A combination of liver and heart dysfunction worsens the prognosis of human survival. The aim of this study was to investigate whether empagliflozin (a sodium-glucose transporter-2 inhibitor) has beneficial effects not only on cardiac and renal function but also on hepatic function. Adult (6-month-old) male spontaneously hypertensive rats (SHR) were fed a high-fat diet (60% fat) for four months to induce hepatic steatosis and mild heart failure. For the last two months, the rats were treated with empagliflozin (empa, 10 mg.kg-1.day-1 in the drinking water). Renal function and oral glucose tolerance test were analyzed in control (n=8), high-fat diet (SHR+HF, n=10), and empagliflozin-treated (SHR+HF+empa, n=9) SHR throughout the study. Metabolic parameters and echocardiography were evaluated at the end of the experiment. High-fat diet feeding increased body weight and visceral adiposity, liver triglyceride and cholesterol concentrations, and worsened glucose tolerance. Although the high-fat diet did not affect renal function, it significantly worsened cardiac function in a subset of SHR rats. Empagliflozin reduced body weight gain but not visceral fat deposition. It also improved glucose sensitivity and several metabolic parameters (plasma insulin, uric acid, and HDL cholesterol). In the liver, empagliflozin reduced ectopic lipid accumulation, lipoperoxidation, inflammation and pro-inflammatory HETEs, while increasing anti-inflammatory EETs. In addition, empagliflozin improved cardiac function (systolic, diastolic and pumping) independent of blood pressure. The results of our study suggest that hepatoprotection plays a decisive role in the beneficial effects of empagliflozin in preventing the progression of cardiac dysfunction induced by high-fat diet feeding.

• Klíčová slova
• Cardiac function, Kidney function, Liver steatosis, Metabolic parameters, SGLT-2 inhibition,
• MeSH
• benzhydrylové sloučeniny * farmakologie   MeSH
• dieta s vysokým obsahem tuků * škodlivé účinky   MeSH
• glifloziny * farmakologie   MeSH
• glukosidy * farmakologie   MeSH
• hypertenze farmakoterapie   MeSH
• játra * účinky léků   metabolismus   patologie   MeSH
• kardiotonika farmakologie   MeSH
• krevní glukóza metabolismus   účinky léků   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• ledviny účinky léků   metabolismus   patologie   MeSH
• ochranné látky farmakologie   MeSH
• potkani inbrední SHR * MeSH
• ztučnělá játra prevence a kontrola   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzhydrylové sloučeniny * MeSH
• empagliflozin MeSH Prohlížeč
• glifloziny * MeSH
• glukosidy * MeSH
• kardiotonika MeSH
• krevní glukóza MeSH
• ochranné látky MeSH

Lifestyle intervention encompassing nutrition and physical activity are effective strategies to prevent progressive lipid deposition in the liver. This study aimed to explore the effect of dietary change, and/or high-intensity interval training (HIIT) on hepatic lipid accumulation in high fat diet (HFD)-induced obese rats. We divided lean rats into lean control (LC) or HIIT groups (LH), and obese rats into obese normal chow diet (ND) control (ONC) or HIIT groups (ONH) and obese HFD control (OHC) or HIIT groups (OHH). We found that dietary or HIIT intervention significantly decreased body weight and the risk of dyslipidemia, prevented hepatic lipid accumulation. HIIT significantly improved mitochondrial fatty acid oxidation through upregulating mitochondrial enzyme activities, mitochondrial function and AMPK/PPARalpha/CPT1alpha pathway, as well as inhibiting hepatic de novo lipogenesis in obese HFD rats. These findings indicate that dietary alone or HIIT intervention powerfully improve intrahepatic storage of fat in diet induced obese rats. Keywords: Obesity, Exercise, Diet, Mitochondrial function, Lipid deposition.

