Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Peripheral blood mononuclear cells gene expression reflects adaptive response and metabolic damage associated to the intake of diets with an unbalanced proportion of macronutrients

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Evert van Schothorst

PROVIDER: E-GEOD-54897 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Peripheral blood mononuclear cells as a source to detect markers of homeostatic alterations caused by the intake of diets with an unbalanced macronutrient composition.

Díaz-Rúa Rubén R Keijer Jaap J Caimari Antoni A van Schothorst Evert M EM Palou Andreu A Oliver Paula P

The Journal of nutritional biochemistry 20150113 4

Peripheral blood mononuclear cells (PBMCs) are accessible in humans, and their gene expression pattern was shown to reflect overall physiological response of the body to a specific stimulus, such as diet. We aimed to study the impact of sustained intake (4months) of diets with an unbalanced macronutrient proportion (rich in fat or protein) administered isocalorically to a balanced control diet, as physiological stressors on PBMC whole-genome gene expression in rats, to better understand the effe ...[more]

PMID: 25660595

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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.

Project description:How signals from fatty acid metabolism are translated into changes in food intake remains unclear. Previously we reported that mice with a genetic inactivation of Acads (short-chain acyl-CoA dehydrogenase), encoding the enzyme responsible for mitochondrial beta-oxidation of C4-C6 short-chain fatty acids (SCFAs), shift consumption away from fat and toward carbohydrate when offered a choice. This finding demonstrated that the loss of a specific enzyme in fatty acid oxidation alters the choice of diet intake. To our knowledge, there are no reports of studies on the effects of dietary fat on the brain transcriptome in genetic models of fatty acid oxidation deficiency. The current study aimed to identify molecular mediators underlying the effects of SCFA oxidation deficiency on food intake. The current study aimed to identify molecular mediators underlying the effects of SCFA oxidation deficiency on food intake. We performed a transcriptional screen for gene expression in brain tissue of Acads-/- and Acads+/+ mice fed either high-fat (HF) or low-fat (LF) diet for 2 d. Ingenuity Pathway Analysis revealed three top-scoring pathways significantly modified by genotype or diet: oxidative phosphorylation, mitochondrial dysfunction, and CREB signaling in neurons. A comparison of statistically significant responses in HF Acads-/- vs. HF Acads+/+ (3917) and Acads+/+ HF vs. LF Acads+/+ (3879) revealed 2551 genes or approximately 65% in common between the two experimental comparisons. All but one of these genes were expressed in opposite direction with similar magnitude, demonstrating that Acads-deficient mice fed HF diet display transcriptional responses that mimic those of wildtype Acads+/+ mice fed LF diet. Intriguingly, genes involved in energy sensing and metabolism followed this pattern. Quantitative RT-PCR in hypothalamus confirmed the dysregulation of several genes in these pathways. Western blotting showed that the combination of Acads deficiency and HF diet increased hypothalamic AMP-kinase, a key protein in an energy-sensing cascade that responds to depletion of ATP. Our results suggest that the decreased beta oxidation of short-chain fatty acids in Acads-deficient mice fed HF diet produces a state of energy deficiency in the brain and that AMP-kinase is the cellular energy-sensing mechanism linking fatty acid oxidation to feeding behavior in this model. Twelve-week old male BALB/cByJ (Acads-/-) and BALB/cByKZ (Acads+/+) mice were fed a high-fat (D12331; Research Diets) and low-fat (D12329) diet for two days. Total RNA from whole brain tissue was obtained from three mutant (Acads-/-) and three wild-type (Acads+/+) mice of each diet group. All mice had similar body weights before diets were initiated. Gene expression in brain was compared between strains and between diets. Twelve-week old male BALB/cByJ (Acads-/-) and BALB/cByKZ (Acads+/+) mice were fed a high-fat (D12331; Research Diets) and low-fat (D12329) diet for two days. Total RNA from liver was obtained from three mutant (Acads-/-) and three wild-type (Acads+/+) mice of each diet group. All mice had similar body weights before diets were initiated. Gene expression in liver was compared between strains and diets.

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Dataset Information

Peripheral blood mononuclear cells gene expression reflects adaptive response and metabolic damage associated to the intake of diets with an unbalanced proportion of macronutrients

Publications

Peripheral blood mononuclear cells as a source to detect markers of homeostatic alterations caused by the intake of diets with an unbalanced macronutrient composition.

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