The effects of ectopic UCP1 expression on gene expression in skeletal muscle
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Evert van Schothorst
PROVIDER: E-GEOD-45993 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Muscle mitohormesis promotes cellular survival via serine/glycine pathway flux.
Ost Mario M Keipert Susanne S van Schothorst Evert M EM Donner Verena V van der Stelt Inge I Kipp Anna P AP Petzke Klaus-Jürgen KJ Jove Mariona M Pamplona Reinald R Portero-Otin Manuel M Keijer Jaap J Klaus Susanne S
FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20141209 4
Recent studies on mouse and human skeletal muscle (SM) demonstrated the important link between mitochondrial function and the cellular metabolic adaptation. To identify key compensatory molecular mechanisms in response to chronic mitochondrial distress, we analyzed mice with ectopic SM respiratory uncoupling in uncoupling protein 1 transgenic (UCP1-TG) mice as model of muscle-specific compromised mitochondrial function. Here we describe a detailed metabolic reprogramming profile associated with ...[more]
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Project description:Recent studies on mouse and human skeletal muscle (SM) demonstrated the important link between mitochondrial function and the cellular metabolic adaptation. To identify key compensatory molecular mechanisms in response to chronic mitochondrial distress, we analyzed mice with ectopic SM respiratory uncoupling in uncoupling protein 1 transgenic (UCP1-TG) mice as model of muscle-specific compromised mitochondrial function. Here we describe a detailed metabolic reprogramming profile associated with mitochondrial perturbations in SM, triggering an increased protein turnover and amino acid metabolism with induced biosynthetic serine/1-carbon/glycine pathway and the longevity-promoting polyamine spermidine as well as the trans-sulfuration pathway. This is related to an induction of NADPH-generating pathways and glutathione metabolism as an adaptive mitohormetic response and defense against increased oxidative stress. Strikingly, consistent muscle retrograde signaling profiles were observed in acute stress states such as muscle cell starvation and lipid overload, muscle regeneration, and heart muscle inflammation, but not in response to exercise. We provide conclusive evidence for a key compensatory stress-signaling network that preserves cellular function, oxidative stress tolerance, and survival during conditions of increased SM mitochondrial distress, a metabolic reprogramming profile so far only demonstrated for cancer cells and heart muscle.-Ost, M., Keipert, S., van Schothorst, E. M., Donner, V., van der Stelt, I., Kipp, A. P., Petzke, K.-J., Jove, M., Pamplona, R., Portero-Otin, M., Keijer, J., and Klaus, S. Muscle mitohormesis promotes cellular survival via serine/glycine pathway flux. Control C57BL/6J wildtype male mice, aged 12 weeks, are compared to UCP1 transgene littermates fed purified low fat diet (BIOCLAIMS, Hoevenaars et al., Genes and Nutrition 2012) for 12 weeks . At the end, mice were sacrificed, gastrocnemius skeletal muscle was immediately dissected and snap frozen in liquid nitrogen. Total RNA was isolated, quantified and qualified, and subsequently used for global gene expression profiling using Agilent 8x60K microarrays. In total, 6 arrays of individual WT and 7 arrays of individual UCP1-TG samples were normalized, together with samples from the complete SUPERSERIES.