• MeSH
• dieta s vysokým obsahem tuků * škodlivé účinky   MeSH
• játra * metabolismus   MeSH
• kondiční příprava zvířat fyziologie   MeSH
• krysa rodu Rattus MeSH
• metabolismus lipidů * MeSH
• obezita * metabolismus   terapie   MeSH
• potkani Sprague-Dawley * MeSH
• vysoce intenzivní intervalový trénink * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Liver sinusoidal endothelial cells (LSECs) play a crucial role in regulating the hepatic function. Endoglin (ENG), a transmembrane glycoprotein, was shown to be related to the development of endothelial dysfunction. In this study, we hypothesized the relationship between changes in ENG expression and markers of liver sinusoidal endothelial dysfunction (LSED) during liver impairment. Male C57BL/6J mice aged 9-12 weeks were fed with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet (intrahepatic cholestasis) or choline-deficient l-amino acid defined high-fat diet (CDAA-HFD) (non-alcoholic steatohepatitis (NASH)). Significant increases in liver enzymes, fibrosis, and inflammation biomarkers were observed in both cholestasis and NASH. Decreased p-eNOS/eNOS and VE-cadherin protein expression and a significant increase in VCAM-1 and ICAM-1 expression were detected, indicating LSED in both mouse models of liver damage. A significant reduction of ENG in the DDC-fed mice, while a significant increase of ENG in the CDAA-HFD group was observed. Both DDC and CDAA-HFD-fed mice showed a significant increase in MMP-14 protein expression, which is related to significantly increased levels of soluble endoglin (sENG) in the plasma. In conclusion, we demonstrated that intrahepatic cholestasis and NASH result in an altered ENG expression, predominantly in LSECs, suggesting a critical role of ENG expression for the proper function of liver sinusoids. Both pathologies resulted in elevated sENG levels, cleaved by MMP-14 expressed predominantly from LSECs, indicating sENG as a liver injury biomarker.

• Klíčová slova
• Endoglin, Liver sinusoidal endothelial dysfunction, MMP-14, Soluble endoglin,
• MeSH
• acetamidy * MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• endoglin metabolismus   MeSH
• endoteliální buňky metabolismus   MeSH
• intrahepatální cholestáza * MeSH
• matrixová metaloproteinasa 14 MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nealkoholová steatóza jater * patologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetamidy * MeSH
• CDAA MeSH Prohlížeč
• endoglin MeSH
• Eng protein, mouse MeSH Prohlížeč
• matrixová metaloproteinasa 14 MeSH

INTRODUCTION: Regular physical activity and dietary variety are modifiable and influential factors of health outcomes. However, the cumulative effects of these behaviors are not well understood. Metabolomics may have a promising research potential to extend our knowledge and use it in the attempts to find a long-term and sustainable personalized approach in exercise and diet recommendations. OBJECTIVE: The main aim was to investigate the effect of the 12 week very low carbohydrate high fat (VLCHF) diet and high-intensity interval training (HIIT) on lipidomic and metabolomic profiles in individuals with overweight and obesity. METHODS: The participants (N = 91) were randomly allocated to HIIT (N = 22), VLCHF (N = 25), VLCHF + HIIT (N = 25) or control (N = 19) groups for 12 weeks. Fasting plasma samples were collected before the intervention and after 4, 8 and 12 weeks. The samples were then subjected to untargeted lipidomic and metabolomic analyses using reversed phase ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry. RESULTS: The VLCHF diet affected plasma lipids considerably while the effect of HIIT was unremarkable. Already after 4 weeks of intervention substantial changes of plasma lipids were found in both VLCHF diet groups. The changes persisted throughout the entire 12 weeks of the VLCHF diet. Specifically, acyl carnitines, plasmalogens, fatty acyl esters of hydroxy fatty acid, sphingomyelin, ceramides, cholesterol esters, fatty acids and 4-hydroxybutyric were identified as lipid families that increased in the VLCHF diet groups whereas lipid families of triglycerides and glycerophospholipids decreased. Additionally, metabolomic analysis showed a decrease of theobromine. CONCLUSIONS: This study deciphers the specific responses to a VLCHF diet, HIIT and their combination by analysing untargeted lipidomic and metabolomic profile. VLCHF diet caused divergent changes of plasma lipids and other metabolites when compared to the exercise and control group which may contribute to a better understanding of metabolic changes and the appraisal of VLCHF diet benefits and harms. CLINICAL TRIAL REGISTRY NUMBER: NCT03934476, registered 1st May 2019 https://clinicaltrials.gov/ct2/show/NCT03934476?term=NCT03934476&draw=2&rank=1 .

