The metabolic action of oxytocin has recently been intensively studied to assess the ability of the peptide to regulate energy homeostasis. Despite the obvious weight-reducing effect of oxytocin observed in experimental studies, plasma oxytocin levels were found to be unchanged or even elevated in human obesity. The aim of our study was to evaluate the changes in the oxytocin system in Zucker rats, an animal model closely mirroring morbid obesity in humans. Plasma oxytocin levels were measured in obese Zucker rats and lean controls by enzyme immunoassay after plasma extraction. The expression of oxytocin and oxytocin receptor (OXTR) was assessed at the mRNA and protein levels by quantitative real-time PCR and immunoblotting respectively. Plasma and tissue activity of oxytocinase, the main enzyme involved in oxytocin degradation, were measured by fluorometric assay using an arylamide derivate as the substrate. Obese Zucker rats displayed a marked reduction in plasma oxytocin levels. Elevated liver and adipose tissue oxytocinase activity was noticed in obese Zucker rats. Hypothalamic oxytocin gene expression was not altered by the obese phenotype. OXTR mRNA and protein levels were upregulated in the adipose tissue of obese animals in contrast to the reduced OXTR protein levels in skeletal muscle. Our results show that obesity is associated with reduced plasma oxytocin due to increased peptide degradation by liver and adipose tissue rather than changes in hormone synthesis. This study highlights the importance of the oxytocin system in the pathogenesis of obesity and suggests oxytocinase inhibition as a candidate approach in the therapy of obesity.

• MeSH
• cystinylaminopeptidasa krev   MeSH
• játra metabolismus   MeSH
• kosterní svaly metabolismus   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• morbidní obezita genetika   metabolismus   MeSH
• oxytocin krev   MeSH
• potkani Zucker MeSH
• proteolýza MeSH
• receptory oxytocinu genetika   metabolismus   MeSH
• tuková tkáň metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• androstadieny farmakologie   MeSH
• dinoproston biosyntéza   MeSH
• financování organizované MeSH
• inhibitory cyklooxygenasy MeSH
• kyseliny mastné neesterifikované krev   MeSH
• ledviny enzymologie   MeSH
• membránové proteiny MeSH
• obezita enzymologie   MeSH
• potkani Zucker MeSH
• prostaglandinové endoperoxidy syntetické analýza   MeSH
• thromboxan B2 biosyntéza   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH

BACKGROUND: Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, demonstrates antihypertensive and organ protective effects in hypertension. We investigated the efficacy of AZL-M to ameliorate metabolic syndrome and kidney damage associated with type 2 diabetes using Zucker diabetic fatty (ZDF) rats. METHODS: ZDF rats were treated with vehicle or AZL-M for 8 weeks. Zucker diabetic lean (ZDL) rats were used as controls. Urine and plasma samples were collected for biochemical analysis, and kidney tissues were used for histopathological and immunohistopathological examination at the end of the 8-week protocol. RESULTS: ZDF rats were diabetic with hyperglycemia and impaired glucose tolerance, and AZL-M ameliorated the diabetic phenotype. ZDF rats were hypertensive compared with ZDL rats (181±6 vs. 129±7mm Hg), and AZL-M decreased blood pressure in ZDF rats (116±7mm Hg). In ZDF rats, there was marked renal damage with elevated proteinuria, albuminuria, nephrinuria, 2-4-fold higher tubular cast formation, and glomerular injury compared with ZDL rats. AZL-M treatment reduced renal damage in ZDF rats. ZDF rats demonstrated renal inflammation and oxidative stress with elevated urinary monocyte chemoattractant protein 1 excretion, renal infiltration of macrophages, and elevated kidney malondialdehyde levels. AZL-M reduced oxidative stress and inflammation in ZDF rats. CONCLUSIONS: Overall, we demonstrate that AZL-M attenuates kidney damage in type 2 diabetes. We further demonstrate that anti-inflammatory and antioxidative activities of AZL-M contribute to its kidney protective action.

