Metabolomic signatures for liver tissue and cecum contents in high-fat diet-induced obese mice based on UHPLC-Q-TOF/MS

Abstract Background The incidence of obesity is increasing worldwide, and it is a risk factor for diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Our previous study had demonstrated that high-fat diet induced increased weight gain, fat weight, serum cholesterol, triglyceride, and ATL levels in liver, and influenced the diversity and composition of cecal microbiota in mice. Hence, this study aimed to investigate the roles of the gut microbially derived metabolites and liver metabolites between the obese and lean mice, focusing on their association with the progression of obesity induced by high-fat diet (HFD). Methods An obesity model in mice was established with HFD for 16 weeks. Cecal contents and liver tissues metabolomics based on ultraperformance liquid chromatography-quadrupole-time-of-flight mass spectrometry and orthogonal partial least squares discriminant analyses (OPLS-DA) was performed to identify the alterations in metabolites associated with obese mice. Results Obese and lean groups were clearly discriminated from each other on OPLS-DA score plot and major metabolites contributing to the discrimination were mainly involved in glycerophospholipid metabolism, primary bile acid biosynthesis, and biosynthesis of unsaturated fatty acids pathways. HFD-induced alterations of 19 metabolites in liver and 43 metabolites in cecum contents were identified as potential biomarkers related to obesity. Specifically, chenodeoxycholic acid, taurochenodeoxycholate, and tauroursodeoxycholic acid in liver were elevated 35.94, 24.36, and 18.71-fold, respectively. PI(P-16:0/18:1(9Z)), PG(19:0/16:0), PS(P-16:0/20:2(11Z,14Z)), PI(22:1(11Z)/12:0), and PE(21:0/0:0) in cecum were enhanced 884, 640.96, 226.63, 210.10, 45.13-fold in comparison with the lean mice. These metabolites were the most important biomarkers for discriminating between the obese and lean mice. In addition, cecum contents metabolites were strongly correlated with hepatic metabolites through gut-liver axis analysis. Conclusions HFD increased lipid profiles (i.e. glycerophospholipids, PC, PE, PI, PG, and PS) and total bile acid (primary and secondary bile acid) in liver and cecum, suggesting that they may play an important role in the progression of obesity. These metabolites can be used to better understand obesity and related disease induced by HFD. Furthermore, the level alterations of these metabolites can be used to assess the risk of obesity and the therapeutic effect of obesity management.

Download Full-text

Hypotriglyceridemic effects of brown seaweed consumption via regulation of bile acid excretion and hepatic lipogenesis in high fat diet-induced obese mice

Nutrition Research and Practice ◽

10.4162/nrp.2020.14.6.580 ◽

2020 ◽

Vol 14 (6) ◽

pp. 580

Author(s):

A-Reum Han ◽

Jae-Hoon Kim ◽

Eunyoung Kim ◽

Jiamei Cui ◽

In-Suk Chai ◽

...

Keyword(s):

Bile Acid ◽

High Fat Diet ◽

Brown Seaweed ◽

Hepatic Lipogenesis ◽

Obese Mice ◽

Acid Excretion ◽

High Fat ◽

Bile Acid Excretion

Download Full-text

Psoralea corylifolia L. Seed Extract Attenuates Nonalcoholic Fatty Liver Disease in High-Fat Diet-Induced Obese Mice

Nutrients ◽

10.3390/nu8020083 ◽

2016 ◽

Vol 8 (2) ◽

pp. 83 ◽

Cited By ~ 12

Author(s):

Eunhui Seo ◽

Yoon Sin Oh ◽

Hee-Sook Jun

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Seed Extract ◽

Obese Mice ◽

Psoralea Corylifolia ◽

High Fat ◽

Nonalcoholic Fatty Liver

Download Full-text

High-fat diet overfeeding promotes nondetrimental liver steatosis in female mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00022.2018 ◽

2018 ◽

Vol 315 (5) ◽

pp. G772-G780 ◽

Cited By ~ 4

Author(s):

Lino Arisqueta ◽

Hiart Navarro-Imaz ◽

Ibone Labiano ◽

Yuri Rueda ◽

Olatz Fresnedo

Keyword(s):

Liver Disease ◽

Bile Acid ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Enterohepatic Circulation ◽