• Klíčová slova
• Carbohydrates, Diet, Exercise, Lipidomics, Lipids, Metabolomics,
• MeSH
• dieta s vysokým obsahem tuků MeSH
• lidé MeSH
• lipidomika * MeSH
• metabolomika MeSH
• sacharidy MeSH
• triglyceridy MeSH
• vysoce intenzivní intervalový trénink * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• sacharidy MeSH
• triglyceridy MeSH

The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is associated with abnormalities of liver lipid metabolism. On the contrary, a diet enriched with n-3 polyunsaturated fatty acids (n-3-PUFAs) has been reported to ameliorate the progression of NAFLD. The aim of our study was to investigate the impact of dietary n-3-PUFA enrichment on the development of NAFLD and liver lipidome. Mice were fed for 6 weeks either a high-fat methionine choline-deficient diet (MCD) or standard chow with or without n-3-PUFAs. Liver histology, serum biochemistry, detailed plasma and liver lipidomic analyses, and genome-wide transcriptome analysis were performed. Mice fed an MCD developed histopathological changes characteristic of NAFLD, and these changes were ameliorated with n-3-PUFAs. Simultaneously, n-3-PUFAs decreased serum triacylglycerol and cholesterol concentrations as well as ALT and AST activities. N-3-PUFAs decreased serum concentrations of saturated and monounsaturated free fatty acids (FAs), while increasing serum concentrations of long-chain PUFAs. Furthermore, in the liver, the MCD significantly increased the hepatic triacylglycerol content, while the administration of n-3-PUFAs eliminated this effect. Administration of n-3-PUFAs led to significant beneficial differences in gene expression within biosynthetic pathways of cholesterol, FAs, and pro-inflammatory cytokines (IL-1 and TNF-α). To conclude, n-3-PUFA supplementation appears to represent a promising nutraceutical approach for the restoration of abnormalities in liver lipid metabolism and the prevention and treatment of NAFLD.

• Klíčová slova
• lipidome, lipids, n-3 fatty acids, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis,
• MeSH
• cholesterol metabolismus   MeSH
• cholin metabolismus   MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• játra metabolismus   MeSH
• kyseliny mastné neesterifikované metabolismus   MeSH
• kyseliny mastné omega-3 * farmakologie   terapeutické užití   metabolismus   MeSH
• methionin metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nealkoholová steatóza jater * etiologie   genetika   MeSH
• nenasycené mastné kyseliny metabolismus   MeSH
• Racemethionin metabolismus   farmakologie   MeSH
• triglyceridy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholesterol MeSH
• cholin MeSH
• kyseliny mastné neesterifikované MeSH
• kyseliny mastné omega-3 * MeSH
• methionin MeSH
• nenasycené mastné kyseliny MeSH
• Racemethionin MeSH
• triglyceridy MeSH

Recent data suggest that the orexigenic peptide ghrelin and liver-expressed antimicrobial peptide 2 (LEAP2) have opposing effects on food intake regulation. Although circulating ghrelin is decreased in obesity, peripheral ghrelin administration does not induce food intake in obese mice. Limited information is available on ghrelin resistance in relation to LEAP2. In this study, the interplay between ghrelin and LEAP2 in obesity induced by a high-fat (HF) diet in mice was studied. First, the progression of obesity and intolerance to glucose together with plasma levels of active and total ghrelin, leptin, as well as liver LEAP2 mRNA expression at different time points of HF diet feeding was examined. In addition, the impact of switch from a HF diet to a standard diet on plasma ghrelin and LEAP2 production was studied. Second, sensitivity to the stable ghrelin analogue [Dpr3]Ghrelin or our novel LEAP2 analogue palm-LEAP2(1-14) during the progression of HF diet-induced obesity and after the switch for standard diet was investigated. Food intake was monitored after acute subcutaneous administration. HF diet feeding decreased both active and total plasma ghrelin and increased liver LEAP2 mRNA expression along with intolerance to glucose and the switch to a standard diet normalized liver LEAP2 mRNA expression and plasma level of active ghrelin, but not of total ghrelin. Additionally, our study demonstrates that a HF diet causes resistance to [Dpr3]Ghrelin, reversible by switch to St diet, followed by resistance to palm-LEAP2(1-14). Further studies are needed to determine the long-term effects of LEAP2 analogues on obesity-related ghrelin resistance.

