Integrating Metabolism and Immunity | EK16

Jan 25, 2021 ‐ Jan 28, 2021



Sessions

Characterizing the cystine/glutamate antiporter system xC in the context of islet function.

Jan 25, 2021 12:00am ‐ Jan 25, 2021 12:00am

Characterizing the cystine/glutamate antiporter system xC in the context of islet function. Axel de Baat, Leila Rachid, Helene Mereau Adriano Fontana, Marianne Boeni-Schnetzler, Marc Donath. Clinic of Endocrinology, Diabetes and Metabolism University Hospital Basel, Basel, Switzerland, and Department of Biomedicine, University of Basel, Basel, Switzerland. Hyperglycemia associated redox stress is a major contributor to the diabetes. Due to the commitment of beta cells to oxidative phosphorylation in order to function as accurate glucose sensors, beta cells are especially vulnerable to redox stress. When cells experience redox stress, the expression of glutamate cystine antiporter system xC is upregulated to increase the uptake of the sulphur amino acid cystine in exchange for glutamate. This phenomenon is especially pronounced on immune cells. Cystine is subsequently reduced and incorporated into anti-oxidants such as glutathione, these anti-oxidants are a means of crosstalk between immune and beta cells. In this project mice lacking the gene encoding the critical subunit Slc7a11 of system xC were metabolically phenotyped and have been found to exhibit reduced insulin secretion both in vitro and in vivo. Current work is focused on elucidating the mechanism and source of the impaired insulin secretion, using cre-specific expression models. This project will contribute to the understanding of cystine in islet and immune metabolism and could create a basis for redox oriented strategies to maintain beta cell mass and improve immune function in the context of diabetes.

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Therapeutic manipulation of glutamine metabolism reduce HSV-1 induced pathological lesions

Jan 25, 2021 12:00am ‐ Jan 25, 2021 12:00am

Therapeutic manipulation of glutamine metabolism reduce HSV-1 induced pathological lesions Authors name and their affiliations- Deepak Sumbria, Engin Berber and Barry T Rouse- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, TN, 37996, USA Engin Berber- Department of Virology, Faculty of Veterinary Medicine, Erciyes University, Turkey Abstract- Ocular infection, with herpes simplex virus can result in a vision- impairing inflammatory reaction largely orchestrated by pro-inflammatory CD4 T cells. The severity of lesions can be limited if the balance of cell types involved is changed to increase the representation of regulatory T cells and M2 mononuclear cells. This reshaping might be achieved by exploiting differences in the major metabolic pathways employed by cells with different functions. In this report we investigate if the differential requirements for glutamine by cell types can be exploited to minimize the severity of ocular inflammatory reactions. We blocked glutamine by injecting intraperitoneally low dose (0.3 mg/kg) of 6-Diazo-5-oxo-L-norleucine (DON) from 6th until day 15th post infection by HSV-1. The corneal levels of CD4 Th1, Th17 T cells, neutrophils and macrophages was reduced in the DON treated group but the frequency of Treg was increased. In the trigeminal ganglion (TG), decreased levels of CD4 Th1, neutrophils and macrophages was observed. Reduced number of CD4 Th1, Th17 T cells, neutrophils and macrophages was also evident in the drainage lymph node (DLN) and in the DLN an increase in the ratio of T regulatory (Treg) to Th1 and Th17 cells was evident. The addition of DON in cultures to induce CD4 T cell subsets in-vitro reduced the magnitude of induced Th17 responses but not Th1 cells. However, Treg induction expanded. Glutamine metabolism was also shown relevant for the maintenance of herpesvirus latency. Thus when TG from infected mice were culture in vitro, a procedure that results in reactivation from latency, inhibiting glutamine metabolism significantly delayed the reactivation process. Taken together, our result indicates that glutamine metabolism is necessary for the full expression of an antiviral inflammatory response and is also needed for the maintenance of herpes virus latency.

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The Contribution of Arachidonic Acid Metabolites EETs to Inflammation in Obesity

Jan 25, 2021 12:00am ‐ Jan 25, 2021 12:00am

The Contribution of Arachidonic Acid Metabolites EETs to Inflammation in Obesity Mona Mashayekhi1, Celestine N. Wanjalla1, Christian M. Warren1, Joshua D. Simmons1, Samuel S. Bailin1, Curtis L. Gabriel1, Spyros A. Kalams1, John R. Koethe1, Nancy J. Brown2, J. Matthew Luther1 1Vanderbilt University Medical Center, Nashville, TN; 2Yale School of Medicine, New Haven, CT Background: Obesity is associated with increased prevalence of type 2 diabetes and cardiovascular disease (CVD). Adipose tissue (AT) contains a complex immune environment and is a central contributor to heightened systemic inflammation in obese persons.1 Increased chronic inflammation in obesity contributes to metabolic disease by increasing insulin resistance, and to CVD by causing an atherogenic dyslipidemia and increasing endothelial cell dysfunction and activation.2 Despite these links between inflammation and cardiometabolic disease in obesity, there are no current targeted therapies to prevent or reverse chronic inflammation in AT. Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules that act as potent vasodilators and promote sodium excretion in the kidney. Increasing EETs in rodents protects against hypertension and endothelial dysfunction. In humans, circulating EETs correlate with insulin sensitivity and are decreased in individuals with insulin resistance.3 EETs also decrease the inflammatory response to obesity in animal models, but the effect of EETs on inflammation in humans is currently unknown. EETs are hydrolyzed to less active forms by the enzyme soluble epoxide hydrolase (sEH), and we hypothesized that pharmacologic sEH inhibition with a specific inhibitor GSK2256294 (GSK) in obese patients would decrease AT inflammation. Methods: Thirty-four obese prediabetic individuals were treated with placebo and GSK in a crossover design (NCT03486223). Participants had a seven-week washout in between drugs, and the order of drug was randomized and blinded. In a subgroup of patients, we collected subcutaneous AT by liposuction and characterized T cell phenotypes by flow cytometry (N=7 paired samples). Results: GSK decreased sEH activity in plasma (47.3% vs placebo; P=0.008) and in AT (58.8% vs placebo; P=0.002). GSK also decreased serum F2-isoprostanes (P=0.03), which are markers of oxidative damage and inflammation. In seven paired AT samples stimulated in vitro, T helper (Th) 1 cells producing the pro-inflammatory cytokine IFNγ were reduced by treatment with GSK as compared with placebo (% of total lymphocytes: Placebo 13.6% ± 6.9, GSK 11.0% ± 5.6, P=0.03 Wilcoxon Signed Rank). In this small sample, we did not detect significant differences in the percentage of other IFNγ-producing cells after treatment with GSK (IFNγ+ natural killer: Placebo 19.0% ± 9.0, GSK 13.3% ± 4.9, P=0.18; IFNγ+ CD8: Placebo 12.0 ± 11.0, GSK 6.1 ± 4.6, P=0.61). In addition, we did not detect any change in Th17, Th2, or regulatory T cells. Conclusions: In a pilot study of seven individuals treated with placebo or an sEH inhibitor, we found that the sEH inhibitor decreased pro-inflammatory Th1 cells as compared with placebo in matched AT samples. Understanding the contribution of the EET/sEH pathway to inflammation in obesity could lead to new strategies to modulate AT and systemic inflammation and reduce the risk of CVD. References: 1. Exley MA, Hand L, O'Shea D, Lynch L. Interplay between the immune system and adipose tissue in obesity. J Endocrinol. 2014;223(2):R41-48. 2. Wang Z, Nakayama T. Inflammation, a link between obesity and cardiovascular disease. Mediators Inflamm. 2010;2010:535918. 3. Gangadhariah MH, Dieckmann BW, Lantier L, et al. Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans. Diabetologia. 2017;60(6):1066-1075. Funding sources: T32DK007061, 5UL1TR002243-03, R01DK117875, R01DK112262, AHA 17SFRN33520017, Vanderbilt Faculty Research Scholars Program

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Detrimental and beneficial consequences of metabolic manipulations in the herpes simplex encephalitis (HSE) and blood brain barrier (BBB) integrity

Jan 25, 2021 12:00am ‐ Jan 25, 2021 12:00am

Detrimental and beneficial consequences of metabolic manipulations in the herpes simplex encephalitis (HSE) and blood brain barrier (BBB) integrity Detrimental and beneficial consequences of metabolic manipulations in the herpes simplex encephalitis (HSE) and blood brain barrier (BBB) integrity Engin Berber 1,2 Deepak Sumbria 1 Barry T. Rouse 1 1 Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA 2 Department of Virology, Faculty of Veterinary Medicine, Erciyes University, Kayseri, Turkey HSV-1 is often associated with development of stromal keratitis (SK) and angiogenesis which are inflammatory events orchestrated mainly by proinflammatory T cells. HSV-1 can also cause encephalitis where immune cells enter the brain likely by crossing the BBB. We wished to measure some metabolic events required for BBB function with the view that modulating such events might provide an approach to prevent encephalitis. BBB permeability was significantly increased in the 2DG (competitor and inhibitor of glucose) given group when compared to HSV-1 infected animals. BBB leakage was confirmed by measuring the escape from the blood vasculature of injected Evans blue dye in Balb/C mice. In mice that received 2DG, animals expressed higher BBB permeability which was demonstrated by leakage of Evans blue with extravasation study. 2DG treated mice also developed diminished Th1 but not Th17 T cells response in the brain. The trigeminal ganglions (TGs) were removed from latently HSV infected mice and cultured in-vitro. Virus reactivation occurred more rapidly in 2DG added TGs when compared to untreated TGs. Virus replication increased the expression of IL-1b and IL-23 in brain microenvironment as well as when compared to control group. IL-1b and IL-23 are also driving cytokines that responsible the Th17 development. Besides 2DG addition to Th17 in-vitro induction culture was increased the IL-17A expression in Th17 cells. Findings from this study revealed that virus induced pro-inflammatory environment which stimulated brain accumulated naïve T cells to become IL-17A expressing Th17 cell phenotype in response to 2DG treatment. Balb/C mice were given metformin to inhibit gluconeogenesis during the acute infection of HSV-1. Mice were treated with metformin reduced Th17 response in the draining lymph nodes by in-vivo and dose dependently by in-vitro induction culture. Animals treated with metformin diminished the facial lesions and failed the encephalitis. Our results indicate the expression of herpetic encephalitis depend on the permeability of BBB along with appropriate generation of inflammatory T cells.

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Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques

Jan 25, 2021 12:00am ‐ Jan 25, 2021 12:00am

Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques Jeroen Baardman1,#, Sanne G.S. Verberk2,#, Saskia van der Velden1, Marion J.J. Gijbels1,3, Cindy P.P.A. van Roomen1, Judith C. Sluimer3,4, Jelle Y. Broos5,6, Guillermo R. Griffith1, Koen H.M. Prange1, Michel van Weeghel7,8, Soufyan Lakbir2,9, Douwe Molenaar9, Elisa Meinster2, Annette E. Neele1, Gijs Kooij5, Helga E. de Vries5, Esther Lutgens1,10, Kathryn E. Wellen11, Menno P.J. de Winther1,10,# & Jan Van den Bossche1,2,# 1Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands 2Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands 3Department of Pathology and Molecular Genetics, CARIM, Maastricht University, Maastricht, Netherlands 4 BHF Centre for Cardiovascular Sciences (CVS), University of Edinburgh, Edinburgh, UK 5Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, MS Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands 6 Leiden University Medical Center, Center for Proteomics & Metabolomics, Leiden, Netherlands 7Laboratory Genetic Metabolic Diseases, Amsterdam Cardiovascular sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands 8Core Facility Metabolomics, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands 9Systems Bioinformatics, Vrije Universiteit Amsterdam, Amsterdam, Netherlands 10Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University, Munich, Germany 11Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA #These authors contributed equally. Macrophages represent a major immune cell population in atherosclerotic plaques and play central role in the progression of this lipid-driven chronic inflammatory disease. Targeting immunometabolism is proposed as a strategy to revert aberrant macrophage activation to improve disease outcome. Here, we show ATP citrate lyase (Acly) to be activated in inflammatory macrophages and human atherosclerotic plaques. We demonstrate that myeloid Acly deficiency induces a stable plaque phenotype characterized by increased collagen deposition and fibrous cap thickness, along with a smaller necrotic core. In-depth functional, lipidomic, and transcriptional characterization indicate deregulated fatty acid and cholesterol biosynthesis and reduced liver X receptor activation within the macrophages in vitro. This results in macrophages that are more prone to undergo apoptosis, whilst maintaining their capacity to phagocytose apoptotic cells. Together, our results indicate that targeting macrophage metabolism improves atherosclerosis outcome and we reveal Acly as a promising therapeutic target to stabilize atherosclerotic plaques.

