scholarly journals Taurine Reprograms Mammary-Gland Metabolism and Alleviates Inflammation Induced by Streptococcus uberis in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Riguo Lan ◽  
Zhixin Wan ◽  
Yuanyuan Xu ◽  
Zhenglei Wang ◽  
Shaodong Fu ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Metabolic Diseases ◽  
Inflammatory Responses ◽  
Mammary Glands ◽  
Metabolic Reprogramming ◽  
Cellular Damage ◽  
Economic Losses ◽  
Metabolic Dysfunction ◽  
Metabolic Homeostasis ◽  
Streptococcus Uberis

Streptococcus uberis (S. uberis) is an important pathogen causing mastitis, which causes continuous inflammation and dysfunction of mammary glands and leads to enormous economic losses. Most research on infection continues to be microbial metabolism-centric, and many overlook the fact that pathogens require energy from host. Mouse is a common animal model for studying bovine mastitis. In this perspective, we uncover metabolic reprogramming during host immune responses is associated with infection-driven inflammation, particularly when caused by intracellular bacteria. Taurine, a metabolic regulator, has been shown to effectively ameliorate metabolic diseases. We evaluated the role of taurine in the metabolic regulation of S. uberis-induced mastitis. Metabolic profiling indicates that S. uberis exposure triggers inflammation and metabolic dysfunction of mammary glands and mammary epithelial cells (the main functional cells in mammary glands). Challenge with S. uberis upregulates glycolysis and oxidative phosphorylation in MECs. Pretreatment with taurine restores metabolic homeostasis, reverses metabolic dysfunction by decrease of lipid, amino acid and especially energy disturbance in the infectious context, and alleviates excessive inflammatory responses. These outcomes depend on taurine-mediated activation of the AMPK–mTOR pathway, which inhibits the over activation of inflammatory responses and alleviates cellular damage. Thus, metabolic homeostasis is essential for reducing inflammation. Metabolic modulation can be used as a prophylactic strategy against mastitis.

scholarly journals Taurine reprograms mammary-gland metabolism and alleviates inflammation induced by Streptococcus uberis

2021 ◽  
Author(s):  
Riguo Lan ◽  
Zhixin Wan ◽  
Yuanyuan Xu ◽  
Zhenglei Wang ◽  
Shaodong Fu ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Metabolic Regulation ◽  
Inflammatory Responses ◽  
Mammary Epithelial Cells ◽  
Mammary Glands ◽  
Mammary Epithelial ◽  
Economic Losses ◽  
Intracellular Bacteria ◽  
Metabolic Dysfunction ◽  
Streptococcus Uberis

Abstract Streptococcus uberis (S. uberis) is an important pathogen causing mastitis,which causes continuous inflammation and dysfunction of mammary glands and leads to enormous economic losses. Most research on infection continues to be microbial metabolism-centric, and many overlook the fact that pathogens require energy from host. In this perspective, we uncover metabolic reprogramming during host immune responses is associated with infection-driven inflammation, particularly when caused by intracellular bacteria. Taurine, a metabolic regulator, has been shown to effectively ameliorate metabolic diseases. We evaluated the role of taurine in the metabolic regulation of S. uberis-induced mastitis. Metabolic profiling indicates that S. uberis exposure triggers inflammation and metabolic dysfunction of msmmary glands and mammary epithelial cells (MECs, the main functional cells in mammary glands). Challenge with S. uberis upregulates glycolysis and oxidative phosphorylation in MECs. Pretreatment with taurine restores metabolic homeostasis, reverses metabolic dysfunction by decrease of lipid, amino acid and especially energy disturbance in the infectious context, and alleviates excessive inflammatory responses. These outcomes depend on taurine-mediated activation of the AMPK–mTOR pathway, which inhibits the over activation of inflammatory responses and alleviates cellular damage. Thus, metabolic homeostasis is essential for reducing inflammation. Metabolic modulation can be used as a prophylactic strategy against mastitis. IMPORTANCE: Mastitis, especially caused by Streptococcus uberis, induces continuous inflammation and dysfunction of mammary glands, leading to enormous economic losses in dairy industry. Mammary epithelial cells (MECs) are mammary gland-resident major functional cells which occupy a significant role in maintaining homeostasis in mammary glands. MECs can adopt an inflammatory trending in response to S. uberis infection and try to clear these intracellular bacteria. Researchers at Nanjing Agricultural University in China found that S. uberis induces MECs acute inflammation caused by metabolic dysregulation, that is, increased oxidative phosphorylation (OXPHOS) and glycolysis. However, taurine pretreatment can enhance metabolic fitness and anti-inflammatory activity. As a potential therapy, metabolic regulation with taurine restored MECs homeostasis and reduced excessive inflammation. The findings suggest that modulating MECS metabolism might be a new therapeutic strategy for mastitis as well as other bacterial infections.