2015-02-17 | E-GEOD-45991 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE36716: Muscle Involvement in Preservation of Metabolic Flexibility by Treatment using n-3 PUFA or Rosiglitazone in Dietary-Obese Mice GSE36717: Muscle Involvement in Preservation of Metabolic Flexibility by a Combination Treatment using n-3 PUFA and Rosiglitazone in Dietary-Obese Mice Refer to individual Series
2012-09-07 | E-GEOD-36718 | biostudies-arrayexpress
Project description:Impaired resistance to insulin, the key defect in type 2 diabetes (T2D), is associated with a low capacity to adapt fuel oxidation to fuel availability, i.e., metabolic inflexibility. The hampered metabolic adaptability triggers a further damage of insulin signaling. Since skeletal muscle is the main site of glucose uptake, effectiveness of T2D treatment depends in large on the improvement of insulin sensitivity and metabolic adaptability of the muscle. We have shown previously in mice fed an obesogenic high-fat diet that a combination treatment using n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and thiazolidinedione (TZD) anti-diabetic drugs preserved metabolic health and synergistically improved muscle insulin sensitivity. We investigated here whether TZD rosiglitazone could elicit the additive beneficial effects on metabolic flexibility when combined with n-3 LC-PUFA. Adult male C57BL/6J mice were fed an obesogenic corn oil-based high-fat diet (cHF) for 8 weeks, or randomly assigned to various dietary treatments: (i) cHF+F, cHF with n-3 LC-PUFA concentrate replacing 15% of dietary lipids; (ii) cHF+ROSI, cHF with 10 mg rosiglitazone/kg diet; and (iii) cHF+F+ROSI, or chow-fed. Indirect calorimetry demonstrated superior preservation of metabolic flexibility to carbohydrates in response to the combination treatment. Metabolomic and gene expression analyses in the muscle suggested distinct and complementary effects of the single treatments, with rosiglitazone augmenting insulin sensitivity by the modulation of branched-chain amino acid metabolism, and n-3 LC PUFA supporting complete oxidation of fatty acids in mitochondria. These beneficial metabolic effects were associated with the activation of the switch between glycolytic and oxidative muscle fibers, especially in the cHF+F+ROSI mice. Our results further support the idea that the combination treatment using n-3 LC-PUFA and TZDs could improve the efficacy of the treatment of obese and diabetic patients. Male C57BL/6N mice had free access to water and Chow. Three-month-old mice were randomly assigned (8 animals per group) to cHF+ROSI diet (lipid content ~35% wt/wt) supplemented with 10 mg rosiglitazone/kg diet, or cHF+F+ROSI in which n-3 LC-PUFA concentrate (46% DHA, 14% EPA, wt/wt, as triglycerides; product EPAX 1050 TG) replaced 15% wt/wt of dietary lipids. The treatment lasted for 8 weeks, whereafter the animals were first fasted for 10 hours during the light phase of the day (between 8.00hr and 18.00hr), than re-fed Chow (starting at 18.00hr), and killed the following day by cervical dislocation under pentobarbital anesthesia (between 9.00hr and 11.00hr); the so-called 'diet-switch protocol'. Gastrocnemius muscle was isolated and used for total RNA isolation.
2012-09-07 | E-GEOD-36717 | biostudies-arrayexpress
Project description:Impaired resistance to insulin, the key defect in type 2 diabetes (T2D), is associated with a low capacity to adapt fuel oxidation to fuel availability, i.e., metabolic inflexibility. The hampered metabolic adaptability triggers a further damage of insulin signaling. Since skeletal muscle is the main site of glucose uptake, effectiveness of T2D treatment depends in large on the improvement of insulin sensitivity and metabolic adaptability of the muscle. We have shown previously in mice fed an obesogenic high-fat diet that a combination treatment using n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and thiazolidinedione (TZD) anti-diabetic drugs preserved metabolic health and synergistically improved muscle insulin sensitivity. We investigated here whether TZD rosiglitazone could elicit the additive beneficial effects on metabolic flexibility when combined with n-3 LC-PUFA. Adult male C57BL/6N mice were fed an obesogenic corn oil-based high-fat diet (cHF) for 8 weeks, or randomly assigned to various dietary treatments: (i) cHF+F, cHF with n-3 LC-PUFA concentrate replacing 15% of dietary lipids; (ii) cHF+ROSI, cHF with 10 mg rosiglitazone/kg diet; and (iii) cHF+F+ROSI, or chow-fed. Indirect calorimetry demonstrated superior preservation of metabolic flexibility to carbohydrates in response to the combination treatment. Metabolomic and gene expression analyses in the muscle suggested distinct and complementary effects of the single treatments, with rosiglitazone augmenting insulin sensitivity by the modulation of branched-chain amino acid metabolism, and n-3 LC PUFA supporting complete oxidation of fatty acids in mitochondria. These beneficial metabolic effects were associated with the activation of the switch between glycolytic and oxidative muscle fibers, especially in the cHF+F+ROSI mice. Our results further support the idea that the combination treatment using n-3 LC-PUFA and TZDs could improve the efficacy of the treatment of obese and diabetic patients. Male C57BL/6N mice had free access to water and Chow. Three-month-old mice were randomly assigned (8 animals per group) to cHF diet (lipid content ~35% wt/wt) or to the following 'treatments' by isocaloric cHF-based diets, namely (i) cHF+F, cHF diet supplemented with n-3 LC-PUFA concentrate (46% DHA, 14% EPA, wt/wt, as triglycerides; product EPAX 1050 TG), which replaced 15% wt/wt of dietary lipids; (ii) cHF+ROSI, cHF diet supplemented with 10 mg rosiglitazone/kg diet; and (iii) cHF+F+ROSI, cHF diet supplemented with both n-3 LC-PUFA concentrate and rosiglitazone. cHF+ROSI at a higher dose, namely 100 mg rosiglitazone/kg diet was also included in the study, but not in the final microarray analysis. The treatment lasted for 8 weeks, whereafter the animals were first fasted for 10 hours during the light phase of the day (between 8.00hr and 18.00hr), than re-fed Chow (starting at 18.00hr), and killed the following day by cervical dislocation under pentobarbital anesthesia (between 9.00hr and 11.00hr); the so-called 'diet-switch protocol'. Gastrocnemius muscle was isolated and used for total RNA isolation.