High Fat ◽

Nonalcoholic Fatty Liver ◽

Female Mice

High-fat diet (HFD) feeding or leptin-deficient mice are extensively used as models resembling features of human nonalcoholic fatty liver disease (NAFLD). The concurrence of experimental factors as fat content and source or total caloric intake leads to prominent differences in the development of the hepatic steatosis and related disturbances. In this work, we characterized the hepatic lipid accumulation induced by HFD in wild-type (WT) and ob/ ob mice with the purpose of differentiating adaptations to HFD from those specific of increased overfeeding due to leptin deficiency-associated hyperphagia. Given that most published works have been done in male models, we used female mice with the aim of increasing the body of evidence regarding NAFLD in female subjects. HFD promoted liver lipid accumulation only in the hyperphagic strain. Nevertheless, a decrease of lipid droplet-associated cholesteryl ester (CE) in both WT and obese animals was observed. These changes were accompanied by an improvement in the profile of lipoproteins that transport cholesterol and liver function markers in plasma from ob/ ob mice and a lower hepatic index. Using primary hepatocytes from female mice, overaccumulation of CE induced by 0.4 mM oleic acid reversed in the presence of a specific Takeda G protein-coupled bile acid receptor agonist. Nevertheless, hepatocytes from male mice were not responsive. This study suggests that enterohepatic circulation of bile acids might be one of the factors that can affect sex dimorphism in NAFLD development, which underlines the importance of including female models in the NAFLD research field. NEW & NOTEWORTHY This work provides new insight into the use of high-fat diet as a model to induce nonalcoholic fatty liver disease in wild-type and ob/ ob female mice. We show that high-fat diet induces steatosis only in ob/ ob mice while, surprisingly, several health indicators improve. Noteworthy, experiments with primary hepatocytes from male and female mice show that they express Takeda G protein-coupled bile acid receptor and that it and bile acid enterohepatic circulation might be accountable for sex dimorphism in nonalcoholic fatty liver disease development.

Download Full-text

Salicornia Extract Ameliorates Salt-Induced Aggravation of Nonalcoholic Fatty Liver Disease in Obese Mice Fed a High-Fat Diet

Journal of Food Science ◽

10.1111/1750-3841.13777 ◽

2017 ◽

Vol 82 (7) ◽

pp. 1765-1774 ◽

Cited By ~ 7

Author(s):

Jae Hwan Kim ◽

Sujin Suk ◽

Woo Jung Jang ◽

Chang Hyung Lee ◽

Jong-Eun Kim ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Obese Mice ◽

High Fat ◽

Nonalcoholic Fatty Liver

Download Full-text

Plasticity of histone modifications around Cidea and Cidec genes with secondary bile in the amelioration of developmentally-programmed hepatic steatosis

Scientific Reports ◽

10.1038/s41598-019-52943-7 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Jeenat Ferdous Urmi ◽

Hiroaki Itoh ◽

Keiko Muramatsu-Kato ◽

Yukiko Kohmura-Kobayashi ◽

Natsuyo Hariya ◽

...

Keyword(s):

Dna Methylation ◽

Bile Acid ◽

Hepatic Steatosis ◽

Histone Modifications ◽

High Fat Diet ◽

High Fat ◽

Secondary Bile Acid ◽

Regulated Expression ◽

Hepatic Fat ◽

Insight Into

AbstractWe recently reported that a treatment with tauroursodeoxycholic acid (TUDCA), a secondary bile acid, improved developmentally-deteriorated hepatic steatosis in an undernourishment (UN, 40% caloric restriction) in utero mouse model after a postnatal high-fat diet (HFD). We performed a microarray analysis and focused on two genes (Cidea and Cidec) because they are enhancers of lipid droplet (LD) sizes in hepatocytes and showed the greatest up-regulation in expression by UN that were completely recovered by TUDCA, concomitant with parallel changes in LD sizes. TUDCA remodeled developmentally-induced histone modifications (dimethylation of H3K4, H3K27, or H3K36), but not DNA methylation, around the Cidea and Cidec genes in UN pups only. Changes in these histone modifications may contribute to the markedly down-regulated expression of Cidea and Cidec genes in UN pups, which was observed in the alleviation of hepatic fat deposition, even under HFD. These results provide an insight into the future of precision medicine for developmentally-programmed hepatic steatosis by targeting histone modifications.

Download Full-text

Effect of Seyoeum on Obesity, Insulin Resistance, and Nonalcoholic Fatty Liver Disease of High-Fat Diet-Fed C57BL/6 Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/4658543 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Hyun-Young Na ◽

Mi Hyeon Seol ◽

Mia Kim ◽

Byung-Cheol Lee

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Liver Disease ◽

Fatty Liver ◽

Insulin Receptor ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Obese Mice ◽

High Fat ◽

Nonalcoholic Fatty Liver

Background. This study was performed to evaluate the effect of Seyoeum (SYE), a novel herbal meal replacement, on insulin resistance and nonalcoholic fatty liver disease (NAFLD) in obese mice fed with a high-fat diet (HFD).Methods. SYE contained six kinds of herbal powder such asCoix lacryma-jobi,Oryza sativa,Sesamum indicum,Glycine max,Liriope platyphylla,andDioscorea batatas. Male C57BL/6 mice were divided into four groups: normal chow (NC), HFD, SYE, and HFD plus SYE (HFD + SYE). The mice in groups other than NC were fed HFD for 9 weeks to induce obesity and then were fed each diet for 6 weeks. Clinical markers related to obesity, diabetes, and NAFLD were examined and gene expressions related to inflammation and insulin receptor were determined.Results. Compared with HFD group, body weight, serum glucose, serum insulin, HOMA-IR, total cholesterol, triglyceride, epididymal fat pad weight, liver weight, and inflammatory gene expression were significantly reduced in SYE group. Insulin receptor gene expression increased in SYE group.Conclusions. Based on these results, we conclude that SYE improved obesity and insulin resistance in high-fat fed obese mice. Our findings suggest that SYE could be a beneficial meal replacement through these antiobesity and anti-insulin resistance effects.

