scholarly journals Oocyte developmental failure in response to elevated nonesterified fatty acid concentrations: mechanistic insights

Reproduction ◽  
2013 ◽  
Vol 145 (1) ◽  
pp. 33-44 ◽  
Author(s):  
V Van Hoeck ◽  
J L M R Leroy ◽  
M Arias Alvarez ◽  
D Rizos ◽  
A Gutierrez-Adan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Energy Metabolism ◽  
Ovarian Follicle ◽  
Developmental Competence ◽  
Nonesterified Fatty Acid ◽  
Mitochondrial Morphology ◽  
Functional Perspective ◽  
Expression Of Genes ◽  
Mitochondrial Fatty Acid

Elevated plasma nonesterified fatty acid (NEFA) concentrations are associated with negative energy balance and metabolic disorders such as obesity and type II diabetes. Such increased plasma NEFA concentrations induce changes in the microenvironment of the ovarian follicle, which can compromise oocyte competence. Exposing oocytes to elevated NEFA concentrations during maturation affects the gene expression and phenotype of the subsequent embryo, notably prompting a disrupted oxidative metabolism. We hypothesized that these changes in the embryo are a consequence of modified energy metabolism in the oocyte. To investigate this, bovine cumulus oocyte complexes were matured under elevated NEFA conditions, and energy metabolism-related gene expression, mitochondrial function, and ultrastructure evaluated. It was found that expression of genes related to REDOX maintenance was modified in NEFA-exposed oocytes, cumulus cells, and resultant blastocysts. Moreover, the expression of genes related to fatty acid synthesis in embryos that developed from NEFA-exposed oocytes was upregulated. From a functional perspective, inhibition of fatty acid β-oxidation in maturing oocytes exposed to elevated NEFA concentrations restored developmental competence. There were no clear differences in mitochondrial morphology or oxygen consumption between treatments, although there was a trend for a higher mitochondrial membrane potential in zygotes derived from NEFA-exposed oocytes. These data show that the degree of mitochondrial fatty acid β-oxidation has a decisive impact on the development of NEFA-exposed oocytes. Furthermore, the gene expression data suggest that the resulting embryos adapt through altered metabolic strategies, which might explain the aberrant energy metabolism previously observed in these embryos originating from NEFA-exposed maturing oocytes.

Independent and combined effects of acute physiological hyperglycaemia and hyperinsulinaemia on metabolic gene expression in human skeletal muscle

2013 ◽  
Vol 124 (11) ◽  
pp. 675-686 ◽  
Author(s):  
Kostas Tsintzas ◽  
Luke Norton ◽  
Kamal Chokkalingam ◽  
Nusrat Nizamani ◽  
Scott Cooper ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Energy Metabolism ◽  
Human Skeletal Muscle ◽  
Insulin Signalling ◽  
Additive Effect ◽  
Pyruvate Dehydrogenase Kinase ◽  
Fatty Acid Transport ◽  
Expression Of Genes

Physiological hyperglycaemia and hyperinsulinaemia are strong modulators of gene expression, which underpins some of their well-known effects on insulin action and energy metabolism. The aim of the present study was to examine whether acute in vivo exposure of healthy humans to hyperinsulinaemia and hyperglycaemia have independent or additive effects on expression of key metabolic genes in skeletal muscle. On three randomized occasions, seven young subjects underwent a 4 h (i) hyperinsulinaemic (50 m-units·m−2·min−1) hyperglycaemic (10 mmol/l) clamp (HIHG), (ii) hyperglycaemic (10 mmol/l) euinsulinaemic (5 m-units·m−2·min−1) clamp (LIHG) and (iii) hyperinsulinaemic (50 m-units·m−2·min−1) euglycaemic (4.5 mmol/l) clamp (HING). Muscle biopsies were obtained before and after each clamp for the determination of expression of genes involved in energy metabolism, and phosphorylation of key insulin signalling proteins. Hyperinsulinaemia and hyperglycaemia exerted independent effects with similar direction of modulation on PI3KR1 (phosphatidylinositol 3-kinase, regulatory 1), LXRα (liver X receptor α), PDK4 (pyruvate dehydrogenase kinase 4) and FOXO1 (forkhead box O1A) and produced an additive effect on PI3KR1, the gene that encodes the p85α subunit of PI3K in human skeletal muscle. Acute hyperglycaemia itself altered the expression of genes involved in fatty acid transport and oxidation [fatty acid transporter (CD36), LCAD (long-chain acyl-CoA dehydrogenase) and FOXO1], and lipogenesis [LXRα, ChREBP (carbohydrate-responseelement-binding protein), ABCA1 (ATP-binding cassette transporter A1) and G6PD (glucose-6-phosphate dehydrogenase). Surperimposing hyperinsulinaemia on hyperglycaemia modulated a number of genes involved in insulin signalling, glucose metabolism and intracellular lipid accumulation and exerted an additive effect on PI3KR1. These may be early molecular events that precede the development of glucolipotoxicity and insulin resistance normally associated with more prolonged periods of hyperglycaemia and hyperinsulinaemia.