2012-09-07 | E-GEOD-36716 | biostudies-arrayexpress
Project description:Intake of high-protein (HP) diets has increased over the last years, mainly due to their popularity for body weight control. Liver is the main organ handling ingested macronutrients and it is associated with the beginning of different pathologies. We aimed to deepen our knowledge on molecular pathways affected by long-term intake of an HP diet. We performed a transcriptome analysis on liver of rats chronically fed with a casein-rich HP diet and analyzed molecular parameters related to liver injury. Chronic increase in the dietary protein/carbohydrate ratio up-regulated processes related with amino acid uptake/metabolism and lipid synthesis, promoting a molecular environment indicative of hepatic triacylglycerol (TG) deposition. Moreover, changes in expression of genes involved in acidâbase maintenance and oxidative stress indicate alterations in the pH balance due to the high acid load of the diet, which has been linked to liver/health damage. Up-regulation of immune-related genes was also observed. In concordance with changes at gene expression level, we observed increased liver TG content and increased serum markers of hepatic injury/inflammation (aspartate transaminase, C-reactive protein and TNF-alpha). Moreover, the HP diet strongly increased hepatic mRNA and protein levels of HSP90, a marker of liver injury. Thus, we show for the first time that long-term consumption of an HP diet, resulting in a high acid load, results in a hepatic transcriptome signature reflecting increased TG deposition and increased signs of health risk (increased inflammation, alterations in the acidâbase equilibrium and oxidative stress). Persistence of this altered metabolic status could have unhealthy consequences. Wistar wildtype male rats, aged 8 weeks, received a low fat diet, high protein or high fat diet for 4 months. After sacrification, livers were dissected, and immediately snap frozen in liquid nitrogen. Total RNA was isolated, quantified and qualified, and subsequently used for global gene expression profiling using Agilent 4x44K microarrays.
2017-05-02 | E-GEOD-57858 | biostudies-arrayexpress
Project description:Using standardized, semipurified diets is a crucial factor for reproducibility of experimental nutritional studies. For the purpose of comparability and integration of research, two European consortia, Mitofood and BIOCLAIMS, proposed an AIN-93-based standard reference diet, the standardized BIOCLAIMS low-fat diet (LFD) as well as a high-fat diet (HFD). In order to evaluate the BIOCLAIMS LFD and HFD, we performed short-term (5 days) and long-term (12 weeks) feeding experiments using male C57BL/6 mice. The HFD has the same composition as the LFD except the fat content is increased to 40% energy in exchange for carbohydrates. Both diets were accepted by the animals and proof of principle was given that the BIOCLAIMS HFD increases body weight and body fat and affects glucose homeostasis. Short-term feeding trials (5 days) were performed in order to identify metabolic and molecular parameters which can serve as acute predictors for metabolic disorders due to high-fat diet-induced obesity. We analyzed gene expression in gonadal white adipose tissue of short- and long-term fed animals with whole genome microarrays. The BIOCLAIMS HFD strongly influenced gene expression in white adipose tissue after short- and long-term intervention. A total number of 973 and 4678 transcripts were significantly different between both diets after 5 days feeding and 12 weeks feeding, respectively. A total number of 764 transcripts encoding 549 genes were significantly differentially regulated between LF and HF animals after 12 weeks feeding as well as after 5 days feeding. Of these 549 overlapping genes, a substantial number (434 genes) were expressed at a lower level and 115 genes were expressed at a higher level in the HF mice compared to the LF mice. Without exception, all genes were regulated equally. Pathway analysis revealed a prominent role for genes involved in lipid metabolism, carbohydrate metabolism and oxidative phosphorylation. This was confirmed by quantitative real-time reverse transcription PCR. The high predictive value of gene expression changes in our short-term study compared to long-term high fat feeding is a promising step to get well-defined, early biomarkers that could shorten animal trials considerably and allow a more rapid and efficient screening of different compounds. C57BL/6J wildtype male mice, aged 12 weeks, received a low-fat diet or a high-fat diet for 5 days or 12 weeks. After sacrification, white adipose tissue depots were dissected, and immediately snap frozen in liquid nitrogen. Total RNA was isolated, quantified and qualified, and subsequently used for global gene expression profiling using Agilent 4x44K microarrays.