Download Full-text

Dietary Momordica Cochinchinensis aril ameliorates metabolic dysfunction, nonalcoholic fatty liver, and gut microbiota in diet-induced obese mice

10.21203/rs.2.20237/v1 ◽

2020 ◽

Author(s):

Yu-Chun Lin ◽

Hsiu-Chen Huang ◽

Yu-Heng Lai ◽

Jui-Chieh Chen ◽

Hsiao-Hsuan Tien ◽

...

Keyword(s):

Insulin Resistance ◽

Gut Microbiota ◽

Fatty Liver ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Metabolic Dysfunction ◽

Obese Mice ◽

High Fat ◽

Nonalcoholic Fatty Liver ◽

Momordica Cochinchinensis

Abstract Background Obesity and its associated conditions, such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), are a particular worldwide health problem at present. Momordica cochinchinensis fruit is consumed widely in Southeast Asia. However, whether it has functional effects on fat-induced metabolic dysfunction and gut microbiota remains unclear. This study was conducted to determine how Momordica cochinchinensis aril (MCA) affects obesity, nonalcoholic fatty liver, insulin resistance and gut microbiota in diet-induced obese mice.Methods Wild type male mice at age of 5 weeks received four different kinds of diets: a normal diet, high-fat diet (HFD), or HFD supplemented with 1% or 3% (wt:wt) lyophilized MCA for 10 weeks. Body weight, adipose tissue and liver weight, serum biochemical parameters, glucose tolerance and liver lipids were measured. Gut microbial composition was analyzed.Results MCA protected the mice against high-fat diet (HFD)-induced body weight gain, hyperlipidemia and hyperglycemia, compared with mice that were not treated. MCA inhibited the expansion of adipose tissue and adipocyte hypertrophy. In addition, the insulin sensitivity-associated index that evaluates insulin function was also significantly restored. MCA also regulated the secretion of adipokines in HFD-induced obese mice. Moreover, hepatic fat accumulation and liver inflammation were reduced, which suggested that fatty liver was prevented by MCA. Furthermore, MCA supplementation suppressed hepatic lipid accumulation by activation of AMPK and PPAR-alpha signaling pathway in the human fatty liver HuS-E/2 cell model. Supplementation with MCA resulted in microbiota populations changed significantly.Conclusion Our data indicate that dietary MCA is involved in the prevention of HFD-induced adiposity, insulin resistance and nonalcoholic fatty liver disease and altered the microbial contents of the gut and modulated microbial dysbiosis in the host.

Download Full-text

Protective effect of agaro-oligosaccharides on gut dysbiosis and colon tumorigenesis in high-fat diet-fed mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00324.2015 ◽

2016 ◽

Vol 310 (6) ◽

pp. G367-G375 ◽

Cited By ~ 44

Author(s):

Yasuki Higashimura ◽

Yuji Naito ◽

Tomohisa Takagi ◽

Kazuhiko Uchiyama ◽

Katsura Mizushima ◽

...

Keyword(s):

Bile Acid ◽

High Fat Diet ◽

Control Diet ◽

Aberrant Crypt Foci ◽

Bile Acid Metabolism ◽

Serum Bile Acid ◽

High Fat ◽

Microbial Composition ◽

Secondary Bile Acid ◽

Gut Dysbiosis

High-fat diet (HFD)-induced alteration in the gut microbial composition, known as dysbiosis, is increasingly recognized as a major risk factor for various diseases, including colon cancer. This report describes a comprehensive investigation of the effect of agaro-oligosaccharides (AGO) on HFD-induced gut dysbiosis, including alterations in short-chain fatty acid contents and bile acid metabolism in mice. C57BL/6N mice were fed a control diet or HFD, with or without AGO. Terminal restriction fragment-length polymorphism (T-RFLP) analysis produced their fecal microbiota profiles. Profiles of cecal organic acids and serum bile acids were determined, respectively, using HPLC and liquid chromatography-tandem mass spectrometry systems. T-RFLP analyses showed that an HFD changed the gut microbiota significantly. Changes in the microbiota composition induced by an HFD were characterized by a decrease in the order Lactobacillales and by an increase in the Clostridium subcluster XIVa. These changes of the microbiota community generated by HFD treatment were suppressed by AGO supplementation. As supported by the data of the proportion of Lactobacillales order, the concentration of lactic acid increased in the HFD + AGO group. Data from the serum bile acid profile showed that the level of deoxycholic acid, a carcinogenic secondary bile acid produced by gut bacteria, was increased in HFD-receiving mice. The upregulation tended to be suppressed by AGO supplementation. Finally, results show that AGO supplementation suppressed the azoxymethane-induced generation of aberrant crypt foci in the colon derived from HFD-treated mice. Our results suggest that oral intake of AGO prevents HFD-induced gut dysbiosis, thereby inhibiting colon carcinogenesis.

Download Full-text