scholarly journals An AMPK-dependent, non-canonical p53 pathway plays a key role in adipocyte metabolic reprogramming

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Hong Wang ◽  
Xueping Wan ◽  
Paul F Pilch ◽  
Leif W Ellisen ◽  
Susan K Fried ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
P53 Protein ◽  
Metabolic Reprogramming ◽  
Metabolic Dysfunction ◽  
Acid Lipase ◽  
P53 Expression ◽  
Knockout Mouse Model ◽  
Amp Activated Protein Kinase ◽  
Transcriptional Target

It has been known adipocytes increase p53 expression and activity in obesity, however, only canonical p53 functions (i.e. senescence and apoptosis) are attributed to inflammation-associated metabolic phenotypes. Whether or not p53 is directly involved in mature adipocyte metabolic regulation remains unclear. Here we show p53 protein expression can be up-regulated in adipocytes by nutrient starvation without activating cell senescence, apoptosis, or a death-related p53 canonical pathway. Inducing the loss of p53 in mature adipocytes significantly reprograms energy metabolism and this effect is primarily mediated through a AMP-activated protein kinase (AMPK) pathway and a novel downstream transcriptional target, lysosomal acid lipase (LAL). The pathophysiological relevance is further demonstrated in a conditional and adipocyte-specific p53 knockout mouse model. Overall, these data support a non-canonical p53 function in the regulation of adipocyte energy homeostasis and indicate that the dysregulation of this pathway may be involved in developing metabolic dysfunction in obesity.

scholarly journals Amino Acid Sensing in Metabolic Homeostasis and Health

2020 ◽  
Author(s):  
Xiaoming Hu ◽  
Feifan Guo
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Metabolic Regulation ◽  
Metabolic Diseases ◽  
Nutrient Sensing ◽  
The Body ◽  
Bioactive Molecules ◽  
Metabolic Homeostasis ◽  
Amino Acid Availability ◽  
Amino Acid Sensing

Abstract Sensing and responding to changes in nutrient levels, including those of glucose, lipids, and amino acids, by the body is necessary for survival. Accordingly, perturbations in nutrient sensing are tightly linked with human pathologies, particularly metabolic diseases such as obesity, type 2 diabetes mellitus, and other complications of metabolic syndromes. The conventional view is that amino acids are fundamental elements for protein and peptide synthesis, while recent studies have revealed that amino acids are also important bioactive molecules that play key roles in signaling pathways and metabolic regulation. Different pathways that sense intracellular and extracellular levels of amino acids are integrated and coordinated at the organismal level, and, together, these pathways maintain whole metabolic homeostasis. In this review, we discuss the studies describing how important sensing signals respond to amino acid availability and how these sensing mechanisms modulate metabolic processes, including energy, glucose, and lipid metabolism. We further discuss whether dysregulation of amino acid sensing signals can be targeted to promote metabolic disorders, and discuss how to translate these mechanisms to treat human diseases. This review will help to enhance our overall understanding of the correlation between amino acid sensing and metabolic homeostasis, which have important implications for human health.

scholarly journals Metabolic reprogramming in pulmonary arterial hypertension: is it a cancer-like disease?