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Inhibition of acetate metabolism enhances host anti-tumor immunity.

Jan 25, 2021 12:00am ‐ Jan 25, 2021 12:00am

Inhibition of acetate metabolism enhances host anti-tumor immunity. Katelyn D. Miller, Katherine Pniewski, Seamus O’Connor, Sara Papp, & Zachary T. Schug. The Wistar Institute, Philadelphia, PA. Acquired resistance to anti-cancer therapy is an enormous challenge. One of the main factors contributing to therapy resistance is tumor hypoxia. The stress imposed by tumor hypoxia forces cancer cells to adapt in order to survive. These metabolically adapted cancer cells are often more invasive, more malignant, and more drug resistant. As a result, the cancer cells that emerge from hypoxic tumor regions are more likely to cause patient relapse. There is therefore a critical need to understand the mechanisms that promote the survival of cancer cells in stressful tumor microenvironments. We previously showed that the enzyme acetyl-CoA synthetase 2 (ACSS2) supports cancer cell metabolism in hypoxic and nutrient-depleted environments. ACSS2 endows cancer cells with the ability to use acetate as an alternative nutrient source to drive acetyl-CoA biosynthesis during stress and genetic silencing of ACSS2 inhibits human breast tumor growth in xenograft models. Given the important role of acetate metabolism in breast cancer we expanded upon our studies by using immunocompetent hosts and syngeneic mouse tumor models. Our results revealed a previously unknown role of ACSS2 in modulating host anti-tumor immunity. We found that ACSS2 deficient tumors are unable to grow when host immunity is intact. Depletion of host immunity (T cells) using genetic or pharmacological models rescues the growth of ACSS2 deficient tumors. Pharmacological inhibition of ACSS2 in tumors in vivo displayed gene signatures associated immune infiltration and activation within the tumor microenvironment. Moreover, ACSS2 deficient breast cancer cell lines show a marked susceptibility to T cell killing in vitro. Our current research demonstrates a novel role for acetate metabolism in supporting tumor extrinsic modulation of host anti-tumor immunity. Since activation of acetate metabolism via ACSS2 is a near universal hallmark of metabolically stressed cancer cells, targeting acetate metabolism represents an unrealized opportunity with significant upside for improving current therapeutic modalities in breast cancer.

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Lactate metabolism in the control of microglial function

Jan 25, 2021 12:00am ‐ Jan 25, 2021 12:00am

Lactate metabolism in the control of microglial function Katia Monsorno (1) - Kyllian Ginggen (1)- Arnaud L Lalive (2) - Anna Tchenio (2) - Manuel Mameli (2) - Rosa Chiara Paolicelli (1) (1) University of Lausanne, Department of Biomedical Sciences, Lausanne, Switzerland (2) University of Lausanne, Department of Fundamental Neurosciences, Lausanne, Switzerland Microglia are the tissue-resident macrophages of the brain. Beyond their innate immunity roles, they are implicated in a variety of physiological processes required for proper brain development, including removal of apoptotic neurons and remodeling of synapses. Not surprisingly, dysregulation of microglial function is linked with the onset of neuropathology. Accumulating evidences point towards the involvement of metabolism and differential substrates catabolism in the regulation of immune cells, including microglia. In particular, lactate, which sustains brain energetics and increases in response to neuronal activity, was shown to regulate inflammatory responses in peripheral immune cells. However, the physiological role for lactate in modulating microglial function is still unexplored. In order to address this question, we generated a microglia-specific conditional knock out (cKO) mouse model for the monocarboxylate transporter 4 (MCT4), which we describe to be specifically upregulated in microglia upon lactate exposure and which is known to be implicated in lactate transport. We analyzed key microglia features during postnatal development, and we found alterations in microglial density and in CD68+ phagocytic structures in the hippocampus of two-week-old cKO mice. This was associated with alterations in presynaptic markers and changes in excitatory post-synaptic currents, indicating that microglia-specific depletion of MCT4 is sufficient to considerably affect neuronal development and function. Additionally, adult cKO mice present an anxiety-like phenotype. In summary, this study highlights the importance of microglial metabolism for correct brain maturation, emphasizing how metabolic flexibility, and in particular lactate metabolism, could be functionally coupled to microglial regulation. Given the established role of microglia in neuropathology, a better mechanistic understanding of lactate-dependent modulations may be relevant for targeting microglia in neurodevelopmental diseases.

