Project description:Lipidomics have a great potential as clinical tool for monitoring metabolic changes in health and disease. Nevertheless hardly anything is known about the heritability of lipids. Therefore, it is necessary to clarify how and how much we can affect these progresses in individuals. In our interventional twin study (46 healthy, non-obese twin pairs) we investigated the lipid profile in plasma samples after switching from a low fat diet to an isocaloric high fat diet (HFD) to characterize the metabolic adaptation. Additionally we used the ACE model for Additive genetics, Common and unique Environment as well as linear mixed modelling to analyse the heritability of lipids. The heritability of lipids varied between 0-62% and applied to lipid species rather than to lipid classes. Phospholipids showed the highest inheritance. In addition, sex, body mass index (BMI) and age were important modifiers. The lipid profile changed already after one week of HFD and diverged further after 5 weeks of additional HFD. Basal concentrations of specific lipids within phospholipids are strongly inherited and are likely to be associated with heritable disease risks. BMI, sex and age were major modifiers. Nutrition strongly alters specific lipid classes, and has to be controlled in clinical association studies.
Project description:The Chrysanthemum morifolium Ramat (CM) is widely used as a traditional medicine and herbal tea by the Asian population for its health benefits related to obesity. However, compared to the flowers of CM, detailed mechanisms underlying the beneficial effects of its leaves on obesity and dyslipidemia have not yet been elucidated. Therefore, to investigate the lipidomic biomarkers responsible for the pharmacological effects of CM leaf extract (CLE) in plasma of mice fed a high-fat diet (HFD), the plasma of mice fed a normal diet (ND), HFD, HFD plus CLE 1.5% diet, and HFD plus luteolin 0.003% diet (LU) for 16 weeks were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) combined with multivariate analysis. In our analysis, the ND, HFD, CLE, and LU groups were clearly differentiated by partial least-squares discriminant analysis (PLS-DA) score plots. The major metabolites contributing to this differentiation were cholesteryl esters (CEs), lysophosphatidylcholines (LPCs), phosphatidylcholines (PCs), ceramides (CERs), and sphingomyelins (SMs). The levels of plasma CEs, LPCs, PCs, SMs, and CERs were significantly increased in the HFD group compared to those in the ND group, and levels of these lipids recovered to normal after administration of CLE or LU. Furthermore, changes in hepatic mRNA expression levels involved in the Kennedy pathway and sphingolipid biosynthesis were also suppressed by treatment with CLE or LU. In conclusion, this study examined the beneficial effects of CLE and LU on obesity and dyslipidemia, which were demonstrated as reduced synthesis of lipotoxic intermediates. These results may provide valuable insights towards evaluating the therapeutic effects of CLE and LU and understanding obesity-related diseases.
Project description:Although it is clear that lipids are responsible for insulin resistance, it is poorly understood what types of lipids are involved. In this study, we verified the characteristic lipid species in skeletal muscle of a chronic exercise training model and a high-fat induced-obesity model. Three different lipidomics analyses revealed phospholipid qualitative changes. As a result, linoleic acid-containing phosphatidylcholine and sphingomyelin and docosahexanoic acid-containing phosphatidylcholine were characterized as chronic exercise training-induced lipids. On the contrary, arachidonic acid-containing phosphatidylcholines, phosphatidylethanolamines, and phosphatidylinositol were characterized as high-fat diet-induced lipids. In addition, minor sphingomyelin, which has long-chain fatty acids, was identified as a high-fat diet-specific lipid. This is the first report to reveal compositional changes in phospholipid molecular species in chronic exercise and high-fat-diet-induced insulin-resistant models. Due to their influence on cell permeability and receptor stability at the cell membrane, these molecules may contribute to the mechanisms underlying insulin sensitivity and several metabolic disorders.
Project description:The beneficial effects of L-carnitine on non-alcoholic fatty liver disease (NAFLD) were revealed in previous reports. However, the underlying mechanisms remain unclear. In this study, we established a high fat diet (HFD)-induced NAFLD mice model and systematically explored the effects and mechanisms of dietary L-carnitine supplementation (0.2% to 4%) on NAFLD. A lipidomics approach was conducted to identify specific lipid species involved in the ameliorative roles of L-carnitine in NAFLD. Compared with a normal control group, the body weight, liver weight, concentrations of TG in the liver and serum AST and ALT levels were dramatically increased by HFD feeding (p < 0.05), accompanied with obvious liver damage and the activation of the hepatic TLR4/NF-κB/NLRP3 inflammatory pathway. L-carnitine treatment significantly improved these phenomena and exhibited a clear dose-response relationship. The results of a liver lipidomics analysis showed that a total of 12 classes and 145 lipid species were identified in the livers. Serious disorders in lipid profiles were noticed in the livers of the HFD-fed mice, such as an increased relative abundance of TG and a decreased relative abundance of PC, PE, PI, LPC, LPE, Cer and SM (p < 0.05). The relative contents of PC and PI were significantly increased and that of DG were decreased after the 4% L-carnitine intervention (p < 0.05). Moreover, we identified 47 important differential lipid species that notably separated the experimental groups based on VIP ≥ 1 and p < 0.05. The results of a pathway analysis showed that L-carnitine inhibited the glycerolipid metabolism pathway and activated the pathways of alpha-linolenic acid metabolism, glycerophospholipid metabolism, sphingolipid metabolism and Glycosylphosphatidylinositol (GPI)-anchor biosynthesis. This study provides novel insights into the mechanisms of L-carnitine in attenuating NAFLD.