2013-08-27 | E-GEOD-38337 | biostudies-arrayexpress
Project description:Gene expression studies in peripheral blood mononuclear cells (PBMC) can provide knowledge that would be difficult to obtain using other types of biological samples, as these cells can reflect overall response of the body to a specific stimulus, such as diet. Here, we aimed to study the impact of sustained intake of isocaloric diets with an unbalanced macronutrient proportion (rich in fat or protein) on PBMC gene expression in rats using transcriptomics, to better understand the effects of these diets on metabolism and health. Macronutrient diet composition (especially increased protein content) affected PBMC gene expression. An important effect was observed in immune response-related genes. High protein (HP) diet produced an activation of genes mainly related to antigen recognition/presentation, whereas the high fat (HF) diet was more related to a decreased expression of these genes. Key energy homeostasis genes (mainly involved in lipid metabolism) were also affected, reflecting a nutritional adaptive response to the diets. Decreased Dhrs3 and increased Pref-1/Dlk1 expression observed in HP-fed animals reflects a lower lipogenic capacity. In addition, HF diet affected the expression of genes related to insulin resistance/signaling (Msra/Slc9a6, Asb6), hypoxia (Akap12), cardiovascular problems (Ethe1, Lr11), cognitive impairment (Tmcc2) and tumorigenesis (Ddx17, Phb, Rnasen/Drosha, and Tsc2). HP diet also impaired the expression of genes related to glucose metabolism and insulinemia (Glut-4/Slc2a4, Sfxn5, Slc16a1), but positively affected genes involved in liver function (Clec4f and St6galnac3) and cardiovascular protection (Sort1). In conclusion, gene expression analysis in PBMC can provide information that could be useful to detect metabolic deviations and health consequences of diets with an unbalanced macronutrient composition. 2 months-old male Wistar rats received a low fat control diet, or a high fat (HF) diet, or a high protein (HP) diet for 4 months, respectively. At the end of the intervention, prior to the sacrifice of the animals, peripheral blood samples (1.5-2.5 mL) were collected from the safena vein, using heparin in NaCl (0.9%) as anticoagulant. Immediately after blood collection, peripheral blood mononuclear cells (PBMC) were isolated by Ficoll gradient separation. Total RNA was isolated from PBMC, quantified and qualified, and subsequently used for global gene expression profiling using Agilent 4x44K microarrays.
2015-12-07 | E-GEOD-54897 | biostudies-arrayexpress
Project description:Fibroblast growth factor 21 (FGF21) is a key metabolic regulator which was recently discovered as stress-induced myokine and common denominator of muscle mitochondrial disease. However, its precise function and pathophysiological relevance remains unknown. Here we demonstrate that white adipose tissue (WAT) is the major target of muscle mitochondrial stress-induced FGF21. Strikingly, substantial browning and metabolic remodeling of subcutaneous WAT, together with the reduction of circulating triglycerides and cholesterol are fully FGF21 dependent. Unexpectedly and in contrast to prior expectations, we found a negligible role of FGF21 in muscle stress-related improved glycemic control, obesity resistance and hepatic lipid homeostasis. Furthermore, we show that the protective muscle mitohormesis and metabolic stress adaptation does not require FGF21 action. Taken together, our data imply that although FGF21 drives WAT remodeling, this effect and FGF21 as stress hormone per se may not be essential for the adaptive response under muscle mitochondrial stress conditions. Wildtype male mice and FGF21-knockout male mice, together with muscle specific UCP1-transgenic male animals, and double cross of FGF21-KO with UCP1-Tg male mice, were kept on a standardized low fat diet for 40 weeks. After sacrifice, subcutaneous white adipose tisseu (scWAT) was rapidly removed, weighed, and snap frozen in liquid nitrogen and used for RNA isolation and whole genome gene expression microarray hybridisation using Agilent arrays.