• MeSH
• dieta s vysokým obsahem tuků * MeSH
• ghrelin * farmakologie   MeSH
• glukosa MeSH
• messenger RNA MeSH
• myši MeSH
• obezita farmakoterapie   MeSH
• receptory ghrelinu MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ghrelin * MeSH
• glukosa MeSH
• messenger RNA MeSH
• receptory ghrelinu MeSH

Obesity has a major socio-economic health impact. There are profound sex differences in adipose tissue deposition and obesity-related conditions. The underlying mechanisms driving sexual dimorphism in obesity and its associated metabolic disorders remain unclear. Histone variant macroH2A1.1 is a candidate epigenetic mechanism linking environmental and dietary factors to obesity. Here, we used a mouse model genetically depleted of macroH2A1.1 to investigate its potential epigenetic role in sex dimorphic obesity, metabolic disturbances and gut dysbiosis. Whole body macroH2A1 knockout (KO) mice, generated with the Cre/loxP technology, and their control littermates were fed a high fat diet containing 60% of energy derived from fat. The diet was administered for three months starting from 10 to 12 weeks of age. We evaluated the progression in body weight, the food intake, and the tolerance to glucose by means of a glucose tolerance test. Gut microbiota composition, visceral adipose and liver tissue morphology were assessed. In addition, adipogenic gene expression patterns were evaluated in the visceral adipose tissue. Female KO mice for macroH2A1.1 had a more pronounced weight gain induced by high fat diet compared to their littermates, while the increase in body weight in male mice was similar in the two genotypes. Food intake was generally increased upon KO and decreased by high fat diet in both sexes, with the exception of KO females fed a high fat diet that displayed the same food intake of their littermates. In glucose tolerance tests, glucose levels were significantly elevated upon high fat diet in female KO compared to a standard diet, while this effect was absent in male KO. There were no differences in hepatic histology. Upon a high fat diet, in female adipocyte cross-sectional area was larger in KO compared to littermates: activation of proadipogenic genes (ACACB, AGT, ANGPT2, FASN, RETN, SLC2A4) and downregulation of antiadipogenic genes (AXIN1, E2F1, EGR2, JUN, SIRT1, SIRT2, UCP1, CCND1, CDKN1A, CDKN1B, EGR2) was detected. Gut microbiota profiling showed increase in Firmicutes and a decrease in Bacteroidetes in females, but not males, macroH2A1.1 KO mice. MacroH2A1.1 KO mice display sexual dimorphism in high fat diet-induced obesity and in gut dysbiosis, and may represent a useful model to investigate epigenetic and metabolic differences associated to the development of obesity-associated pathological conditions in males and females.

• MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• dysbióza * MeSH
• glukosa metabolismus   MeSH
• histony * genetika   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• obezita genetika   metabolismus   MeSH
• tělesná hmotnost MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• glukosa MeSH
• histony * MeSH
• Macroh2a1 protein, mouse MeSH Prohlížeč

OBJECTIVE: The possibility to counteract the development of obesity in humans by recruiting brown or brite/beige adipose tissue (and thus UCP1) has attracted much attention. Here we examine if a diet that can activate diet-induced thermogenesis can exploit pre-enhanced amounts of UCP1 to counteract the development of diet-induced obesity. METHODS: To investigate the anti-obesity significance of highly augmented amounts of UCP1 for control of body energy reserves, we physiologically increased total UCP1 amounts by recruitment of brown and brite/beige tissues in mice. We then examined the influence of the augmented UCP1 levels on metabolic parameters when the mice were exposed to a high-fat/high-sucrose diet under thermoneutral conditions. RESULTS: The total UCP1 levels achieved were about 50-fold higher in recruited than in non-recruited mice. Contrary to underlying expectations, in the mice with highly recruited UCP1 and exposed to a high-fat/high-sucrose diet the thermogenic capacity of this UCP1 was completely inactivate. The mice even transiently (in an adipostat-like manner) demonstrated a higher metabolic efficiency and fat gain than did non-recruited mice. This was accomplished without altering energy expenditure or food absorption efficiency. The metabolic efficiency here was indistinguishable from that of mice totally devoid of UCP1. CONCLUSIONS: Although UCP1 protein may be available, it is not inevitably utilized for diet-induced thermogenesis. Thus, although attempts to recruit UCP1 in humans may become successful as such, it is only if constant activation of the UCP1 is also achieved that amelioration of obesity development could be attained.