scholarly journals Mitochondrial Fission Governed by Drp1 Regulates Exogenous Fatty Acid Usage and Storage in Hela Cells

Metabolites ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 322
Author(s):  
Jae-Eun Song ◽  
Tiago C. Alves ◽  
Bernardo Stutz ◽  
Matija Šestan-Peša ◽  
Nicole Kilian ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Lipid Droplets ◽  
Mitochondrial Fission ◽  
Acid Oxidation ◽  
Mitochondrial Morphology ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
And Storage

In the presence of high abundance of exogenous fatty acids, cells either store fatty acids in lipid droplets or oxidize them in mitochondria. In this study, we aimed to explore a novel and direct role of mitochondrial fission in lipid homeostasis in HeLa cells. We observed the association between mitochondrial morphology and lipid droplet accumulation in response to high exogenous fatty acids. We inhibited mitochondrial fission by silencing dynamin-related protein 1(DRP1) and observed the shift in fatty acid storage-usage balance. Inhibition of mitochondrial fission resulted in an increase in fatty acid content of lipid droplets and a decrease in mitochondrial fatty acid oxidation. Next, we overexpressed carnitine palmitoyltransferase-1 (CPT1), a key mitochondrial protein in fatty acid oxidation, to further examine the relationship between mitochondrial fatty acid usage and mitochondrial morphology. Mitochondrial fission plays a role in distributing exogenous fatty acids. CPT1A controlled the respiratory rate of mitochondrial fatty acid oxidation but did not cause a shift in the distribution of fatty acids between mitochondria and lipid droplets. Our data reveals a novel function for mitochondrial fission in balancing exogenous fatty acids between usage and storage, assigning a role for mitochondrial dynamics in control of intracellular fuel utilization and partitioning.

scholarly journals Coordinated multitissue transcriptional and plasma metabonomic profiles following acute caloric restriction in mice

2006 ◽  
Vol 27 (3) ◽  
pp. 187-200 ◽  
Author(s):  
Colin Selman ◽  
Nicola D. Kerrison ◽  
Anisha Cooray ◽  
Matthew D. W. Piper ◽  
Steven J. Lingard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Caloric Restriction ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Proton Nuclear Magnetic Resonance ◽  
Cellular Transport ◽  
Expression Of Genes ◽  
Transcriptional Changes

Caloric restriction (CR) increases healthy life span in a range of organisms. The underlying mechanisms are not understood but appear to include changes in gene expression, protein function, and metabolism. Recent studies demonstrate that acute CR alters mortality rates within days in flies. Multitissue transcriptional changes and concomitant metabolic responses to acute CR have not been described. We generated whole genome RNA transcript profiles in liver, skeletal muscle, colon, and hypothalamus and simultaneously measured plasma metabolites using proton nuclear magnetic resonance in mice subjected to acute CR. Liver and muscle showed increased gene expressions associated with fatty acid metabolism and a reduction in those involved in hepatic lipid biosynthesis. Glucogenic amino acids increased in plasma, and gene expression for hepatic gluconeogenesis was enhanced. Increased expression of genes for hormone-mediated signaling and decreased expression of genes involved in protein binding and development occurred in hypothalamus. Cell proliferation genes were decreased and cellular transport genes increased in colon. Acute CR captured many, but not all, hepatic transcriptional changes of long-term CR. Our findings demonstrate a clear transcriptional response across multiple tissues during acute CR, with congruent plasma metabolite changes. Liver and muscle switched gene expression away from energetically expensive biosynthetic processes toward energy conservation and utilization processes, including fatty acid metabolism and gluconeogenesis. Both muscle and colon switched gene expression away from cellular proliferation. Mice undergoing acute CR rapidly adopt many transcriptional and metabolic changes of long-term CR, suggesting that the beneficial effects of CR may require only a short-term reduction in caloric intake.

scholarly journals Mitochondrial pyruvate and fatty acid flux modulate MICU1-dependent control of MCU activity

2020 ◽  
Vol 13 (628) ◽  
pp. eaaz6206 ◽  
Author(s):  
Neeharika Nemani ◽  
Zhiwei Dong ◽  
Cassidy C. Daw ◽  
Travis R. Madaris ◽  
Karthik Ramachandran ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Tca Cycle ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Mitochondrial Morphology ◽  
Autophagic Flux ◽  
Fatty Acid Transport ◽  
Mitochondrial Matrix ◽  
Genetic Ablation ◽  
Mitochondrial Fatty Acid