2016-01-07 | E-GEOD-71749 | biostudies-arrayexpress
Project description:Dietary flavonoids are supposed to be protective against cardiovascular diseases (CVD). Elevated circulating lipid levels and hepatic lipid accumulation are known risk factors for CVD. We investigated the effects and underlying molecular mechanisms of the flavonoid quercetin on hepatic lipid metabolism in mice with diet induced body weight gain and hepatic lipid accumulation. Adult male mice received a high-fat diet without or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Body weight gain was 29% lower in quercetin-fed mice (p<0.01), while the energy intake was not significantly different. Quercetin supplementation reduced hepatic lipid accumulation with 71% (p<0.05). 1H nuclear magnetic resonance serum lipid profiling revealed that the supplementation lowered serum lipids (p<0.0001). Global gene expression profiling of liver showed that key target genes of the transcription factor Constitutive androstane receptor (Car; official symbol Nr1i3) were regulated, in particular Cytochrome P450 2b (Cyp2b) genes. Quercetin can decrease high-fat diet induced body weight gain, hepatic lipid accumulation and serum lipid levels, which might be explained by the regulation of Cytochrome P450 genes under transcriptional control of CAR, an effect which is likely dependent on dietary background. Liver samples were obtained from 24 C57BL/6J male adult mice. All mice started with a three week adaptation phase, in which they were fed a normal-fat diet. During the intervention of 12 weeks, the mice received a high-fat diet without (HF) or with supplementation of 0.33% (w/w) quercetin (HF-Q). Based on visual inspection, three arrays lacked homogenous hybridization and were therefore excluded.
2014-10-14 | E-GEOD-51343 | biostudies-arrayexpress
Project description:We previously reported that a low versus high glycemic index (GI) diet on a high fat (30% kcal fat) background (LGI and HGI, respectively) significantly retarded adverse health effects in C57BL/6J male mice. The LGI diet enhanced whole body insulin sensitivity and repressed high fat diet-induced body and adipose tissue weight gain, resulting in reduced serum leptin and resistin levels (Faseb J 2009; 23: 1092-1101). How white adipose tissue (WAT) is effected is examined in the present study. We characterized the molecular mechanisms underlying the GI-mediated effects in WAT using whole genome transcriptomics technology. We show that a LGI vs. HGI diet mainly exerts its beneficial effects on substrate metabolism, especially insulin signaling of fatty acid metabolism. In addition, cell adhesion and cytoskeleton remodeling showed reduced expression in line with lower WAT mass, but it might also be due to altered insulin sensitivity. An important transcription factor showing enhanced expression is PPARgamma. Furthermore, serum levels of triglycerides, total cholesterol, HDL- and LDL-cholesterol were significantly reduced by a LGI vs. HGI diet, and muscle insulin sensitivity was significantly increased as analyzed by PKB/Akt phosphorylation. Cumulatively, even though these mice were fed a high fat diet, the low versus high GI induced significantly favorable changes in metabolism in WAT. These effects suggest a partial overlap with pharmacological approaches by thiazolidinediones (TZDs) to treat insulin resistance and statins and plantsterols/stanols for hypercholesterolemia. It is therefore tempting to speculate that such a dietary approach might beneficially support pharmacological treatment of insulin resistance or hypercholesterolemia in humans. We analyzed 19 epididymal whie adipose tissue (epiWAT) samples from a 13 week High fat diet, Low glycemic index dietary group (LGI, n=9) versus a High fat diet, High glycemic index dietary group (HGI, n=10) after 13 weeks of feeding wildtype C57BL/6J male adult mice. Of the 19 arrays, we excluded 2 arrays for downstream analysis based on quality control (total final set contains 8 LGI and 9 HGI samples).
2011-09-12 | E-GEOD-26930 | biostudies-arrayexpress