Untargeted Metabolomic Characteristics of Skeletal Muscle Dysfunction in Rabbits Induced by a High Fat Diet

Type 2 diabetes and metabolic syndrome caused by a high fat diet (HFD) have become public health problems worldwide. These diseases are characterized by the oxidation of skeletal muscle mitochondria and disruption of insulin resistance, but the mechanisms are not well understood. Therefore, this study aims to reveal how high-fat diet causes skeletal muscle metabolic disorders. In total, 16 weaned rabbits were randomly divided into two groups, one group was fed a standard normal diet (SND) and the other group was fed a high fat diet (HFD) for 5 weeks. At the end of the five-week experiment, skeletal muscle tissue samples were taken from each rabbit. Untargeted metabolomic analysis was performed using ultra-performance liquid chromatography combined with mass spectrometry (UHPLC-MS/MS). The results showed that high fat diet significantly altered the expression levels of phospholipids, LCACs, histidine, carnosine, and tetrahydrocorticosterone in skeletal muscle. Principal component analysis (PCA) and least squares discriminant analysis (PLS-DA) showed that, compared with the SND group, skeletal muscle metabolism in HFD group was significantly up-regulated. Among 43 skeletal muscle metabolites in the HFD group, phospholipids, LCACs, histidine, carnosine, and tetrahydrocorticosteroids were identified as biomarkers of skeletal muscle metabolic diseases, and may become potential physiological targets of related diseases in the future. Untargeted metabonomics analysis showed that high-fat diet altered the metabolism of phospholipids, carnitine, amino acids and steroids in skeletal muscle of rabbits. Notably, phospholipids, LCACs, histidine, carnopeptide, and tetrahydrocorticosteroids block the oxidative capacity of mitochondria and disrupt the oxidative capacity of glucose and the fatty acid-glucose cycle in rabbit skeletal muscle.

Download Full-text

Untargeted Metabolomic Characteristics of Skeletal Muscle Dysfunction in Rabbits Induced by a High Fat Diet

10.21203/rs.3.rs-159084/v1 ◽

2021 ◽

Author(s):

Huimei Fan ◽

YanHong Li ◽

Jie Wang ◽

Jiahao Shao ◽

Tao Tang ◽

...

Keyword(s):

Skeletal Muscle ◽

High Fat Diet ◽

Metabolic Diseases ◽

Muscle Metabolism ◽

Principal Component ◽

Least Square ◽

Rabbit Skeletal Muscle ◽

Untargeted Metabolomics ◽

High Fat ◽

Skeletal Muscle Metabolism

Abstract Background: Type 2 diabetes and metabolic syndrome caused by a high fat diet (HFD) have become public health problems around the world. These diseases are characterized by disrupted mitochondrial oxidation and insulin resistance in skeletal muscle, but the mechanism is not clear. Therefore, this study aims to reveal how a high-fat diet induces skeletal muscle metabolism disorder.Methods：Sixteen weaned rabbits were randomly divided into two groups, one fed with a standard normal diet (SND) and another one fed a HFD for five weeks. Skeletal muscle tissue samples were extracted from each rabbit at the end of the 5-week trial. An untargeted metabolomics profiling was performed using ultraperformance liquid chromatography combined with mass spectrometry (UHPLC-MS/MS).Results: The HFD significantly altered the expression levels of phospholipids, LCACs, histidine, carnosine and tetrahydrocorticosterone in skeletal muscle. Principal component analysis (PCA) and least square discriminant analysis (PLS-DA) indicated that rabbit skeletal muscle metabolism in the HFD group was significantly up-regulated compared with that of the SND group. Among the 43 skeletal muscle metabolites in the HFD group, phospholipids, LCACs, histidine, carnosine and tetrahydrocorticosterone were identified as biomarkers for skeletal muscle metabolic diseases, and may also serve as potential physiological targets for related diseases in the future.Conclusion: The untargeted metabolomics analysis revealed that a HFD altered the rabbit skeletal muscle metabolism of phospholipids, carnitine, amino acids, and steroids. Notably, phospholipids, LCACs, histidine, carnosine and tetrahydrocorticosterone blocked the oxidative ability of mitochondria, and disturbed the oxidative ability of glucose and the fatty acid-glucose cycle in rabbit skeletal muscle.