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
C Ferreira ◽  
M Abreu ◽  
G Castro ◽  
L Goncalves ◽  
R Baptista ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Cancer Cells ◽  
Inflammatory Responses ◽  
Aerobic Glycolysis ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Acid Oxidation ◽  
Metabolic Dysfunction ◽  
Pulmonary Arterial

Abstract Background Idiopathic pulmonary arterial hypertension (iPAH) is a rare and chronic disease associated with poor outcomes. Previously considered a disease restricted to the pulmonary circulation, PAH is now being recognized as a systemic disorder that is associated with metabolic dysfunction. The aim of this study is to analyze the metabolic reprogramming in the lung and peripheral blood mononuclear cell (PBMCs) of iPAH patients and explore their potential roles in PAH pathophysiology. Methods Five independent datasets, containing transcriptomic data of human PBMCs (GSE22356 and GSE33463) and lung (GSE48149 GSE113439 and GSE117261) samples, from 139 iPAH patients and 96 healthy controls, were downloaded at the GEO database. In each dataset, the samples were normalized and a pair-wise comparison between control and iPAH samples was performed using limma package, for the R programming language. Genes with a p-value lower than 0.05 were considered differentially expressed between the two groups. A subset of metabolism related genes was selected, and their expression was compared across the datasets. Results Among the 13 genes with differential expression identified, only 10 had a coherent expression across all datasets (Figure 1). Firstly, we report an association with insulin resistance through impairment of PI3K signaling in iPAH patients, by expressing lower levels of the heterodimer PIK3CD and regulatory PIK3IP1 and PIKR1 subunits in PBMCs, and by expressing higher levels of its downstream targets in the lung (TBC1D4). However, more extensive metabolic dysfunction was observed. A significant glycolytic shift in the lung and PBMCs was present, as a consequence of deregulation in genes involved in aerobic glycolysis and decreased fatty acid oxidation, namely increased expression of PD1K and lower levels of expression of LDHB. The findings of decreased SLC25A1 protein in both PBMCs and lung suggest impairment of the tricarboxylic acid (TCA) cycle flux in PAH. Additionally, SLC1A5 highlights the involvement of glutamine metabolism and glutaminolysis derangements in PAH. Conversely, SREBP1 is involved in sterol biosynthesis and lower levels in PMBCs results in impaired resolution of inflammatory responses. Finally, although the role of autophagy in iPAH is complex, higher levels of expression of ATG13 in PBMCs and lower levels in the lung confirm autophagy deregulation in iPAH. Interestingly, all the metabolic pathways identified (Figure 2) are hallmarks of the metabolic reprogramming seen in cancer cells, a finding already suggested by the clonal proliferation of pulmonary artery smooth muscle cells described in plexiform lesions. Conclusion Our results provide novel insights into the metabolic regulation in iPAH. Molecularly, these cells exhibit many features common to cancer cells, suggesting the opportunity to exploit therapeutic strategies used in cancer to treat iPAH. FUNDunding Acknowledgement Type of funding sources: None.

scholarly journals Extracellular vesicles in metabolic disease

Diabetologia ◽  
2019 ◽  
Vol 62 (12) ◽  
pp. 2179-2187 ◽  
Author(s):  
Naveed Akbar ◽  
Valerio Azzimato ◽  
Robin P. Choudhury ◽  
Myriam Aouadi
Keyword(s):  
Metabolic Disease ◽  
Extracellular Vesicles ◽  
Metabolic Regulation ◽  
Metabolic Diseases ◽  
Recipient Cell ◽  
Plasma Concentrations ◽  
Parent Cell ◽  
Metabolic Dysfunction

