We investigated the sex-dependent effects of inflammatory responses in visceral adipose tissue (VAT) and perivascular adipose tissue (PVAT), as well as hematological status, in relation to cardiovascular disorders associated with prediabetes. Using male and female hereditary hypertriglyceridemic (HHTg) rats-a nonobese prediabetic model featuring dyslipidemia, hepatic steatosis, and insulin resistance-we found that HHTg females exhibited more pronounced hypertriglyceridemia than males, while HHTg males had higher non-fasting glucose levels. Additionally, HHTg females had higher platelet counts, larger platelet volumes, and lower antithrombin inhibitory activity. Regarding low-grade chronic inflammation, HHTg males exhibited increased serum leptin and leukocyte levels, while females had increased serum interleukin-6 (IL-6). Both sexes had increased circulating plasminogen activator inhibitor-1 (PAI-1), higher PAI-1 gene expression in VAT and PVAT, and elevated intercellular adhesion molecule-1 (ICAM-1) gene expression in the aorta, contributing to endothelial dysfunction in the HHTg strain. However, HHTg females had lower tumor necrosis factor alpha (TNFα) gene expression in the aorta. Severe dyslipidemia in this prediabetic model was associated with hypercoagulation and low-grade chronic inflammation. The increase in PAI-1 expression in both VAT and PVAT seems to indicate a link between inflammation and vascular dysfunction. Despite the more pronounced dyslipidemia and procoagulation status in females, their milder inflammatory response may reflect an association between reduced cardiovascular damage and prediabetes.
- MeSH
- dyslipidemie * metabolismus patologie genetika MeSH
- inhibitor aktivátoru plazminogenu 1 * metabolismus genetika MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech * MeSH
- nemoci cév metabolismus patologie etiologie genetika MeSH
- nitrobřišní tuk * metabolismus patologie MeSH
- pohlavní dimorfismus MeSH
- zánět * metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Menopause brings about profound physiological changes, including the acceleration of insulin resistance and other abnormalities, in which adipose tissue can play a significant role. This study analyzed the effect of ovariectomy and estradiol substitution on the metabolic parameters and transcriptomic profile of adipose tissue in prediabetic females of hereditary hypertriglyceridemic rats (HHTgs). The HHTgs underwent ovariectomy (OVX) or sham surgery (SHAM), and half of the OVX group received 17β-estradiol (OVX+E2) post-surgery. Ovariectomy resulted in weight gain, an impaired glucose tolerance, ectopic triglyceride (TG) deposition, and insulin resistance exemplified by impaired glycogenesis and lipogenesis. Estradiol alleviated some of the disorders associated with ovariectomy; in particular, it improved insulin sensitivity and reduced TG deposition. A transcriptomic analysis of perimetrial adipose tissue revealed 809 differentially expressed transcripts in the OVX vs. SHAM groups, mostly pertaining to the regulation of lipid and glucose metabolism, and oxidative stress. Estradiol substitution affected 1049 transcripts with overrepresentation in the signaling pathways of lipid metabolism. The principal component and hierarchical clustering analyses of transcriptome shifts corroborated the metabolic data, showing a closer resemblance between the OVX+E2 and SHAM groups compared to the OVX group. Changes in the adipose tissue transcriptome may contribute to metabolic abnormalities accompanying ovariectomy-induced menopause in HHTg females. Estradiol substitution may partially mitigate some of these disorders.
- Publikační typ
- časopisecké články MeSH
Úvod: Menopauza je často doprovázena nárůstem tělesné hmotnosti, přírůstkem viscerálního tuku, inzulinovou rezistencí, jaterní steatózou a dysregulacemi lipidového a glukózového metabolizmu. Tyto poruchy provází metabolický syndrom (MS), jehož prevalence je výrazně vyšší v postmenopauzálním období než u žen ve fertilní fázi života. Cíl: Pro objasnění mechanizmů rozvoje těchto poruch v jejich raných fázích vývoje jsme sledovali vliv ztráty ovariálního cyklu na inzulinovou senzitivitu tkání, glukózový a lipidový metabolizmus a jaterní steatózu. Metodika: Samicím potkanů kmene Wistar byla ve věku 8 týdnů chirurgicky provedena bilaterální ovariektomie (W-OVX), kontrolám sham operace. Následující 4 měsíce, během nichž se u W-OVX-potkanů rozvíjely poruchy spojené s postmenopauzálním MS, byly samice krmeny standardní dietou ad libitum, byl měřen příjem potravy a sledována tělesná hmotnost. Výsledky: W-OVX-samice vykazovaly o 9 % vyšší příjem potravy (p < 0,01), vyšší tělesnou hmotnost (p < 0,05) a množství viscerálního tuku (p < 0,05), zvýšenou koncentraci leptinu v cirkulaci (p < 0,001) a inzulinovou rezistenci svalové i tukové tkáně v porovnání s kontrolami. Sérové koncentrace glukózy, inzulinu, adiponektinu i hs-CRP stejně jako glukózová tolerance se mezi skupinami nelišily. Ovariektomie vedla k nadměrnému ukládání triacylglycerolů (TAG) do jater (p < 0,001), přestože sérové koncentrace TAG i cholesterolu nebyly zvýšeny. Zvýšená exprese CYP2E1 a snížená aktivita CYP4A v játrech se mohou podílet na snížené oxidaci mastných kyselin a jaterní steatóze pozorované u W-OVX. Zvýšená hladina reaktivního dikarbonylu metylglyoxalu (p < 0,01) a zhoršený poměr GSH/GSSG – indikátoru oxidačního stresu u W-OVX v játrech doprovázené zvýšenými hladinami AST a GGT ukazují na zhoršený oxidační i dikarbonylový stres, který se podílí na patogenezi jaterní steatózy. Závěr: Zhoršený metabolizmus lipidů v játrech hraje důležitou roli v časných fázích postmenopauzálního MS. Tyto změny předchází zvýšení TAG a cholesterolu v séru i zhoršení glukózové tolerance. Zvýšený obsah TAG v játrech a porušená regulace některých izoforem CYP 450 spolu se zvýšeným oxidačním i dikarbonylovým stresem se mohou podílet na rozvoji jaterní steatózy.