• MeSH
• benzimidazoly terapeutické užití   MeSH
• blokátory receptoru 1 pro angiotenzin II terapeutické užití   MeSH
• cévní endotel účinky léků   MeSH
• diabetické nefropatie patologie   prevence a kontrola   MeSH
• glukózový toleranční test MeSH
• hyperglykemie farmakoterapie   MeSH
• krevní glukóza metabolismus   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu rattus MeSH
• oxadiazoly terapeutické užití   MeSH
• oxidační stres účinky léků   MeSH
• porucha glukózové tolerance prevence a kontrola   MeSH
• potkani Zucker MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Insulin resistance (IR) and consequent hyperinsulinemia are hallmarks of Type 2 diabetes (DM2). Akt kinase (Akt) is an important molecule in insulin signaling, implicated in regulation of glucose uptake, cell growth, cell survival, protein synthesis, and endothelial nitric oxide (NO) production. Impaired Akt activation in insulin-sensitive tissues contributes to IR. However, Akt activity in other tissues, particularly those affected by complications of DM2, has been less studied. We hypothesized that hyperinsulinemia could have an impact on activity of Akt and its effectors involved in regulation of renal morphology and function in DM2. To address this issue, renal cortical Akt was determined in obese Zucker rats (ZO), a model of DM2, and lean controls (ZL). We also studied expression and phosphorylation of the mammalian target of rapamycin (mTOR) and endothelial NO synthase (eNOS), molecules downstream of Akt in the insulin signaling cascade, and documented modulators of renal injury. Akt activity was measured by a kinase assay with GSK-3 as a substrate. Expression of phosphorylated (active) and total proteins was measured by immunoblotting and immunohistochemistry. Renal Akt activity was increased in ZO as compared to ZL rats, in parallel with progressive hyperinsulinemia. No differences in Akt were observed in the skeletal muscle. Corresponding to increases in Akt activity, ZO rats demonstrated enhanced phosphorylation of renal mTOR. Acute PI3K inhibition with wortmannin (100 mug/kg) attenuated renal Akt and mTOR activities in ZO, but not in ZL rats. In contrast to mTOR, eNOS phosphorylation was similar in ZO and ZL rats, despite higher total eNOS expression. In conclusion, ZO rats demonstrated increases in renal Akt and mTOR activity and expression. However, eNOS phosphorylation did not follow this pattern. These data suggest that DM2 is associated with selective IR in the kidney, allowing pro-growth signaling via mTOR, whereas potentially protective effects mediated by eNOS are blunted.

• Klíčová slova
• Phosphatidylinositol 3-Kinases,
• MeSH
• androstadieny farmakologie   MeSH
• diabetes mellitus 2. typu metabolismus   MeSH
• financování organizované MeSH
• fosfotransferasy s alkoholovou skupinou jako akceptorem antagonisté a inhibitory   MeSH
• hyperinzulinismus metabolismus   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• inzulin krev   MeSH
• inzulinová rezistence fyziologie   MeSH
• krysa rodu rattus MeSH
• ledviny enzymologie   MeSH
• modely nemocí na zvířatech MeSH
• obezita metabolismus   MeSH
• potkani Zucker MeSH
• proteinkinasy metabolismus   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• synthasa oxidu dusnatého, typ III metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH

The aim of this study was to evaluate the impact of diabetes mellitus type 2 (DM2) on the male endocrine system of Zucker Diabetic Fatty (ZDF) rats. Sexually mature ZDF rats were divided to a lean (control) and obese group, and had diabetes confirmed by blood tests. For the in vivo experiment, fasting blood was collected to obtain blood plasma. In case of the in vitro experiments, testicular fragments were cultured for 24 h, and the culture medium was collected. The concentrations of testosterone (T), androstenedione (A4), dehydroepiandrosterone (DHEA-S), estradiol (E2), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were quantified in the blood plasma and the medium by the ELISA method, while cholesterol (CHOL) was assessed spectrophotometrically. A significant decline of T (36.31 %), A4 (25.11 %) and FSH (26.99 %) as well as a significant increase of CHOL and E2 (36.17 %) was observed in the blood plasma of obese ZDF rats in comparison to the control. Under in vitro conditions, a significant decrease of FSH (23.35 %) accompanied by an increase of E2 was observed in the obese group compared to the control. In the case of CHOL, LH, T, DHEA and A4 no significant differences were observed. Our results suggest that except for FSH and E2 all steroid biomolecules were synthetized normally by the testicular tissue, however a dramatic endocrine disturbance was observed at the system level. We may conclude that DM2 has negative effects on systemic hormone secretion and these alterations are more pronounced in combination with obesity.