The tricarboxylic acid (TCA) cycle converts the end products of glycolysis and fatty acid β-oxidation into the reducing equivalents NADH and FADH2. Although mitochondrial matrix uptake of Ca2+ enhances ATP production, it remains unclear whether deprivation of mitochondrial TCA substrates alters mitochondrial Ca2+ flux. We investigated the effect of TCA cycle substrates on MCU-mediated mitochondrial matrix uptake of Ca2+, mitochondrial bioenergetics, and autophagic flux. Inhibition of glycolysis, mitochondrial pyruvate transport, or mitochondrial fatty acid transport triggered expression of the MCU gatekeeper MICU1 but not the MCU core subunit. Knockdown of mitochondrial pyruvate carrier (MPC) isoforms or expression of the dominant negative mutant MPC1R97W resulted in increased MICU1 protein abundance and inhibition of MCU-mediated mitochondrial matrix uptake of Ca2+. We also found that genetic ablation of MPC1 in hepatocytes and mouse embryonic fibroblasts resulted in reduced resting matrix Ca2+, likely because of increased MICU1 expression, but resulted in changes in mitochondrial morphology. TCA cycle substrate–dependent MICU1 expression was mediated by the transcription factor early growth response 1 (EGR1). Blocking mitochondrial pyruvate or fatty acid flux was linked to increased autophagy marker abundance. These studies reveal a mechanism that controls the MCU-mediated Ca2+ flux machinery and that depends on TCA cycle substrate availability. This mechanism generates a metabolic homeostatic circuit that protects cells from bioenergetic crisis and mitochondrial Ca2+ overload during periods of nutrient stress.

Using muscle gene expression to estimate triacylglyceride deposition, and relative contributions of fatty acid synthesis and fatty acid import in intramuscular fat in cattle

2014 ◽  
Vol 54 (9) ◽  
pp. 1436 ◽  
Author(s):  
B. P. Dalrymple ◽  
B. Guo ◽  
G. H. Zhou ◽  
W. Zhang
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
De Novo ◽  
Acid Synthesis ◽  
Intramuscular Fat ◽  
Muscle Gene Expression ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Muscle Gene ◽  
The Impact

Intramuscular fat content (IMF%) in cattle influences the value of individual animals, especially for higher marbling markets. IMF is triacylglyceride (TAG) in lipid droplets in the intramuscular adipocytes. However, there are many different pathways from feed intake to the final common process of TAG synthesis and storage as IMF. To evaluate the relative importance of different pathways we compared changes in the expression of genes encoding proteins involved in the TAG and fatty acid (FA) synthesis pathways in the longissimus muscle of Piedmontese × Hereford (P×H) and Wagyu × Hereford (W×H) crosses. Based on these changes we have estimated the relative contributions of FA synthesised de novo in the intramuscular adipocyte and the uptake of circulating FA (both free and from TAG), from the diet or synthesised de novo in other tissues, to TAG deposition as IMF. We have analysed the impact of different developmental times and different diets on these processes. Increased de novo FA synthesis in intramuscular adipocytes appeared to contribute more than increased FA uptake from circulation to the additional TAG deposition in W×H compared with P×H cattle between 12 and 25 months (forage diet). Changing diet from forage to concentrate appeared to increase the importance of FA uptake from circulation relative to de novo FA synthesis for TAG synthesis in intramuscular adipocytes. These results are consistent with the literature based on analysis of lipid composition. Gene expression appears to provide a simple assay for identification of the source of FA for the deposition of IMF.

3,5-Diiodo-l-thyronine rapidly enhances mitochondrial fatty acid oxidation rate and thermogenesis in rat skeletal muscle: AMP-activated protein kinase involvement

2009 ◽  
Vol 296 (3) ◽  
pp. E497-E502 ◽  
Author(s):  
A. Lombardi ◽  
P. de Lange ◽  
E. Silvestri ◽  
R. A. Busiello ◽  
A. Lanni ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Energy Metabolism ◽  
Fatty Acid Oxidation ◽  
Atp Synthesis ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Amp Activated Protein Kinase

