Chronic unpredictive mild stress leads to altered hepatic metabolic profile and gene expression

Jia, Hongmei; Qi, Li; Zhou, Chao; Meng, Yijun; Yong, Yang; Zhang, Hongwu; Ding, Gang; Shang, Hai; Zou, Zhong‐Mei

doi:10.1038/srep23441

Cited by 61 publications

(47 citation statements)

References 55 publications

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“…Allostatic overload can be caused by chronic stress, and the consequences of allostatic load include increased risk of cardiovascular disease, abnormal hepatic metabolism, atrophy of neurons in the whole brain, and poor kidney outcomes [12][13][14] . The underlying pathologic mechanisms of diseases associated with allostatic overload may be involved in oxidative stress and systemic inflammation, disturbances in the autonomic nervous system and circadian rhythm, as well as metabolite abnormalities in the main stress-targeted tissues 2,5 .…”

Section: Discussionmentioning

confidence: 99%

Systematic impacts of chronic unpredictable mild stress on metabolomics in rats

Geng

Guo

Wang³

et al. 2020

Sci Rep

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Depression is the most common disabling psychiatric disease, with a high prevalence and mortality. Chronic unpredictable mild stress (CUMS) is a well-accepted method used to mimic clinical depression. Recent evidence has consistently suggested that the cumulative effects of CUMS could lead to allostatic overload in the body, thereby inducing systemic disorders; however, there are no previous systematic metabonomics studies on the main stress-targeted tissues associated with depression. A non-targeted gas chromatography-mass spectrometry (GC-MS) approach was used to identify metabolic biomarkers in the main stress-targeted tissues (serum, heart, liver, brain, and kidney) in a CUMS model of depression. Male Sprague-Dawley rats were randomly allocated to the CUMS group (n = 8) or a control group (n = 8). Multivariate analysis was performed to identify the metabolites that were differentially expressed between the two groups. There were 10, 10, 9, 4, and 7 differentially expressed metabolites in the serum, heart, liver, brain and kidney tissues, respectively, between the control and CUMS groups. These were linked to nine different pathways related to the metabolism of amino acids, lipids, and energy. In summary, we provided a comprehensive understanding of metabolic alterations in the main stress-targeted tissues, helping to understand the potential mechanisms underlying depression. An increasing body of evidence has revealed that the cumulative effect of stress can trigger allostatic overload 1-3. "Allostatic load" refers to the effects of prolonged continuous or intermittent activation of effectors involved in allostasis 4-6. Allostatic load has been associated with many diseases, such as cardiovascular disease, diabetes, stroke, chronic kidney disease, abdominal obesity, and depression 7,8. These all involve the whole body. Thus, the stress-induced allostatic overload involved in depression is focused on in our study. Depression is a seriously debilitating psychiatric disease, characterized by high mortality and morbidity. The chronic unpredictable mild stress (CUMS) model, a well-accepted animal model of depression, is used to explore the mechanisms underlying depression 9-11. One proposed mechanism involves allostatic load, a multidimensional biologic construct that involves biomarkers across the physiologic domains of neuroendocrine, autonomic, immune, and metabolic function 7. Allostatic overload resulting from CUMS in animal models causes atrophy of neurons in the hippocampus and prefrontal cortex 4,5 , myocardial ischemia 9 , abnormal hepatic metabolism 12 , and poor kidney outcomes 8,13. Thus, the impact of stress involves the whole body and depression is linked to multiple diseases such as cardiovascular disease 9. However, there are no previous systematic metabonomics studies focusing on the main stress-targeted tissues. Thus, the aim of the present study was to provide a panoramic and systematic view of metabolic alterations in stress-targeted tissues (serum, heart, liver, brain, and kidney) in the conte...