• Klíčová slova
• Adipostat, Beige adipose tissue, Body weight regulation, Diet-induced thermogenesis, Glucose homeostasis, UCP1,
• MeSH
• béžová tuková tkáň metabolismus   MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• energetický metabolismus MeSH
• hnědá tuková tkáň * metabolismus   MeSH
• lidé MeSH
• myši MeSH
• obezita * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Alzheimer's disease (AD) is a progressive brain disorder characterized by extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles formed by hyperphosphorylated Tau protein and neuroinflammation. Previous research has shown that obesity and type 2 diabetes mellitus, underlined by insulin resistance (IR), are risk factors for neurodegenerative disorders. In this study, obesity-induced peripheral and central IR and inflammation were studied in relation to AD-like pathology in the brains and periphery of APP/PS1 mice, a model of Aβ pathology, fed a high-fat diet (HFD). APP/PS1 mice and their wild-type controls fed either a standard diet or HFD were characterized at the ages of 3, 6 and 10 months by metabolic parameters related to obesity via mass spectroscopy, nuclear magnetic resonance, immunoblotting and immunohistochemistry to quantify how obesity affected AD pathology. The HFD induced substantial peripheral IR leading to central IR. APP/PS1-fed HFD mice had more pronounced IR, glucose intolerance and liver steatosis than their WT controls. The HFD worsened Aβ pathology in the hippocampi of APP/PS1 mice and significantly supported both peripheral and central inflammation. This study reveals a deleterious effect of obesity-related mild peripheral inflammation and prediabetes on the development of Aβ and Tau pathology and neuroinflammation in APP/PS1 mice.

• Klíčová slova
• APP/PS1, Alzheimer’s disease, amyloid-β, glucose intolerance, inflammation, insulin resistance, neuroinflammation, obesity, tau protein,
• MeSH
• Alzheimerova nemoc * etiologie   MeSH
• amyloidní beta-protein MeSH
• diabetes mellitus 2. typu * MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• inzulinová rezistence * MeSH
• myši MeSH
• neurozánětlivé nemoci MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amyloidní beta-protein MeSH

Non-alcoholic fatty liver disease (NAFLD) is a general term for fatty liver disease not caused by viruses or alcohol. Fibrotic hepatitis, cirrhosis, and hepatocellular carcinoma can develop. The recent increase in NAFLD incidence worldwide has stimulated drug development efforts. However, there is still no approved treatment. This may be due in part to the fact that non-alcoholic steatohepatitis (NASH) pathogenesis is very complex, and its mechanisms are not well understood. Studies with animals are very important for understanding the pathogenesis. Due to the close association between the establishment of human NASH pathology and metabolic syndrome, several animal models have been reported, especially in the context of overnutrition. In this study, we investigated the induction of NASH-like pathology by enhancing cholesterol absorption through treatment with hydroxypropyl-beta-cyclodextrin (CDX). Female Sprague-Dawley rats were fed a normal diet with normal water (control group); a high-fat (60 kcal%), cholesterol (1.25 %), and cholic acid (0.5 %) diet with normal water (HFCC group); or HFCC diet with 2 % CDX water (HFCC+CDX group) for 16 weeks. Compared to the control group, the HFCC and HFCC+CDX groups showed increased blood levels of total cholesterol, aspartate aminotransferase, and alanine aminotransferase. At autopsy, parameters related to hepatic lipid synthesis, oxidative stress, inflammation, and fibrosis were elevated, suggesting the development of NAFLD/NASH. Elevated levels of endoplasmic reticulum stress-related genes were evident in the HFCC+CDX group. In the novel rat model, excessive cholesterol intake and accelerated absorption contributed to NAFLD/NASH pathogenesis.

• MeSH
• cholesterol MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• hydroxypropyl beta cyklodextrin metabolismus   terapeutické užití   MeSH
• hypercholesterolemie * metabolismus   MeSH
• hyperlipidemie * MeSH
• játra metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• nealkoholová steatóza jater * chemicky indukované   MeSH
• potkani Sprague-Dawley MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholesterol MeSH
• hydroxypropyl beta cyklodextrin MeSH