Project description:Ectopic fat accumulation in non-adipose tissues is closely related to diabetes-related myocardial dysfunction. Nevertheless, the complete picture of the lipid metabolites involved in the metabolic-related myocardial alterations is not fully characterized. The aim of this study was to characterize the specific lipid profile in hearts in an animal model of obesity/insulin resistance induced by a high-fat diet (HFD). The cardiac lipidome profiles were assessed via liquid chromatography-mass spectrometry (LC-MS)/MS-MS and laser desorption/ionization-mass spectrometry (LDI-MS) tissue imaging in hearts from C57BL/6J mice fed with an HFD or standard-diet (STD) for 12 weeks. Targeted lipidome analysis identified a total of 63 lipids (i.e., 48 triacylglycerols (TG), 5 diacylglycerols (DG), 1 sphingomyelin (SM), 3 phosphatidylcholines (PC), 1 DihydroPC, and 5 carnitines) modified in hearts from HFD-fed mice compared to animals fed with STD. Whereas most of the TG were up-regulated in hearts from animals fed with an HFD, most of the carnitines were down-regulated, thereby suggesting a reduction in the mitochondrial β-oxidation. Roughly 30% of the identified metabolites were oxidated, pointing to an increase in lipid peroxidation. Cardiac lipidome was associated with a specific biochemical profile and a specific liver TG pattern. Overall, our study reveals a specific cardiac lipid fingerprint associated with metabolic alterations induced by HFD.
Project description:Impairments in ATP production and transport in renal proximal tubule cells (RPTCs) result in obesity-induced chronic kidney disease (CKD), manifested by kidney dysfunction, inflammation, adiposity, and fibrosis. Here we assessed the role of adenine nucleotide transporter 2 (ANT2), the main regulator of cellular ATP content in RPTCs, in the development of obesity-induced CKD and its metabolic abnormalities. Obese RPTC-ANT2-/- mice exhibited normal renal morphology, function, and lack of kidney adiposity and fibrosis as well as an improvement in whole-body energy metabolism, manifested by normal glucose and lipid homeostasis and reduced hepatic steatosis. ANT2-depleted RPTCs rewired their primary metabolic program from oxidizing fatty acids as a primary energy source toward aerobic glycolysis, mediated via the testis-selective ANT4. We propose that RPTC-ANT2 plays an important role in the development of obesity-induced CKD, and that its nullification triggers mitochondrial protection, RPTC cellular survival, kidney preservation, and improvements in systemic metabolism.
Project description:Obesity is a serious health problem in the US and is associated with increased risks of various human diseases. To date, the mechanisms by which obesity increases the risks of a wide range of human diseases are not well understood. Here we used a LC-MS/MS-based lipidomics, which can analyze >100 bioactive lipid mediators produced by cyclooxygenase, lipoxygenase, and cytochrome P450 enzymes, to analyze plasma profiles of lipid mediators in high-fat diet induced obesity in C57BL/6 mice. Our results show that the plasma concentrations of epoxyoctadecenoic acids (EpOMEs, also termed as leukotoxins) are significantly increased in plasma of high-fat diet-fed mice, in addition, EpOMEs are among the most abundant lipid mediators detected in mouse plasma. Since substantial studies have shown that EpOMEs and their metabolites have a large array of detrimental effects on health, enhanced levels of EpOMEs could contribute to the pathology of obesity.
Project description:Accumulation of visceral fat, more so than subcutaneous fat, is strongly associated with severe metabolic complications. However, the factors regulating depot-specific adipogenesis are poorly understood. In this study, we show differential expression of pregnancy-associated plasma protein-A (PAPP-A), a secreted regulator of local insulin-like growth factor (IGF) action, in adipose tissue of mice. PAPP-A mRNA expression was fivefold higher in visceral (mesenteric) fat compared with subcutaneous (inguinal, subscapular), perirenal, and brown fat of mice. To investigate the possible role of depot-specific PAPP-A expression in fat accumulation, wild-type (WT) and PAPP-A knockout (KO) mice were fed a high-fat diet (HFD) for up to 20 wk. Adipocyte size increased in subcutaneous and perirenal depots similarly in WT and PAPP-A KO mice. However, fat cell size and in vivo lipid uptake were significantly reduced in mesenteric fat of PAPP-A KO compared with WT mice. After 20 wk on HFD, phosphorylation of AKT, a downstream signaling intermediate of IGF-I and insulin receptor activation, was significantly decreased by 50% in mesenteric compared with subcutaneous fat in WT mice, but was significantly increased threefold in mesenteric compared with subcutaneous fat in PAPP-A KO mice. This appeared to be because of enhanced insulin-stimulated signaling in mesenteric fat of PAPP-A KO mice. These data establish fat depot-specific expression of PAPP-A and indicate preferential impact of PAPP-A deficiency on visceral fat in the mouse that is associated with enhanced insulin receptor signaling. Thus, PAPP-A may be a potential target for treatment and/or prevention strategies for visceral obesity and related morbidities.