- Publikační typ
- abstrakt z konference MeSH
Hypolipidemic and cardioprotective effects of statins can be associated with the development of myopathies and new-onset type 2 diabetes. These adverse effects may be related to increased oxidative stress. The plant extract silymarin (SM) is known for its antioxidant and anti-inflammatory actions. We tested the hypothesis that the combination of atorvastatin (ATV) with SM could improve therapy efficacy and eliminate some negative effects of statin on hypertriglyceridemia-induced metabolic disorders. Hereditary hypertriglyceridemic rats were fed a standard diet for four weeks without supplementation; supplemented with ATV (5 mg/kg b. wt./day) or a combination of ATV with 1 % micronized SM (ATV+SM). ATV treatment elevated plasma levels of HDL-cholesterol (p<0.01), glucose and insulin and decreased triglycerides (p<0.001). The combination of ATV+SM led to a significant reduction in insulin, an improvement of glucose tolerance, and the hypolipidemic effect was enhanced compared to ATV alone. Furthermore, ATV supplementation increased skeletal muscle triglycerides but its combination with SM decreased triglycerides accumulation in the muscle (p<0.05) and the liver (p<0.01). In the liver, ATV+SM treatment increased the activities of antioxidant enzymes, glutathione and reduced lipid peroxidation (p<0.001). The combined administration of ATV with SM potentiated the hypolipidemic effect, reduced ectopic lipid accumulation, improved glucose metabolism, and increased antioxidant and anti-inflammatory actions. Our results show that SM increased the effectiveness of statin therapy in a hypertriglyceridemic rat model of metabolic syndrome.
- MeSH
- anticholesteremika škodlivé účinky MeSH
- antioxidancia farmakologie MeSH
- atorvastatin škodlivé účinky MeSH
- diabetes mellitus 2. typu chemicky indukované farmakoterapie patologie MeSH
- hypercholesterolemie krev MeSH
- hyperlipidemie farmakoterapie MeSH
- kombinovaná farmakoterapie MeSH
- krysa rodu rattus MeSH
- metabolický syndrom farmakoterapie genetika patologie MeSH
- modely nemocí na zvířatech MeSH
- oxidační stres účinky léků MeSH
- silymarin farmakologie MeSH
- triglyceridy krev MeSH
- zánět farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Introduction: The development of metabolic syndrome-associated renal dysfunction is exacerbated by a number of factors including dyslipidemia, ectopic deposition of lipids and their toxic metabolites, impairment of lipid metabolism, and insulin resistance. Renal dysfunction is also affected by the production of proinflammatory and profibrotic factors secreted from adipose tissue, which can in turn directly impair kidney cells and potentiate insulin resistance. In this study, we investigated the manifestation of renal lipid accumulation and its effect on renal dysfunction in a model of metabolic syndrome-the hereditary hypertriglyceridemic rat (HHTg)-by assessing microalbuminuria and targeted urinary proteomics. Male Wistar control rats and HHTg rats were fed a standard diet and observed over the course of ageing at 3, 12, and 20 months of age. Results: Chronically elevated levels of triglycerides in HHTg rats were associated with increased levels of NEFA during OGTT and over a period of 24 hours (+80%, P < 0.01). HHTg animals exhibited qualitative changes in NEFA fatty acid composition, represented by an increased proportion of saturated fatty acids (P < 0.05) and a decreased proportion of n-3 PUFA (P < 0.01). Ectopic lipid deposition in the kidneys of HHTg rats-triglycerides (+30%) and cholesterol (+10%)-was associated with markedly elevated microalbuminuria as ageing increased, despite the absence of microalbuminuria at the young age of 3 months in these animals. According to targeted proteomic analysis, 3-month-old HHTg rats (in comparison to age-matched controls) exhibited increased urinary secretion of proinflammatory parameters (MCP-1, IL-6, IL-8, P < 0.01) and decreased urinary secretion of epidermal growth factor (EGF, P < 0.01) before manifestation of microalbuminuria. Elevation in the urinary secretion of inflammatory cytokines can be affected by increased relative expression of MCP-1 in the renal cortex (P < 0.05). Conclusions: Our results confirm dyslipidemia and ectopic lipid accumulation to be key contributors in the development of metabolic syndrome-associated renal dysfunction. Assessing urinary secretion of proinflammatory cytokines and epidermal growth factor can help in detecting early development of metabolic syndrome-associated renal dysfunction.
- MeSH
- albuminurie etiologie moč MeSH
- analýza moči MeSH
- biologické markery krev moč MeSH
- časná diagnóza MeSH
- časové faktory MeSH
- cytokiny moč MeSH
- epidermální růstový faktor moč MeSH
- hypertriglyceridemie krev komplikace genetika moč MeSH
- lipidy krev MeSH
- mediátory zánětu moč MeSH
- metabolický syndrom krev komplikace genetika moč MeSH
- modely nemocí na zvířatech MeSH
- nemoci ledvin krev etiologie moč MeSH
- potkani transgenní MeSH
- potkani Wistar MeSH
- prediktivní hodnota testů MeSH
- proteomika * MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