• MeSH
• dehydroepiandrosteron MeSH
• diabetes mellitus 2. typu * MeSH
• estradiol MeSH
• folikuly stimulující hormon MeSH
• krysa rodu rattus MeSH
• luteinizační hormon * MeSH
• obezita MeSH
• potkani Zucker MeSH
• testosteron MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Insulin signaling and Tau protein phosphorylation in the hippocampi of young and old obese Zucker fa/fa rats and their lean controls were assessed to determine whether obesity-induced peripheral insulin resistance and aging are risk factors for central insulin resistance and whether central insulin resistance is related to the pathologic phosphorylation of the Tau protein. RESULTS: Aging and obesity significantly attenuated the phosphorylation of the insulin cascade kinases Akt (protein kinase B, PKB) and GSK-3β (glycogen synthase kinase 3β) in the hippocampi of the fa/fa rats. Furthermore, the hyperphosphorylation of Tau Ser396 alone and both Tau Ser396 and Thr231 was significantly augmented by aging and obesity, respectively, in the hippocampi of these rats. CONCLUSIONS: Both age-induced and obesity-induced peripheral insulin resistance are associated with central insulin resistance that is linked to hyperTau phosphorylation. Peripheral hyperinsulinemia, rather than hyperglycemia, appears to promote central insulin resistance and the Tau pathology in fa/fa rats.

• MeSH
• fosforylace MeSH
• glukózový toleranční test MeSH
• hipokampus patofyziologie   MeSH
• inzulin metabolismus   MeSH
• inzulinová rezistence fyziologie   MeSH
• kinasa 3 glykogensynthasy metabolismus   MeSH
• obezita patofyziologie   MeSH
• potkani Zucker MeSH
• proteiny tau genetika   metabolismus   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• signální transdukce MeSH
• stárnutí fyziologie   MeSH
• western blotting MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• konjugované kyseliny linolové fyziologie   MeSH
• krevní tlak MeSH
• potkani Zucker MeSH
• renin-angiotensin systém fyziologie   MeSH
• tuková tkáň fyziologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• kongresy MeSH

Impaired diabetic wound healing is an important current medical issue, mainly concerning patients recovering from complicated operations or patients with ulcers on their feet. The obese Zucker diabetic fatty rat, with a mutation in leptin receptors, may be a good choice for studying impaired wound healing. Male and female rats were fed a diabetogenic high-fat diet. Wound size changes of air-exposed excisional 2 cm circular wounds were measured until Day 10. Wound tissue was analyzed morphologically, histologically, and immunohistochemically. The hydroxyproline content in the granulation tissue (GT) was determined. mRNA expression was assayed by DNA-array analysis and real-time reverse transcription-polymerase chain reaction. Wound-size changes were retarded in diabetic rats and differed between the sexes. Diabetic wounds were characterized by impaired contraction, abundant crust production, increased inflammation, and pus formation. On Day 10, the GT contained a significantly increased amount of intercalated fat tissue and showed an irregular arrangement of GT and collagen fibers. Interestingly, the length of new epithelium was increased in diabetic wounds. The concentration of hydroxyproline in the GT of diabetic animals was significantly decreased to about one half when compared with the nondiabetic controls. The expression of interleukin-6, myeloperoxidase, stromelysin-1, and collagenase-3 was increased in the GT of diabetic rats on Day 10, while the expression of type I collagen and elastin was decreased. Taken together, Zucker diabetic fatty rats exhibited impairments in wound-size reduction, inflammatory response, tissue organization, and connective tissue turnover and are thus proposed as a new model for studying impaired repair.

