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

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.

Project description:Considering global climate changes, incidences of combined drought and heat stress are likely to increase in the future and will considerably influence plant-pathogen interactions. Until now, little is known about plants exposed to simultaneously occurring abiotic and biotic stresses. To shed some light on molecular plant responses to multiple stress factors, a versatile multi-factorial test system, allowing simultaneous application of heat, drought and virus stress, was developed. Comparative analysis of single, double and triple stress responses by transcriptome and metabolome analysis revealed that gene expression under multi-factorial stress is not predictable from single stress treatments. Hierarchical cluster and principal component analysis identified heat as the major stress factor clearly separating heat-stressed from non-heat stressed plants. We identified 11 genes differentially regulated in all stress combinations as well as 23 genes specifically-regulated under triple stress. Furthermore, we showed that virus treated plants displayed enhanced expression of defense genes, which was abolished in plants additionally subjected to heat and drought stress. Triple stress also reduced expression of genes involved in the R-mediated disease response and increased the cytoplasmic protein response which was not seen under single stress conditions. These observations suggested that abiotic stress factors significantly altered TuMV-specific signaling networks which lead to a deactivation of defense responses and a higher susceptibility of plants. Collectively, our transcriptome and metabolome data provide a powerful resource to study plant responses during multi-factorial stress and allows identifying metabolic processes and functional networks involved in tripartite interactions of plants with their environment. Stress induced gene expression in Arabidopsis leaves was measured after exposure to single and combined abiotic and biotic stress. Plants were grown on soil for 21 days till virus infection. Eight days later controlled drought stress was applied. At the end of the treatments heat was applied for three days. Four biological replicates have been hybridized for each treatment. Furthermore, Arabidopsis plants were exposed to a single severe heat stress (37Â°C day/33Â°C night) to mimic the severity of the triple stress experiment.

Project description:Considering global climate changes, incidences of combined drought and heat stress are likely to increase in the future and will considerably influence plant-pathogen interactions. Until now, little is known about plants exposed to simultaneously occurring abiotic and biotic stresses. To shed some light on molecular plant responses to multiple stress factors, a versatile multi-factorial test system, allowing simultaneous application of heat, drought and virus stress, was developed. Comparative analysis of single, double and triple stress responses by transcriptome and metabolome analysis revealed that gene expression under multi-factorial stress is not predictable from single stress treatments. Hierarchical cluster and principal component analysis identified heat as the major stress factor clearly separating heat-stressed from non-heat stressed plants. We identified 11 genes differentially regulated in all stress combinations as well as 23 genes specifically-regulated under triple stress. Furthermore, we showed that virus treated plants displayed enhanced expression of defense genes, which was abolished in plants additionally subjected to heat and drought stress. Triple stress also reduced expression of genes involved in the R-mediated disease response and increased the cytoplasmic protein response which was not seen under single stress conditions. These observations suggested that abiotic stress factors significantly altered TuMV-specific signaling networks which lead to a deactivation of defense responses and a higher susceptibility of plants. Collectively, our transcriptome and metabolome data provide a powerful resource to study plant responses during multi-factorial stress and allows identifying metabolic processes and functional networks involved in tripartite interactions of plants with their environment. Stress induced gene expression in Arabidopsis leaves was measured after exposure to single and combined abiotic and biotic stress. Plants were grown on soil for 21 days till virus infection. Eight days later controlled drought stress was applied. At the end of the treatments heat was applied for three days. In parallel, a homozougus T-DNA insertion line SALK_021115C (N672283), located in the Arabidopsis gene At5g45000 has been exposed to the same stress conditions. Four biological replicates have been hybridized for each treatment.

Project description:Considering global climate changes, incidences of combined drought and heat stress are likely to increase in the future and will considerably influence plant-pathogen interactions. Until now, little is known about plants exposed to simultaneously occurring abiotic and biotic stresses. To shed some light on molecular plant responses to multiple stress factors, a versatile multi-factorial test system, allowing simultaneous application of heat, drought and virus stress, was developed. Comparative analysis of single, double and triple stress responses by transcriptome and metabolome analysis revealed that gene expression under multi-factorial stress is not predictable from single stress treatments. Hierarchical cluster and principal component analysis identified heat as the major stress factor clearly separating heat-stressed from non-heat stressed plants. We identified 11 genes differentially regulated in all stress combinations as well as 23 genes specifically-regulated under triple stress. Furthermore, we showed that virus treated plants displayed enhanced expression of defense genes, which was abolished in plants additionally subjected to heat and drought stress. Triple stress also reduced expression of genes involved in the R-mediated disease response and increased the cytoplasmic protein response which was not seen under single stress conditions. These observations suggested that abiotic stress factors significantly altered TuMV-specific signaling networks which lead to a deactivation of defense responses and a higher susceptibility of plants. Collectively, our transcriptome and metabolome data provide a powerful resource to study plant responses during multi-factorial stress and allows identifying metabolic processes and functional networks involved in tripartite interactions of plants with their environment. Stress induced gene expression in Arabidopsis leaves was measured after exposure to single and combined abiotic and biotic stress. Plants were grown on soil for 21 days till virus infection. Eight days later controlled drought stress was applied. At the end of the treatments heat was applied for three days. Four biological replicates have been hybridized for each treatment.

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Transcription profiling of mouse liver after 4.5 days of repeated combined acoustic and restraint stress vs. control

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