-peptide levels compared to WT mice, suggesting improved insulin sensitivity. Remarkably, all KO animals exhibited higher circulating adiponectin levels, suggesting that this phenotype can occur even in the absence of a significant reduction in adipose tissue weight, as observed in females and, thus, may be a specific effect related to the (P)RR. CONCLUSIONS: (P)RR may be an important therapeutic target for the treatment of obesity and its associated complications such as type 2 diabetes.

• Klíčová slova
• (P)RR, prorenin/renin receptor, (Pro)renin receptor, ANG, Angiotensin, Adipose tissue, Adipose tissue knock-out mice, BAT, brown adipose tissue, BB, beam break, HACT, horizontal activity, HFD, high-fat diet, HRP, handle-region peptide, Insulin resistance, KO, knock-out, ND, normal diet, OGTT, oral glucose tolerance test, Obesity, PGF, perigonadal fat, PPAR-γ, peroxisome proliferator-activated receptor-γ, PRA, plasma renin activity, PRF, perirenal fat, RAS, renin-angiotensin system, Renin-angiotensin system, SE, standard error, SFC, abdominal subcutaneous fat, SM, skeletal muscle, SMG, submandibular gland, TG, triglycerides, V-ATPase, vacuolar proton pump H+-ATPase, VCO2, carbon dioxide production, VO2, oxygen consumption, WT, wild-type,
• Publikační typ
• časopisecké články MeSH