Gene-Expression Based Measure of Chronic Stress Exposure
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE100454 | GEO | 2018/01/01
SECONDARY ACCESSION(S): PRJNA391865
REPOSITORIES: GEO
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Project description:Chronic stress episodes increase metabolic disease risk even after recovery. We propose that persistent stress detrimentally impacts hepatic metabolic reprogramming, particularly mitochondrial function. In male C57BL/6 mice chronic variable stress (Cvs) reduced energy expenditure (EE) and body mass despite increased energy intake versus controls. This coincided with decreased glucose metabolism and increased lipid β-oxidation, correlating with EE. After Cvs, mitochondrial function revealed increased thermodynamic efficiency (ƞ-opt) of complex CI, positively correlating with blood glucose and NEFA and inversely with EE. After Cvs recovery, the metabolic flexibility of hepatocytes was lost. Reduced CI-driving NAD+/NADH ratio, and diminished methylation-related one-carbon cycle components hinted at epigenetic regulation. Although initial DNA methylation differences were minimal after Cvs, they diverged during the recovery phase. Here, the altered enrichment of mitochondrial DNA methylation and linked transcriptional networks were observed. In conclusion, Cvs rapidly initiates the reprogramming of hepatic energy metabolism, supported by lasting epigenetic modifications.
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Project description:Chronic stress episodes increase metabolic disease risk even after recovery. We propose that persistent stress detrimentally impacts hepatic metabolic reprogramming, particularly mitochondrial function. In male C57BL/6 mice chronic variable stress (Cvs) reduced energy expenditure (EE) and body mass despite increased energy intake versus controls. This coincided with decreased glucose metabolism and increased lipid β-oxidation, correlating with EE. After Cvs, mitochondrial function revealed increased thermodynamic efficiency (ƞ-opt) of complex CI, positively correlating with blood glucose and NEFA and inversely with EE. After Cvs recovery, the metabolic flexibility of hepatocytes was lost. Reduced CI-driving NAD+/NADH ratio, and diminished methylation-related one-carbon cycle components hinted at epigenetic regulation. Although initial DNA methylation differences were minimal after Cvs, they diverged during the recovery phase. Here, the altered enrichment of mitochondrial DNA methylation and linked transcriptional networks were observed. In conclusion, Cvs rapidly initiates the reprogramming of hepatic energy metabolism, supported by lasting epigenetic modifications.
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Project description:Chronic stress disorders lead to metabolic complications, including hepatic lipid accumulation. Here we address the role of FGF21 in the hepatic metabolic regulation in a mouse model for chronic variable stress (Cvs). Global FGF21KO and WT mice show an intact stress response with short-term Cvs induced alterations in hepatic lipid metabolism, mitochondrial function and gene expression. Hepatic steatosis is found with the highest significance in enrichment analyses of hepatic transcriptome data, with PPARa and SREBP-1 as main upstream regulatory molecules, which are directly associated to FGF21. After 3 months recovery, stress-related metabolic improvements are not visible in FGF21KO mice in contrast to WT mice, indicating the crucial role of FGF21 in the post-stress metabolic adaptations. Overall, we suggest that Cvs-induced gene regulation determines the metabolic late effects after stress. Furthermore, FGF21 is a key player in the protection from stress-induced hepatic lipid accumulation.