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Francisella-primed lymphocytes shift toward glycolysis during control of intramacrophage bacterial growth

Jan 25, 2021 12:00am ‐ Jan 25, 2021 12:00am

Francisella-primed lymphocytes shift toward glycolysis during control of intramacrophage bacterial growth Lara Mittereder-1, Karen L. Elkins-1 1-Laboratory of Mucosal Pathogens and Cellular Immunology, DBPAP, CBER, FDA Francisella tularensis is a pathogenic intracellular bacterium that causes tularemia via inhalation and has been classified as an agent of bioterrorism. F. tularensis Live Vaccine Strain (LVS) provides partial protection in animals and humans but is not licensed. To study vaccine mechanisms, we have previously established an in vitro co-culture assay that measures control of intramacrophage bacterial replication by immune T cells as a tool to identify potential correlates of protection against Francisella and to further understand protective T cell responses. Previous work suggested that virulent Francisella infection of mouse macrophages inhibits the metabolic shift from oxidative phosphorylation to glycolysis that is required for appropriate activation. To study the role of metabolic shifts in protective T cell responses, we adapted co-cultures to profile metabolic activities of co-cultures containing both LVS-infected macrophages and splenic or peripheral blood lymphocytes from naïve or LVS-primed mice. Further, we studied activities of separated cell populations. Consistent with previous results, co-cultures containing LVS-primed lymphocytes controlled bacterial replication in macrophages and produced high levels of IFN-gamma and nitric oxide. Compared to co-cultures containing naïve lymphocytes, co-cultures with LVS-primed cells gradually shifted metabolically toward glycolysis and exhibited less aerobic respiration. Similar metabolic differences were observed in cell populations separated after co-culture, suggesting that interactions between infected macrophages and LVS-primed lymphocytes induced metabolic shifts in both populations. Further, LVS-primed lymphocytes exhibited a significant loss of respiratory capacity over time in co-culture, indictive of transition to a T effector state. Taken together, we find that LVS-primed lymphocytes override metabolic dysregulation and are better able to achieve effector status to control bacterial infection compared to naïve lymphocytes. These results support future study exploring the use of metabolic intermediates as potential correlates of protection.

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NETosis in the gut as mediator of the metabolic effects of high fat died-modified microbiota