• MeSH
• diabetes mellitus 2. typu patofyziologie   MeSH
• elastin metabolismus   MeSH
• granulační tkáň metabolismus   patologie   MeSH
• hnisání patologie   MeSH
• hojení ran fyziologie   MeSH
• hydroxyprolin metabolismus   MeSH
• interleukin-6 metabolismus   MeSH
• kolagen typu I metabolismus   MeSH
• krysa rodu rattus MeSH
• kůže zranění   patologie   MeSH
• matrixová metaloproteinasa 13 metabolismus   MeSH
• matrixová metaloproteinasa 3 metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• obezita patofyziologie   MeSH
• peroxidasa metabolismus   MeSH
• potkani Zucker MeSH
• sexuální faktory MeSH
• zánět patologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Obesity is associated with increased sympathetic nervous system activation, possibly contributing to higher cardiovascular risk. The aim of this study was to assess the relationship between body adiposity and sympathoadrenergic contractions in rat isolated mesenteric arteries, and the modulatory effect of mesenteric perivascular adipose tissue (PVAT). Experiments were performed on male 38-week-old Wistar, Zucker lean (ZL) and Zucker diabetic fatty (ZDF) rats. Paired rings of isolated rat superior mesenteric arteries with or without PVAT were prepared and connected to a force-displacement transducer for the recording of isometric tension. Contractile responses were elicited by increasing doses of exogenous noradrenaline and by endogenous noradrenaline released during electrical stimulation of perivascular adrenergic nerves. In ZDF rats, mesenteric PVAT had marked anticontractile effect leading to significant reduction in adrenergic contractions of their superior mesenteric arteries; however, in arterial preparations without PVAT, obese rats showed significantly increased sensitivity in their contractile responses to adrenergic stimulation when compared to other rat groups. In Wistar rats, ranging in the level of body adiposity between ZL and ZDF rats, neurogenic contractions in arterial preparations with preserved PVAT were higher compared to those without PVAT. No vasomodulatory effect of PVAT was detected in mesenteric arteries from ZL rats. The results of this study indicate that the modulatory effect of mesenteric PVAT on arterial adrenergic contractions did not change in proportion with increasing adiposity; however, it could be influenced by the rat strain-specific distribution of sympathetic nerves between PVAT and the proper mesenteric arterial wall. In ZDF rats, characterized by higher vascular sympathetic tone, the mesenteric arteries might be specifically regulated by the anticontractile effect of PVAT, leading to higher mesenteric blood flow. This could be associated with hyperphagia and increased nutrient-induced mesenteric vasodilatation in this rat strain.

• MeSH
• adipozita * MeSH
• arteria mesenterica superior inervace   MeSH
• druhová specificita MeSH
• elektrická stimulace MeSH
• modely nemocí na zvířatech MeSH
• noradrenalin farmakologie   MeSH
• obezita patofyziologie   MeSH
• potkani Wistar MeSH
• potkani Zucker MeSH
• sympatický nervový systém účinky léků   metabolismus   patofyziologie   MeSH
• vazokonstrikce * účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Diabetes mellitus is known to produce various cell-damaging events and thereby underlie heart dysfunction and remodeling. However, very little is known about its inflammation-associated pathomechanisms due to necrosis-like cell death. For this purpose, we aimed to investigate signaling pathways of necroptosis and pyroptosis, known to produce plasma membrane rupture with the resultant promotion of inflammation. One-year old Zucker diabetic fatty (ZDF) rats did not exhibit significant heart dysfunction as revealed by echocardiographic measurement. On the other hand, there was a decrease in heart rate due to diabetes. Immunoblotting analysis showed that the left ventricles of ZDF rats overexpress neither the main necroptotic proteins including receptor-interacting protein kinase 3 (RIP3) and mixed lineage domain kinase-like pseudokinase (MLKL), nor the pyroptotic regulators including NLR family pyrin domain containing 3 protein (NLRP3), caspase-1, interleukin-1 beta (IL-1beta and the N-terminal gasdermin D (GSDMD-N). On the other hand, the increased activation of the RIP3 kinase due to phosphorylation was found in such hearts. In summary, we showed for the first time that the activation of cardiac RIP3 is upregulated due to disturbances in glucose metabolism which, however, did not proceed to necrosis-like cell death. These data can indicate that the activated RIP3 might also underlie other pleiotropic, non-necroptotic signaling pathways under basal conditions.

• MeSH
• apoptóza MeSH
• diabetes mellitus 2. typu * MeSH
• krysa rodu rattus MeSH
• nekróza MeSH
• potkani Zucker MeSH
• proteinkinasy metabolismus   MeSH
• pyroptóza * MeSH
• signální transdukce MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH