Obesity and fatty acid oxidation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE474 | GEO | 2003/07/16
SECONDARY ACCESSION(S): PRJNA85153
REPOSITORIES: GEO
Similar Datasets
Project description:It has been found that fat oxidation is reduced in the skeletal muscle of obese humans. This study aims to identify the mRNA of proteins involved in fat oxidation that may be reduced in obese and morbidly obese individuals. Information gathered will help in understanding how obesity contributes to cardiovascular disease via insulin resistance. Samples were obtained from patients undergoing elective abdominal surgery.
2007-09-28 | E-GEOD-474 | biostudies-arrayexpress
Project description:The Hippo signalling pathway effector Yap positively regulates adult skeletal muscle mass. However, the biological processes that are modulated by Yap in skeletal muscle remain elusive. Using an integrated transcriptomics and proteomics approach, we define the transcriptional programme regulated by Yap in adult skeletal muscle and demonstrate that Yap is a regulator of metabolic substrate utilisation. Inhibition of Yap in mammalian skeletal muscle results in increased, but incomplete, oxidation of fatty acids and features of lipotoxicity. In line with these findings, we demonstrate that Yap abundance is reduced in the skeletal musculature of obese db/db mice, and in muscle biopsies from obese, insulin-resistant humans where YAP levels positively correlate with whole-body metabolic flexibility. Increasing Yap abundance in the striated muscle of db/db mice attenuated the accumulation of fat mass and development of hepatic steatosis. Our findings demonstrate a vital role for Yap in skeletal muscle as a mediator of metabolic substrate utilisation. Modulating Yap activity in skeletal muscle warrants consideration as part of comprehensive approaches to treat metabolic disease.
2021-02-18 | GSE144137 | GEO
Project description:The Hippo signalling pathway effector Yap positively regulates adult skeletal muscle mass. However, the biological processes that are modulated by Yap in skeletal muscle remain elusive. Using an integrated transcriptomics and proteomics approach, we define the transcriptional programme regulated by Yap in adult skeletal muscle and demonstrate that Yap is a regulator of metabolic substrate utilisation. Inhibition of Yap in mammalian skeletal muscle results in increased, but incomplete, oxidation of fatty acids and features of lipotoxicity. In line with these findings, we demonstrate that Yap abundance is reduced in the skeletal musculature of obese db/db mice, and in muscle biopsies from obese, insulin-resistant humans where YAP levels positively correlate with whole-body metabolic flexibility. Increasing Yap abundance in the striated muscle of db/db mice attenuated the accumulation of fat mass and development of hepatic steatosis. Our findings demonstrate a vital role for Yap in skeletal muscle as a mediator of metabolic substrate utilisation. Modulating Yap activity in skeletal muscle warrants consideration as part of comprehensive approaches to treat metabolic disease.
2021-02-18 | GSE144135 | GEO
Project description:Thrombospondin 1 (TSP1) is a multifunctional matricellular protein. Previously we have shown that TSP1 plays an important role in obesity-associated metabolic complications including inflammation, insulin resistance, cardiovascular and renal disease. However, its contribution to obesity-associated non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) remains largely unknown and is determined in this study. High fat diet or AMLN diet-induced obese and insulin resistant NAFLD/NASH mouse models were utilized. In addition, tissue specific TSP1 knockout mice were utilized to determine the contribution of different cellular sources of obesity-induced TSP1 to NAFLD/NASH development. The data demonstrated that liver TSP1 levels were increased in experimental obese and insulin resistant NAFLD/NASH mouse models as well as in human obese NASH patients. Moreover, TSP1 deletion in hepatocyte or adipocytes did not protect mice from diet-induced NAFLD/NASH. However, myeloid/macrophage-specific TSP1 deletion protected mice against obesity-associated liver injury, accompanied by reduced liver inflammation and fibrosis. Importantly, this protection is independent of the levels of obesity and hepatic steatosis. Mechanistically, through an autocrine effect, macrophage-derived TSP1 suppressed SMPDL3B expression in liver, which amplified liver pro-inflammatory signaling (TLR4 signal pathway) and promoted NAFLD progression. Together, out data suggest that macrophage-derived TSP1 is a significant contributor to obesity-associated NAFLD/NASH development and progression and may serve as a therapeutic target for this disease.
2020-12-07 | GSE155973 | GEO
Project description:The DNA damage response is essential for preserving genome integrity and eliminating damaged cells. Although cellular metabolism plays a central role in cell fate decision between proliferation, survival or death, the metabolic response to DNA damage remains largely obscure. Here, we show that DNA damage induces fatty acid oxidation (FAO), which is required for DNA damage-induced cell death. Mechanistically, FAO induction increases cellular acetyl-CoA levels and promotes N-alpha-acetylation of caspase-2, leading to cell death. Whereas chemotherapy increases FAO related genes through PPARα, accelerated hypoxia-inducible factor-1α stabilization by tumor cells in obese mice impedes the upregulation of FAO, which contributes to its chemoresistance. Finally, we find that improving FAO by PPARα activation ameliorates obesity-driven chemoresistance and enhances the outcomes of chemotherapy in obese mice. These findings reveal the shift toward FAO induction is an important metabolic response to DNA damage and may provide effective therapeutic strategies for cancer patients with obesity.
2024-03-20 | GSE208632 | GEO
Project description:Maternal obesity is linked with increased adverse outcomes for mother and fetus. However, the metabolic impact of excessive fat accumulation within the altered hormonal context of pregnancy is not well understood. We used a murine model of obesity, the high fat diet-fed C57BL/6J mouse to determine adipose tissue-mediated molecular mechanisms driving metabolic dysfunction throughout pregnancy. Remarkably, obese mice exhibited a normalization of visceral fat accumulation at late-stage pregnancy (-53%, P<0.001 E18.5) to achieve levels comparable in mass (per gram of body weight) to that of non pregnant, control diet fed mice. Moreover, whilst obese pregnant mice showed a marked glucose intolerance and apparent insulin resistance at mid-stage pregnancy (E14.5), glucose homeostasis converged with that of lean pregnant mice at late-stage pregnancy, suggesting an unexpected amelioration of the worsening metabolic dysfunction in obese pregnant mice. Transcriptomic analysis of the late-stage visceral fat indicated reduced de novo lipogenic drive (Me1, Fasn, Scd1, Dgat2), retinol metabolism (Rdh11, Rbp4) and inflammation (Mcp1, Tnfα) in obese pregnant mice that was confirmed functionally by their lower adipose proinflammatory macrophage density. Elevated expression of estrogen receptor a (ERα) in visceral adipose tissue was identified as potential unifying mechanism for the transcriptional changes and reduced adiposity of late stage obese pregnancy. Support for a role for ERα was provided by experiments showing that the ERα selective agonist PPT suppressed lipogenesis in primary mouse adipocytes and suppressed Me1, Fasn, SCD1 and Dgat2 mRNA levels in mature female human ChubS7 clonal fat cells. Our data reveal a novel role for elevated visceral adipocyte estrogen signaling as a protective mechanism against visceral fat hypertrophy and inflammation in late pregnancy. Pregnant high fat, pregnant control fat, non pregnant high fat, non pregnant control fat. Five biologial replictes each (20 samples).
2013-12-31 | E-GEOD-48811 | biostudies-arrayexpress
Project description:Transcription profiling of human skeletal muscle from obese vs.normal individuals to identify the mRNA of proteins involved in fat oxidation that may be reduced in obese and morbidly obese individuals
2014-07-03 | E-GEOD-474 | ExpressionAtlas
Project description:Early perturbations in vascular health can be detected by imposing subjects to a high fat (HF) challenge and measure response capacity. Subtle responses can be determined by assessment of whole-genome transcriptional changes. We aimed to magnify differences in health by comparing gene-expression changes in peripheral blood mononuclear cells (PBMCs) towards a high MUFA or SFA challenge between subjects with different cardiovascular disease risk profiles and to identify fatty-acid specific gene-expression pathways. METHODS AND RESULTS: In a cross-over study, 17 lean and 15 obese men (50-70y) received two 95g fat shakes, high in SFAs or MUFAs. PBMC gene-expression profiles were assessed fasted and 4h postprandially. Comparisons were made between groups and shakes. During fasting, 294 genes were significantly different expressed between lean and obese. The challenge increased differences to 607 genes after SFA and 2516 genes after MUFA. In both groups, SFA decreased expression of cholesterol biosynthesis and uptake genes and increased cholesterol efflux genes. MUFA increased inflammatory genes and PPAR? targets involved in ?-oxidation. CONCLUSION: Based upon gene-expression changes, we conclude that a HF challenge magnifies differences in health, especially after MUFA. Our findings also demonstrate how SFAs and MUFAs exert distinct effects on lipid handling pathways in immune cells. In a double-blind cross-over study, 17 lean and 15 obese men (aged 50-70y) received two high-fat milkshakes containing 95g fat, either high in saturated (SFA) or monounsaturated (MUFA) fatty acids. PBMC gene expression profiles were determined before and 4h after shake consumption.
2015-05-13 | E-GEOD-53232 | biostudies-arrayexpress
Project description:vanEunen2013 - Network dynamics of fatty acid β-oxidation (time-course model)
Lipid metabolism plays an important role in the development of metabolic syndrome, a major risk factor for cardiovascular disease and diabetes. This model gives insights into the response of lipid oxidation to dietart and medical interventions. The model predicts the rate of lipid oxidation and the time course of most acyl carnitines. There are two models described in the paper, (i) steady-state model [ BIOMD0000000505
], (ii) time-course model [ BIOMD0000000506
]. This model corresponds to the time-course model.
This model is described in the article:
Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload.
van Eunen K, Simons SM, Gerding A, Bleeker A, den Besten G, Touw CM, Houten SM, Groen BK, Krab K, Reijngoud DJ, Bakker BM.
PLoS Comput Biol. 2013;9(8):e1003186.
Abstract:
Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid β-oxidation, we constructed a detailed computational model of the pathway and subjected it to a fat overload condition. The model contains reversible and saturable enzyme-kinetic equations and experimentally determined parameters for rat-liver enzymes. It was validated by adding palmitoyl CoA or palmitoyl carnitine to isolated rat-liver mitochondria: without refitting of measured parameters, the model correctly predicted the β-oxidation flux as well as the time profiles of most acyl-carnitine concentrations. Subsequently, we simulated the condition of obesity by increasing the palmitoyl-CoA concentration. At a high concentration of palmitoyl CoA the β-oxidation became overloaded: the flux dropped and metabolites accumulated. This behavior originated from the competition between acyl CoAs of different chain lengths for a set of acyl-CoA dehydrogenases with overlapping substrate specificity. This effectively induced competitive feedforward inhibition and thereby led to accumulation of CoA-ester intermediates and depletion of free CoA (CoASH). The mitochondrial [NAD⁺]/[NADH] ratio modulated the sensitivity to substrate overload, revealing a tight interplay between regulation of β-oxidation and mitochondrial respiration.
This model is hosted on BioModels Database
and identified
by: BIOMD0000000506
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2014-01-15 | BIOMD0000000506 | BioModels
Project description:vanEunen2013 - Network dynamics of fatty acid β-oxidation (steady-state model)
Lipid metabolism plays an important role in the development of metabolic syndrome, a major risk factor for cardiovascular disease and diabetes. This model gives insights into the response of lipid oxidation to dietart and medical interventions. The model predicts the rate of lipid oxidation and the time course of most acyl carnitines. There are two models described in the paper, (i) steady-state model [ BIOMD0000000505
], (ii) time-course model [ BIOMD0000000506
]. This model corresponds to the steady-state model.
This model is described in the article:
Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload.
van Eunen K, Simons SM, Gerding A, Bleeker A, den Besten G, Touw CM, Houten SM, Groen BK, Krab K, Reijngoud DJ, Bakker BM.
PLoS Comput Biol. 2013;9(8):e1003186.
Abstract:
Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid β-oxidation, we constructed a detailed computational model of the pathway and subjected it to a fat overload condition. The model contains reversible and saturable enzyme-kinetic equations and experimentally determined parameters for rat-liver enzymes. It was validated by adding palmitoyl CoA or palmitoyl carnitine to isolated rat-liver mitochondria: without refitting of measured parameters, the model correctly predicted the β-oxidation flux as well as the time profiles of most acyl-carnitine concentrations. Subsequently, we simulated the condition of obesity by increasing the palmitoyl-CoA concentration. At a high concentration of palmitoyl CoA the β-oxidation became overloaded: the flux dropped and metabolites accumulated. This behavior originated from the competition between acyl CoAs of different chain lengths for a set of acyl-CoA dehydrogenases with overlapping substrate specificity. This effectively induced competitive feedforward inhibition and thereby led to accumulation of CoA-ester intermediates and depletion of free CoA (CoASH). The mitochondrial [NAD⁺]/[NADH] ratio modulated the sensitivity to substrate overload, revealing a tight interplay between regulation of β-oxidation and mitochondrial respiration.
This model is hosted on BioModels Database
and identified
by: BIOMD0000000505
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2014-01-15 | BIOMD0000000505 | BioModels