Abstract Extracellular vesicles (EVs) are submicron-sized lipid envelopes that are produced and released from a parent cell and can be taken up by a recipient cell. EVs are capable of mediating cellular signalling by carrying nucleic acids, proteins, lipids and cellular metabolites between cells and organs. Metabolic dysfunction is associated with changes in plasma concentrations of EVs as well as alterations in their EV cargo. Since EVs can act as messengers between parent and recipient cells, they could be involved in cell-to-cell and organ-to-organ communication in metabolic diseases. Recent literature has shown that EVs are produced by cells within metabolic tissues, such as adipose tissue, pancreas, muscle and liver. These vesicles have therefore been proposed as a novel intercellular communication mode in systemic metabolic regulation. In this review, we will describe and discuss the current literature that investigates the role of adipose-derived EVs in the regulation of obesity-associated metabolic disease. We will particularly focus on the EV-dependent communication between adipocytes, the vasculature and immune cells in type 2 diabetes.

scholarly journals NF-κB-Inducing Kinase Rewires Metabolic Homeostasis and Promotes Diet-Induced Obesity

2021 ◽  
Author(s):  
Kathryn M. Pflug ◽  
Dong W. Lee ◽  
Raquel Sitcheran
Keyword(s):  
High Fat Diet ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Metabolic Dysfunction ◽  
Metabolic Homeostasis ◽  
Diet Induced Obesity ◽  
Metabolic Dysregulation ◽  
And Function ◽  
Deficient Mice ◽  
Insulin Insensitivity

AbstractObesity is a predominant risk factor for metabolic syndrome, which refers to a cluster of disorders that include diabetes, cardiovascular disease and fatty liver disease. Obesity and overnutrition are associated with aberrant immune and inflammatory responses resulting in increased local fat deposition, insulin resistance and systemic metabolic dysregulation. Here we show NF-κB-inducing kinase (NIK), a critical regulator of immunity and inflammation has local and systemic effects on metabolic processes. We demonstrate that NIK has NF-κB-independent and -dependent roles on adipose development and function. Independently of noncanonical NF- κB, NIK deficiency regulates mitochondrial spare respiratory capacity (SRC) and proton leak but establishes higher basal oxygen consumption and glycolytic capacity in preadipocytes and ex vivo adipose tissue. In addition, we demonstrate NIK promotes adipogenesis through its role in activation of the noncanonical NF-κB pathway. Strikingly, when challenged with a high fat diet, NIK deficient mice are protected against diet-induced obesity and insulin insensitivity. Overall, mice lacking NIK exhibit decreased overall fat mass and increased energy expenditure. Our results establish that, through its influences on adipose development, metabolic homeostasis and rewiring, NIK is a driver of pathologies associated with metabolic dysfunction.

scholarly journals Cellular and Exosomal Regulations of Sepsis-Induced Metabolic Alterations

2021 ◽  
Vol 22 (15) ◽  
pp. 8295
Author(s):  
Michael G. Appiah ◽  
Eun Jeong Park ◽  
Yuichi Akama ◽  
Yuki Nakamori ◽  
Eiji Kawamoto ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Immune Cells ◽  
Metabolic Regulation ◽  
Inflammatory Diseases ◽  
Cellular Level ◽  
Multiple Organ ◽  
Metabolic Reprogramming ◽  
Target Cells ◽  
Metabolic Dysfunction ◽  
Metabolic Signaling

Sepsis is a sustained systemic inflammatory condition involving multiple organ failures caused by dysregulated immune response to infections. Sepsis induces substantial changes in energy demands at the cellular level leading to metabolic reprogramming in immune cells and stromal cells. Although sepsis-associated organ dysfunction and mortality have been partly attributed to the initial acute hyperinflammation and immunosuppression precipitated by a dysfunction in innate and adaptive immune responses, the late mortality due to metabolic dysfunction and immune paralysis currently represent the major problem in clinics. It is becoming increasingly recognized that intertissue and/or intercellular metabolic crosstalk via endocrine factors modulates maintenance of homeostasis, and pathological events in sepsis and other inflammatory diseases. Exosomes have emerged as a novel means of intercellular communication in the regulation of cellular metabolism, owing to their capacity to transfer bioactive payloads such as proteins, lipids, and nucleic acids to their target cells. Recent evidence demonstrates transfer of intact metabolic intermediates from cancer-associated fibroblasts via exosomes to modify metabolic signaling in recipient cells and promote cancer progression. Here, we review the metabolic regulation of endothelial cells and immune cells in sepsis and highlight the role of exosomes as mediators of cellular metabolic signaling in sepsis.