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Project description:Episodes of chronic stress can result in psychic disorders like post-traumatic stress disorder, but also promote the development of metabolic syndrome and type 2 diabetes. We hypothesize that muscle, as main regulator of whole-body energy expenditure, is a central target of acute and adaptive molecular efects of stress in this context. Here, we investigate the immediate efect of a stress period on energy metabolism in Musculus gastrocnemius in our established C57BL/6 chronic variable stress (Cvs) mouse model. Cvs decreased lean body mass despite increased energy intake, reduced circadian energy expenditure (EE), and substrate utilization. Cvs altered the proteome of metabolic components but not of the oxidative phosphorylation system (OXPHOS), or other mitochondrial structural components. Functionally, Cvs impaired the electron transport chain (ETC) capacity of complex I and complex II, and reduces respiratory capacity of the ETC from complex I to ATP synthase. Complex I-OXPHOS correlated to diurnal EE and complex II-maximal uncoupled respiration correlated to diurnal and reduced nocturnal EE. Bioenergetics assessment revealed higher optimal thermodynamic efciencies (ƞ-opt) of mitochondria via complex II after Cvs. Interestingly, transcriptome and methylome were unafected by Cvs, thus excluding major contributions to supposed metabolic adaptation processes. In summary, the preclinical Cvs model shows that metabolic pressure by Cvs is initially compensated by adaptation of mitochondria function associated with high thermodynamic efciency and decreased EE to manage the energy balance. This counter-regulation of mitochondrial complex II may be the driving force to longitudinal metabolic changes of muscle physiological adaptation as the basis of stress memory.
2023-03-31 | PXD035798 | Pride
Project description:Chronic stress can result in dysregulation of the cellular metabolism leading to severe disorders including depression, posttraumatic stress disorder but also the metabolic syndrome and type 2 diabetes. We aimed to determine the acute and adaptive effect of stress on energy metabolism in muscle tissue as the main determinant of whole-body energy expenditure. C57Bl6 mice under 15 days of chronic variable stress (Cvs) showed decreased lean mass despite increased energy intake. This was accompanied by reduced energy expenditure (EE) with a concomitant shift in substrate utilization depending on the circadian rhythm. The combination of omics approaches excluded stress effects on transcription and methylation processes in gastrocnemius muscle. Nevertheless, Cvs interfered with altered proteome composition in mitochondria on metabolic components, whilst OXPHOS and structural relevant components were unaltered. Functionally, Cvs resulted in impaired complex independent mitochondrial electron flow and reduced coupling efficiency that correlate for oxidative phosphorylation (state 3) of complex I to diurnal energy expenditure (EE) and for maximal uncoupled respiration (state 3u) of complex II to reduced diurnal and nocturnal EE. Bioenergetics assessment of mitochondria revealed higher optimal thermodynamic efficiencies (ƞ-opt) in Cvs muscle. Conclusion: These results show, that the Cvs reduced mitochondria respiration is associate with low rate of total EE, but does not primary affect transcription and genome methylation in muscle. However, the counter regulation by increased efficiency of complex II may be the driving force in to pave the way to longitudinal metabolic changes as basis of stress memory to muscle physiological adaptation.
2023-04-03 | GSE210509 | GEO
Project description:The biological underpinnings of major depressive disorder (MDD) heterogeneity are unknown, in part due to the poor association between MDD models and clinical endpoints. We compared transcriptomic profiles of human postmortem MDD brain tissue and chronic variable stress (CVS)-exposed mice to identify orthologous genes. A downregulation of ribosomal protein genes (RPGs) and upregulation of associated RP pseudogenes in the prefrontal cortex of several independent cohorts from both human MDD and mouse CVS tissue prompted a seeded gene co-expression analysis using the RPGs altered in both groups. Downregulated RPGs were found to regulate synaptic changes in human MDD and mouse CVS through a RP pseudogene-driven mechanism. In vitro and in silico analysis further suggested that the inverse RPG/RP pseudogene association was a glucocorticoid-driven response and reversed during MDD remission. Thus, stress-induced alterations in RPGs may contribute to synaptic dysregulation in MDD, providing a mechanism for the variability in depression presentation.