Download Full-text

Abstract 394: Posttranslational Modification Of Klf5 Mediates Metabolic Dysfunction And Vascular Disease In Metabolic Syndrome

Circulation ◽

10.1161/circ.116.suppl_16.ii_63-a ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Yumiko Oishi ◽

Ichiro Manabe ◽

Kazuyuki Tobe ◽

Takashi Kadowaki ◽

Ryozo Nagai

Keyword(s):

Skeletal Muscle ◽

Metabolic Syndrome ◽

Energy Expenditure ◽

Posttranslational Modifications ◽

High Fat Diet ◽

Metabolic Diseases ◽

C2c12 Myotubes ◽

Metabolic Dysfunction ◽

High Fat ◽

Increased Risk

We have previously shown that a zinc finger transcription factor, Krüppel-like factor 5 (KLF5), plays an important role in pathogenesis of cardiovascular diseases, such as atherosclerosis. KLF5 heterozygous knockout ( KLF5 +/ − ) mice exhibited much less neointima formation, cardiac hypertrophy and fibrosis. We also found that expression of KLF5 correlated with a higher incidence of restenosis following PCI and the SNP located within the KLF5 promoter was associated with an increased risk of hypertension in man. Interestingly, KLF5 is also expressed in metabolic tissues such as adipose tissue, skeletal muscle, and pancreatic β-cells. Thus, we hypothesized that KLF5 might play a role in metabolic diseases. To test this, KLF5 +/ − mice were fed with high-fat diet. Although KLF5 +/ − mice ate more food than wild-type littermates, they were resistant to high-fat diet-induced obesity and protected from dyslipidemia, glucose intolerance and hepatic steatosis, indicating that KLF5 + /− mice were less susceptible to metabolic syndrome. The systemic O 2 consumption and expression of genes involved in energy expenditure in skeletal muscle were increased in KLF5 + /− mice, demonstrating enhanced energy expenditure, which partly explains the phenotype. Knocking down KLF5 by siRNA increased expression levels of UCP2/3 and CPT-1b in C2C12 myotubes, suggesting that KLF5 may inhibit energy expenditure-related genes. Chromatin immunoprecipitation and coimmunoprecipitation assays showed that KLF5 interacted with corepressors, such as SMRT and NCoR, and strongly inhibited the UCP and CPT-1b promoters. We found that this inhibitory activity of KLF5 depended on its SUMOylation. When KLF5 was deSUMOylated, it activated the promoters. These data demonstrate that KLF5 acts as a molecular switch for energy expenditure and the posttranslational modifications of KLF5 including SUMOylation turns on/off the switch function of KLF5. Given that KLF5 also controls tissue remodeling in response to external stress, KLF5 may mediate metabolic dysfunction and atherosclerosis in metabolic syndrome. Our findings also suggest that the posttranscriptional modification of KLF5 is an attractive novel therapeutic target.

Download Full-text

Artificial selection for high-capacity endurance running is protective against high-fat diet-induced insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00500.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. E31-E41 ◽

Cited By ~ 90

Author(s):

Robert C. Noland ◽

John P. Thyfault ◽

Sarah T. Henes ◽

Brian R. Whitfield ◽

Tracey L. Woodlief ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Weight Gain ◽