scholarly journals Flavonoids: Nutraceuticals for Rheumatic Diseases via Targeting of Inflammasome Activation

2021 ◽  
Vol 22 (2) ◽  
pp. 488
Author(s):  
Young-Su Yi
Keyword(s):  
Rheumatic Diseases ◽  
Fruits And Vegetables ◽  
Inflammatory Responses ◽  
Protein Complexes ◽  
Cellular Damage ◽  
Inflammatory Rheumatic Diseases ◽  
Inflammasome Activation ◽  
Central Feature ◽  
Inflammatory Protein ◽  
Anti Inflammatory

Inflammation, an innate immune response that prevents cellular damage caused by pathogens, consists of two successive mechanisms, namely priming and triggering. While priming is an inflammation-preparation step, triggering is an inflammation-activation step, and the central feature of triggering is the activation of inflammasomes and intracellular inflammatory protein complexes. Flavonoids are natural phenolic compounds predominantly present in plants, fruits, and vegetables and are known to possess strong anti-inflammatory activities. The anti-inflammatory activity of flavonoids has long been demonstrated, with the main focus on the priming mechanisms, while increasing numbers of recent studies have redirected the research focus on the triggering step, and studies have reported that flavonoids inhibit inflammatory responses and diseases by targeting inflammasome activation. Rheumatic diseases are systemic inflammatory and autoimmune diseases that primarily affect joints and connective tissues, and they are associated with numerous deleterious effects. Here, we discuss the emerging literature on the ameliorative role of flavonoids targeting inflammasome activation in inflammatory rheumatic diseases.

scholarly journals Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jennifer K. Dowling ◽  
Remsha Afzal ◽  
Linden J. Gearing ◽  
Mariana P. Cervantes-Silva ◽  
Stephanie Annett ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Mitochondrial Dynamics ◽  
Interleukin 10 ◽  
Metabolic Reprogramming ◽  
In Vivo Model ◽  
Macrophage Polarisation ◽  
Inflammatory Status ◽  
Inflammatory Macrophages

AbstractMitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2−/− mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell.

scholarly journals Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)—A Condition Associated with Heightened Sympathetic Activation

2021 ◽  
Vol 22 (8) ◽  
pp. 4241
Author(s):  
Revathy Carnagarin ◽  
Kearney Tan ◽  
Leon Adams ◽  
Vance B. Matthews ◽  
Marcio G. Kiuchi ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Metabolic Diseases ◽  
Treatment Strategies ◽  
Adverse Outcomes ◽  
Metabolic Dysfunction ◽  
Sympathetic Activation ◽  
Beneficial Effects ◽  
Adverse Health Outcomes

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease affecting a quarter of the global population and is often associated with adverse health outcomes. The increasing prevalence of MAFLD occurs in parallel to that of metabolic syndrome (MetS), which in fact plays a major role in driving the perturbations of cardiometabolic homeostasis. However, the mechanisms underpinning the pathogenesis of MAFLD are incompletely understood. Compelling evidence from animal and human studies suggest that heightened activation of the sympathetic nervous system is a key contributor to the development of MAFLD. Indeed, common treatment strategies for metabolic diseases such as diet and exercise to induce weight loss have been shown to exert their beneficial effects at least in part through the associated sympathetic inhibition. Furthermore, pharmacological and device-based approaches to reduce sympathetic activation have been demonstrated to improve the metabolic alterations frequently present in patients with obesity, MetSand diabetes. Currently available evidence, while still limited, suggests that sympathetic activation is of specific relevance in the pathogenesis of MAFLD and consequentially may offer an attractive therapeutic target to attenuate the adverse outcomes associated with MAFLD.

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