2023-10-25 | GSE229905 | GEO
Project description:Episodes of chronic stress can result in psychic disorders like post-traumatic stress disorder, but also promote the development of metabolic syndrome and type 2 diabetes. We hypothesize that muscle, as main regulator of whole-body energy expenditure, is a central target of acute and adaptive molecular effects of stress in this context. Here, we investigate the immediate effect of a stress period on energy metabolism in Musculus gastrocnemius in our established C57BL/6 chronic variable stress (Cvs) mouse model. Cvs decreased lean body mass despite increased energy intake, reduced circadian energy expenditure (EE), and substrate utilization. Cvs altered the proteome of metabolic components but not of the oxidative phosphorylation system (OXPHOS), or other mitochondrial structural components. Functionally, Cvs impaired the electron transport chain (ETC) capacity of complex I and complex II, and reduces respiratory capacity of the ETC from complex I to ATP synthase. Complex I-OXPHOS correlated to diurnal EE and complex II-maximal uncoupled respiration correlated to diurnal and reduced nocturnal EE. Bioenergetics assessment revealed higher optimal thermodynamic efficiencies (ƞ-opt) of mitochondria via complex II after Cvs. Interestingly, transcriptome and methylome were unaffected by Cvs, thus excluding major contributions to supposed metabolic adaptation processes. In summary, the preclinical Cvs model shows that metabolic pressure by Cvs is initially compensated by adaptation of mitochondria function associated with high thermodynamic efficiency and decreased EE to manage the energy balance. This counter-regulation of mitochondrial complex II may be the driving force to longitudinal metabolic changes of muscle physiological adaptation as the basis of stress memory.Chronic stress targets mitochondrial respiratory efficiency in the skeletal muscle of C57BL/6 mice.Nikolic A, Fahlbusch P, Wahlers N, Riffelmann NK, Jacob S, Hartwig S, Kettel U, Dille M, Al-Hasani H, Kotzka J, Knebel B. Cell Mol Life Sci. 2023 Mar 29;80(4):108. doi: 10.1007/s00018-023-04761-4.PMID: 36988756
2024-03-08 | PXD042472 | Pride
Project description:Chronic stress leads post-traumatic stress disorder (PTSD) and to metabolic complications, including fatty liver. It is feasible, that stress immediately initiates molecular mechanisms to alter energy metabolism and glucose homeostasis which interfere with hepatic lipid accumulation after stress recovery. We aim to elucidate these molecular mechanisms of long term stress effects on metabolism and focus on physiological adaptation and the role of FGF21, which is protective in hepatic lipid accumulation. Methods FGF21 knockout and control mice were exposed to chronic variable stress (Cvs) and recovered for 3 months to simulate PTSD. We determined in vivo and ex vivo energy metabolism, mitochondrial function by extracellular flux analysis, alterations in DNA modifying enzymes and gene regulation immediately after stress and after the recovery period to determine long term alterations. Results Chronic stress leads to reduced insulin sensitivity and hepatic lipid accumulation with increased fatty acid uptake (FAU), stress-induced lipolysis, and reduction in NAD+/NAD ratio and Sirt activity. Immediately after stress, PPARa and SREBP-1 target genes are differentially regulated and are involved in the development of stress-induced fatty liver. After recovery, insulin sensitivity increases but insulin-induced de novo lipogenesis (DNL) is reduced and FAU is increased. HDAC and MT activity are suppressed, whereas HAT activity increases, linking metabolic adjustments to transcriptional regulators. Thus, key metabolic genes are differentially regulated and secreted proteins indicate the activation of liver disease by Cvs only in FGF21WT. GR binding to the Cd36 promoter is altered. After stress recovery, serum FGF21 is increased and protects against lipid accumulation. FGF21 interacts by attenuating DNL, increasing FAU and HAT activity, and balancing mitochondrial activity. Higher long-term stress-induced activation and binding of GR to the FGF21 promoter may contribute to the prolonged FGF21 release. Conclusions We show that previous stress exposure determines predisposition to fatty liver disease is regulated by FGF21. Immediately after Cvs, altered gene regulation and activity of DNA-modifying enzymes determine the metabolic late effects seen in PTSD. FGF21 functions after chronic stress exposure i) to protect against hepatic lipid accumulation, ii) to maintain mitochondrial capacity, and iii) to mediate in the modulation of DNA-modifying enzymes. These findings highlight the protective role of FGF21 even in stress-induced hepatic lipid accumulation.
2022-03-10 | PXD025268 | Pride