High Fat Diet ◽

Oxidative Capacity ◽

Male Rats ◽

High Fat ◽

Endurance Running ◽

Muscle Oxidative Capacity ◽

Obesity And Diabetes

Elevated oxidative capacity, such as occurs via endurance exercise training, is believed to protect against the development of obesity and diabetes. Rats bred both for low (LCR)- and high (HCR)-capacity endurance running provide a genetic model with inherent differences in aerobic capacity that allows for the testing of this supposition without the confounding effects of a training stimulus. The purpose of this investigation was to determine the effects of a high-fat diet (HFD) on weight gain patterns, insulin sensitivity, and fatty acid oxidative capacity in LCR and HCR male rats in the untrained state. Results indicate chow-fed LCR rats were heavier, hypertriglyceridemic, less insulin sensitive, and had lower skeletal muscle oxidative capacity compared with HCR rats. Upon exposure to an HFD, LCR rats gained more weight and fat mass, and their insulin resistant condition was exacerbated, despite consuming similar amounts of metabolizable energy as chow-fed controls. These metabolic variables remained unaltered in HCR rats. The HFD increased skeletal muscle oxidative capacity similarly in both strains, whereas hepatic oxidative capacity was diminished only in LCR rats. These results suggest that LCR rats are predisposed to obesity and that expansion of skeletal muscle oxidative capacity does not prevent excess weight gain or the exacerbation of insulin resistance on an HFD. Elevated basal skeletal muscle oxidative capacity and the ability to preserve liver oxidative capacity may protect HCR rats from HFD-induced obesity and insulin resistance.

Download Full-text

Hepatic Metabolomic Analysis in Mice Fed a High Fat Diet with Watermelon and Watermelon Byproducts Shows Improved Lipid Metabolism and Reduction of Chronic Inflammation (P06-023-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz031.p06-023-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Alexandra Becraft ◽

Marlena Sturm ◽

Gavin Pierce ◽

Rufa Mendez ◽

Neil Shay

Keyword(s):

Chronic Inflammation ◽

High Fat Diet ◽

Liver Tissue ◽

Value Added ◽

Principal Component ◽

Metabolomic Analysis ◽

High Fat ◽

Tissue Samples ◽

Metabolic Conditions ◽

Ultrahigh Performance Liquid Chromatography

Abstract Objectives Watermelon is a nutrient-dense fruit shown previously to produce health benefits, particularly regarding blood pressure regulation. We tested the hypothesis that intake of whole watermelon flesh and value-added watermelon components would improve metabolic conditions in C57BL/6 J male mice fed a high-fat, high-sucrose diet modeling an obesogenic Western diet (HF). We further hypothesize that metabolomic profiling will show changes in relative levels of compounds related to lipid and glucose metabolism, and chronic inflammation. Methods In a prior study (Becraft et al., 2018), groups of mice (n = 8) were provided either low-fat diet (LF, 10% kcal fat), high-fat diet (HF, 45% kcal fat), HF plus Watermelon Skin (HF + WS), HF plus Watermelon Rind (HF + WR), or HF plus Watermelon Flesh (HF + WF) for 10 weeks. Watermelon flesh was provided at 10% of total energy and skin and rind were added at ∼ 0.2% (w/w) of diet. After ten weeks, animals were euthanized, and liver tissue saved for metabolomic analysis. Liver tissue samples were homogenized, and an identical mass equivalent of liver was subjected to methanol extraction and split into aliquots for analysis by ultrahigh performance liquid chromatography/mass spectrometry in the positive, negative or polar ion mode. There were 709 biochemicals identified and analyzed between groups. Welch's 2-sample t-test was performed with ArrayStudio (Omicsoft) or R software on log transformed data to compare data between experimental groups. Estimate of the false discovery rate (Q value) was calculated and Q ;< 0.05 used as an indication of high confidence in a result. Results Principal component analysis showed segregation of groups along three different components, representing 24.8%, 19.4%, and 9.0% of the variation. Profound differences were found in LF vs. HF liver tissue. Compared to HF-fed mice, mice fed WF showed reduced levels of bile acids and pro-inflammatory compounds 12-HETE, 15, HETE, and PGF2 (all P < 0.05) in the liver. Conclusions In mice consuming a high-fat western style diet, regular intake of watermelon flesh, and fiber-rich products made from rind and skin all improved metabolism as evidenced by metabolomic analysis of liver tissue. Most notably were reductions in pro-inflammatory compounds including HETEs and Prostaglandin F2. Funding Sources National Watermelon Promotion Board.