Triiodothyronine regulates energy metabolism and thermogenesis. Among triiodothyronine derivatives, 3,5-diiodo-l-thyronine (T2) has been shown to exert marked effects on energy metabolism by acting mainly at the mitochondrial level. Here we investigated the capacity of T2 to affect both skeletal muscle mitochondrial substrate oxidation and thermogenesis within 1 h after its injection into hypothyroid rats. Administration of T2 induced an increase in mitochondrial oxidation when palmitoyl-CoA (+104%), palmitoylcarnitine (+80%), or succinate (+30%) was used as substrate, but it had no effect when pyruvate was used. T2 was able to 1) activate the AMPK-ACC-malonyl-CoA metabolic signaling pathway known to direct lipid partitioning toward oxidation and 2) increase the importing of fatty acids into the mitochondrion. These results suggest that T2 stimulates mitochondrial fatty acid oxidation by activating several metabolic pathways, such as the fatty acid import/β-oxidation cycle/FADH2-linked respiratory pathways, where fatty acids are imported. T2 also enhanced skeletal muscle mitochondrial thermogenesis by activating pathways involved in the dissipation of the proton-motive force not associated with ATP synthesis (“proton leak”), the effect being dependent on the presence of free fatty acids inside mitochondria. We conclude that skeletal muscle is a target for T2, and we propose that, by activating processes able to enhance mitochondrial fatty acid oxidation and thermogenesis, T2 could play a role in protecting skeletal muscle against excessive intramyocellular lipid storage, possibly allowing it to avoid functional disorders.

scholarly journals Correlation between increased atrial expression of genes related to fatty acid metabolism and autophagy in patients with chronic atrial fibrillation

2019 ◽  
Author(s):  
Yasushige Shingu ◽  
Shingo Takada ◽  
Takashi Yokota ◽  
Ryosuke Shirakawa ◽  
Akira Yamada ◽  
...  
Keyword(s):  
Gene Expression ◽  
Atrial Fibrillation ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Right Atrial ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Fatty Acid Binding ◽  
Expression Of Genes

AbstractAtrial metabolic disturbance contributes to the onset and development of atrial fibrillation (AF). Autophagy plays a role in maintaining the cellular energy balance. We examined whether the altered atrial expression of genes related to fatty acid metabolism is linked to that related to autophagy in chronic AF. Right atrial tissue was obtained during heart surgery from 51 patients with sinus rhythm (SR, n=38) or chronic AF (n=13). Preoperative fasting serum free-fatty-acid levels were significantly higher in the AF patients. The atrial gene expression of fatty acid binding protein 3 (FABP3), which is involved in the cells’ fatty acid uptake and intracellular fatty acid transport, was significantly increased in AF patients compared to SR patients; in the SR patients it was positively correlated with the right atrial diameter and intra-atrial EMD, parameters of structural and electrical atrial remodeling that was evaluated by an echocardiography. In contrast, the two groups’ atrial contents of diacylglycerol (DAG), a toxic fatty acid metabolite, were comparable. Importantly, the atrial gene expression of microtubule-associated protein light chain 3 (LC3) was significantly increased in the AF patients, and autophagy-related genes including LC3 were positively correlated with the atrial expression of FABP3. In conclusion, in chronic AF patients, the atrial expression of FABP3 was upregulated in association with autophagy-related genes without altered atrial DAG content. Our findings may support the hypothesis that dysregulated cardiac fatty acid metabolism contributes to the progression of AF and induction of autophagy has a cardioprotective effect against cardiac lipotoxicity in chronic AF.

scholarly journals Energy metabolism adaptations and gene expression reprogramming in a cellular MAFLD model

2021 ◽  
Author(s):  
Tian-Ran Zhou ◽  
Cagla Cömert ◽  
Xiaoyu Zhou ◽  
Lin Lin ◽  
Lars Bolund ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Metabolism ◽  
Cell Model ◽  
Critical Role ◽  
Huh7 Cell ◽  
Mitochondrial Superoxide ◽  
Expression Of Genes ◽  
Bioenergetic Analysis ◽  
Vitro Model

Mitochondrial dysfunction plays a critical role in metabolic associated fatty liver disease (MAFLD). This study aims to characterize mitochondrial dysfunctions in a human MAFLD Huh7 cell model triggered by free fatty acid (FFA) (palmitate and oleate) overload for 24 hours. We investigate its impact on cellular energy metabolism and identify potential targets for MAFLD treatment. FFA-treated cells displayed an accumulation of lipid droplets and slightly decreased viability but no significant changes in mitochondrial superoxide levels. Bioenergetic analysis showed a shift to more respiration and less glycolytic fermentation. Comprehensive transcriptomics and proteomics analyses identified changes in the expression of genes prominently involved in fatty acid handling and metabolism. The expressions of seven genes were consistently and significantly (p<0.05) altered (4 upregulated and 3 downregulated genes) in both proteomics and transcriptomics. The FFA-treated Huh7 cell model is an appropriate in vitro model to study fatty acid metabolism and suitable to investigate the role of mitochondria, glycolysis, and multiple metabolic pathways in MAFLD. Our comprehensive analyses form a basis for drug discovery and screening using this model.

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