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Section: Discussionmentioning

confidence: 99%

Systematic impacts of chronic unpredictable mild stress on metabolomics in rats

Geng

Guo

Wang³

et al. 2020

Sci Rep

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“…Metabolomics is a top-down systems biology approach for studying the metabolic responses of living systems to genetic or environmental stimuli ( 14 , 15 ). It has been increasingly used to diagnose diseases, in pharmacology/toxicology studies, and for the identification of biomarkers ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

Chronic Stress Disturbs Metabolome of Blood Plasma and Urine in Diabetic Rats

Ren

Yang

et al. 2018

Front. Psychiatry

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About 30% of diabetes patients suffer from varying degrees of depression. Diabetes itself is associated with abnormal carbohydrate and energy metabolism. Whether chronic stress-induced depression-like behavior impacts the metabolome of blood plasma and urine in diabetes is not clear. This study aimed to investigate the effect of chronic stress on metabolome of plasma and urine in spontaneously diabetic Goto-Kakizaki (GK) rats. The GK rats were subjected to 8 weeks' chronic unpredictable mild stress (CUMS) to induce depression-like behavior. Metabolome analysis of blood plasma and urine using liquid chromatography mass spectrometry (LC/MS) was performed. Multivariate data analysis was used to evaluate the data. Behavior and biochemical assay confirmed the successful establishment of CUMS-induced depression-like behavior model in rats. Disturbance of 20 plasma metabolites and 16 urine metabolites were altered in CUMS-induced depression GK rats as compared to control ones. These disturbed metabolites were involved in fatty acid metabolism, sphingolipid metabolism, phenylalanine metabolism, citrate cycle, glycolysis, glutathione metabolism, and nicotinate and nicotinamide metabolism. This study suggest that chronic stress-induced depression-like behavior may further disturb diabetes-itself energy metabolome. The plasma and urine lipid metabolites monitoring may be useful for early detection of depression in patients with diabetes mellitus.

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“…Moreover, chronic stress is a well-known risk factor for the development of obesity and metabolic syndrome ( 6 , 7 ). Animal studies further support the hypothesis that chronic stress induces ( 8 ) and aggravates ( 9 , 10 ) liver injury, causes hepatic oxidative stress ( 11 , 12 ) and insulin resistance ( 13 ), alters hepatic metabolism and gene transcription ( 14 ), and disrupts the regulation of lipid synthesis ( 15 ).…”

Section: Introductionmentioning

confidence: 66%

Chronic Psychosocial Stress in Mice Is Associated With Increased Acid Sphingomyelinase Activity in Liver and Serum and With Hepatic C16:0-Ceramide Accumulation

et al. 2018

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Chronic psychosocial stress adversely affects human morbidity and is a risk factor for inflammatory disorders, liver diseases, obesity, metabolic syndrome, and major depressive disorder (MDD). In recent studies, we found an association of MDD with an increase of acid sphingomyelinase (ASM) activity. Thus, we asked whether chronic psychosocial stress as a detrimental factor contributing to the emergence of MDD would also affect ASM activity and sphingolipid (SL) metabolism. To induce chronic psychosocial stress in male mice we employed the chronic subordinate colony housing (CSC) paradigm and compared them to non-stressed single housed control (SHC) mice. We determined Asm activity in liver and serum, hepatic SL concentrations as well as hepatic mRNA expression of genes involved in SL metabolism. We found that hepatic Asm activity was increased by 28% (P = 0.006) and secretory Asm activity by 47% (P = 0.002) in stressed mice. C16:0-Cer was increased by 40% (P = 0.008). Gene expression analysis further revealed an increased expression of tumor necrosis factor (TNF)-α (P = 0.009) and of several genes involved in SL metabolism (Cers5, P = 0.028; Cers6, P = 0.045; Gba, P = 0.049; Gba2, P = 0.030; Ormdl2, P = 0.034; Smpdl3B; P = 0.013). Our data thus provides first evidence that chronic psychosocial stress, at least in mice, induces alterations in SL metabolism, which in turn might be involved in mediating the adverse health effects of chronic psychosocial stress and peripheral changes occurring in mood disorders.

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Chronic unpredictive mild stress leads to altered hepatic metabolic profile and gene expression

Cited by 61 publications

References 55 publications

Systematic impacts of chronic unpredictable mild stress on metabolomics in rats

Systematic impacts of chronic unpredictable mild stress on metabolomics in rats

Chronic Stress Disturbs Metabolome of Blood Plasma and Urine in Diabetic Rats

Chronic Psychosocial Stress in Mice Is Associated With Increased Acid Sphingomyelinase Activity in Liver and Serum and With Hepatic C16:0-Ceramide Accumulation

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