Download Full-text

Sex differences in gut microbiome in high-fat-diet fed rats.

10.21203/rs.3.rs-31327/v1 ◽

2020 ◽

Author(s):

Ying Shi ◽

Fangzhi Yue ◽

Lin Xing ◽

Shanyu Wu ◽

Lin Wei ◽

...

Keyword(s):

Sex Differences ◽

Gut Microbiota ◽

Gut Microbiome ◽

High Fat Diet ◽

Metabolic Diseases ◽

Normal Diet ◽

Female Rats ◽

Male Rats ◽

High Fat ◽

Alcoholic Fatty Liver

Abstract Background Sex differences in obesity and related metabolic diseases are well recognized, however, the mechanism has not been elucidated. Gut microbiota and its metabolites may play a vital role in the development of obesity and metabolic diseases. The aim of the present study was to investigate sex differences in gut microbiota and its metabolites in a high-fat-diet (HFD) obesity rats and identify microbiota genera potentially contributing to such differences in obesity and non-alcoholic fatty liver disease (NAFLD) susceptibility. Results Sprague–Dawley rats were divided into the following groups (seven animals per group): (1) male rats on a normal diet (MND), (2) male rats on HFD (MHFD), (3) female rats on a normal diet (FND), and (4) female rats on HFD (FHFD). HFD induced more body weight gain and fat storage in female rats, however, lower hepatic steatosis in FHFD than in MHFD rats was observed. When considering gut microbiota composition, FHFD rats had lower microbiome diversity than MHFD. A significant increase of Firmicutes phylum and Bilophila genus was detected in MHFD rats, as compared with FHFD, which showed increased relative abundance of Murimonas and Roseburia . Moreover, propionic and lauric acid levels were higher in FHFD than those in MHFD rats. Conclusion HFD induced sex-related alterations in gut microbiome and fatty acids. Furthermore, the genus Bilophila and Roseburia might contribute to sex differences observed in obesity and NAFLD susceptibility.

Download Full-text

Impaired skeletal muscle metabolism in obesity prone rats on a high fat diet

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.1153.4 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Timothy Daniel Allerton ◽

Eli Bench ◽

Stefany Primeaux

Keyword(s):

Skeletal Muscle ◽

High Fat Diet ◽

Muscle Metabolism ◽

High Fat ◽

Skeletal Muscle Metabolism

Download Full-text

Abstract 17649: Inhibition of Src Homology 2 Domain-containing Phosphatase 1 (SHP-1) Increases Insulin Sensitivity in High-fat Diet-induced Insulin Resistant C57black6 Mice

Circulation ◽

10.1161/circ.130.suppl_2.17649 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Janine Krüger ◽