Jan 25, 2021 12:00am ‐ Jan 25, 2021 12:00am

NETosis in the gut as mediator of the metabolic effects of high fat died-modified microbiota Ludovica Migliozzi1,2, Stefano Ciciliot2, Valentina Scattolini3, Serena Tedesco1,2, Roberta Cappellari1,2, Mattia Albiero1,2 and Gian Paolo Fadini1,2 1Veneto Institute of Molecular Medicine, Padova, Italy 2Department of Medicine (DIMED), University of Padova, Padova, Italy 3Department of Biology (DiBio), University of Padova, Padova, Italy Introduction. The discovery of metabolic inflammation has been a major achievement in the understanding of type 2 diabetes (T2D) development. Yet, T2D represents a major threat to human health. Metabolic endotoxemia, i.e. the elevation in circulating concentrations of lypopolysaccharide, is the result of gut dysbiosis and increased intestinal permeability. The role of some immune cells in this process has been investigated, but neutrophils are largely neglected. In response to bacterial challenge, neutrophils cast NETs (neutrophil extracellular traps), composed by sticky chromatin filaments decorated with granule enzymes, and eventually die by NETosis. Since the microbiota can prime neutrophils to undergo NETosis, we aimed to investigate whether NETosis could bridge the effects of a diabetogenic gut flora toward systemic metabolism Methods and results. To blunt NETs release in vivo, we generated a hematopoietic-restricted Padi4 Knock-out (Padi4KO) mouse by crossing Vav1-Cre mice with Padi4fl/fl mice. Padi4 is peptidyl arginine deiminase required for the release of NETs. After 12 weeks of HFD (60% of calories from fat, 21% carbohydrates and 19% from proteins) both Padi4KO and control mice became equally obese. Intraperitoneal Glucose Tolerant Test (ipGTT, 1g/kg) and intraperitoneal Insulin Tolerant Test (ipITT, 0.75 U/kg) showed that Padi4KO mice were protected from the development of glucose intolerance and insulin resistance after HFD. Furthermore, Padi4KO mice showed less recruitment of gut neutrophils, and were completely protected from the surge in circulating LPS induced by HFD and the increase in intestinal permeability, assessed by FITC-dextran permeability assay in vivo. The analysis of intestinal barrier integrity showed a deranged tight-junctions profile in HFD-fed control mice, but not in Padi4KO mice. To perform gut flora transplantation, we ablated the endogenous flora of control and Padi4KO mice with a cocktail of broad-spectrum of antibiotics. Control mice transplanted with a HFD flora became dysmetabolic, even on a chow diet. Interestingly, Padi4KO mice transplanted with an HFD flora were completely protected from the onset of dysmetabolism, as assessed by ipGTT. Conclusions. Our results showed for the first time that NETosis is involved in the pathogenesis of dysmetabolism during the onset of obesity. Mechanistically, we envisage that HFD-modified microbiota promotes the recruitment of neutrophils and triggers NETosis which affect intestinal barrier function. These new data will provide an unprecedented view of the role of neutrophils as mediators of metabolic dysfunction.

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Role of macrophages in regulating stress hormone induced adipogenesis

Jan 25, 2021 12:00am ‐ Jan 25, 2021 12:00am

Role of macrophages in regulating stress hormone induced adipogenesis Raktim Mukherjee*, Dipanjan Guha*,# & Palok Aich* *School of Biological Sciences, National Institute of Science Education and Research (NISER), HBNI, P.O. Bhimpur-Padanpur, Dist. Khurda, Jatni, Odisha 752050, India #Present address: S.N. Bose Innovation Centre, University of Kalyani, Kalyani, West Bengal, India Unrestrained body fat accumulation can result in various metabolic disorders such as Obesity, Type-II diabetes and cardiovascular diseases. Various factors can contribute to the development of metabolic disorders such as unhealthy feeding habit, sedentary life style and psychological stress. Among these, chronic psychological stress has become a salient feature of present-day lifestyle which often acts as a pioneer for metabolic diseases. The effects of stress induced metabolic abnormalities are mainly regulated by primordial stress hormones, which not only augments lipid storage but also attracts several innate immune cells at the site of lipid deposition. This results in chronic mild inflammation, also known as metainflammation. In the present work, we investigated how stress hormones can regulate lipid build-up in murine adipocytes and whether macrophage induced inflammation can augment the process. For this, we treated terminally differentiated murine adipocyte cell line 3T3-L1 with two potent stress hormones, cortisol and serotonin. We found that the said hormones alone and together, gradually augmented lipid storage in differentiated 3T3-L1 cells. The quantity of lipid storage was further enhanced when the cortisol and serotonin treated, differentiated 3T3-L1 cells were co-cultured with murine macrophage RAW264.7 cells. Further, the macrophage cells became gradually pro-inflammatory following this co-culturing from an initial anti-inflammatory phenotype. Our results confirm that stress hormones can potentiate adipogenesis which can be further enhanced by the proximity of immunologically polarized macrophages in murine model. This finding can direct towards using immune modulation as an intervention of metabolic disorders potentiated by chronic stress, following further pre-clinical and clinical studies.

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