Markus Dagnell ◽

Philipp Stawowy ◽

Evren Caglayan ◽

Arne Östman ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Body Weight ◽

Glucose Tolerance ◽

High Fat Diet ◽

Metabolic Diseases ◽

High Fat ◽

Insulin Resistant ◽

Cardiovascular Morbidity And Mortality

Background: Insulin resistance plays a crucial role in the development of type 2 diabetes, and exerts great impact on vascular inflammation and remodeling. At the molecular level a post-insulin receptor (IR) defect in insulin signaling has been suggested to contribute to insulin resistance. IR signaling is antagonized and tightly controlled by protein tyrosine phosphatases (PTPs). The precise role of PTPs in insulin resistance, however, has not been explored. Results: Male C57BL/6J mice were fed a high-fat diet (HFD, 60% kcal from fat) to induce insulin resistance, or a low-fat diet (LFD, 10% kcal from fat) for 10 weeks. Afterwards, HFD mice were treated with PTP-inhibitors for additional 6 weeks. Mice under HFD exhibited a significant increase in body weight as well as decreased respiratory quotient and adiponectin levels, and were characterized by impaired insulin- and glucose tolerance. Organ-based gene expression analyses in insulin-resistant mice demonstrated upregulation of SHP-1, PTP1B, LAR, and DEP-1 in insulin-sensitive organs. SHP-1 was further explored in vitro. Insulin stimulation in murine liver cells induced site-selective hyper-phosphorylation at IR tyrosine-sites Y1158, and Y1361 after inhibition of SHP-1. Furthermore, SHP-1 impairment time-dependently enhanced insulin-induced Akt- and Erk-phosphorylation, and resulted in elevated glucose uptake in skeletal muscle cells. Administration of a SHP-1 inhibitor (Sodium Stibogluconate) and a brought pan-PTP inhibitor (BMOV) in HFD mice led to improvement of both insulin- and glucose tolerance. In accordance, PTP-activity was significantly impaired in epididymal fat, skeletal muscle, and liver under BMOV treatment, being confirmed by reduced ex vivo dephosphorylation of a radioactive labelled peptide (AEEEIYGEFEAKKKK). Finally, BMOV- and SHP-1 treatment also resulted in reduced body weight. Conclusions: IR-antagonizing PTPs were organ-specifically regulated in insulin resistance. The results indicate a central role of PTPs and, in particular, of SHP-1 as endogenous antagonists of the IR. Taken together targeting PTPs led to beneficial effects in insulin resistance, and may thus improve metabolic diseases as well as cardiovascular morbidity and mortality.

Download Full-text

Effect of Ethyl Pyruvate on Skeletal Muscle Metabolism in Rats Fed on a High Fat Diet

Nutrients ◽

10.3390/nu5072372 ◽

2013 ◽

Vol 5 (7) ◽

pp. 2372-2383 ◽

Cited By ~ 2

Author(s):

Robert Olek ◽

Wieslaw Ziolkowski ◽

Tomasz Wierzba ◽

Jan Kaczor

Keyword(s):

Skeletal Muscle ◽

High Fat Diet ◽

Ethyl Pyruvate ◽

Muscle Metabolism ◽

High Fat ◽

Skeletal Muscle Metabolism

Download Full-text

Purple-leaf tea (Camellia sinensis L.) ameliorates high-fat diet induced obesity and metabolic disorder through the modulation of the gut microbiota in mice

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-020-03171-4 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Yu-Chun Lin ◽

Hsu-Feng Lu ◽

Jui-Chieh Chen ◽

Hsiu-Chen Huang ◽

Yu-Hsin Chen ◽

...

Keyword(s):

Insulin Resistance ◽

Gut Microbiota ◽

Camellia Sinensis ◽

High Fat Diet ◽

Metabolic Disorders ◽

Metabolic Diseases ◽

Normal Diet ◽

High Fat ◽

Hepatic Diseases ◽

Purple Leaf

Abstract Background Obesity and its associated diseases have become a major world-wide health problem. Purple-leaf Tea (Camellia sinensis L.) (PLT), that is rich of anthocyanins, has been shown to have preventive effects on obesity and metabolic disorders. The intestinal microbiota has been shown to contribute to inflammation, obesity, and several metabolic disorders. However, whether PLT consumption could prevent obesity and diet-induced metabolic diseases by modulating the gut microbiota, is not clearly understood. Methods In this study, six-week-old male C57BL/6 J mice were fed a normal diet (ND) or a high fat diet (HFD) without or with PLT for 10 weeks. Results PLT modulated the gut microbiota in mice and alleviated the symptoms of HFD-induced metabolic disorders, such as insulin resistance, adipocyte hypertrophy, and hepatic steatosis. PLT increased the diversity of the microbiota and the ratio of Firmicutes to Bacteroidetes. f_Barnesiellaceae, g_Barnesiella, f_Ruminococcaceae, and f_Lachnospiraceae were discriminating faecal bacterial communities of the PLT mice that differed from the HFD mice. Conclusions These data indicate that PLT altered the microbial contents of the gut and prevented microbial dysbiosis in the host, and consequently is involved in the modulation of susceptibility to insulin resistance, hepatic diseases, and obesity that are linked to an HFD.

Download Full-text