bims-aditis Biomed News
on Adipose tissue, inflammation, immunometabolism
Issue of 2022–01–02
eleven papers selected by
Matthew C. Sinton, University of Glasgow
  1. Beige Adipocyte As The Flame Of White Adipose Tissue: Regulation Of Browning And Impact Of Obesity.
  2. Epigenetic Regulators of White Adipocyte Browning.
  3. A systems biology analysis of lipolysis and fatty acid release from adipocytes in vitro and from adipose tissue in vivo.
  4. NAD kinase sustains lipogenesis and mitochondrial metabolismthrough fatty acid synthesis.
  5. Glucocorticoids Coordinate Macrophage Metabolism Through Regulation of the Tricarboxylic Acid Cycle.
  6. The Contribution of Human Herpes Viruses to γδ T Cell Mobilisation in Co-Infections.
  7. IL-17/IL-17 Receptor Pathway-Mediated Inflammatory Response in Apostichopus japonicus Supports the Conserved Functions of Cytokines in Invertebrates.
  8. Circadian Clock Component BMAL1 in the Paraventricular Nucleus Regulates Glucose Metabolism.
  9. Association of IL-9, IL-10, and IL-17 Cytokines With Hepatic Fibrosis in Human Schistosoma mansoni Infection.
  10. The Pyruvate Dehydrogenase Complex in Sepsis: Metabolic Regulation and Targeted Therapy.
  11. Cholesterol metabolism: from lipidomics to immunology.
  1. J Clin Endocrinol Metab. 2021 Dec 30. pii: dgab921. [Epub ahead of print]
    Beige Adipocyte As The Flame Of White Adipose Tissue: Regulation Of Browning And Impact Of Obesity.
    Alev Eroglu Altinova.
      Beige adipocyte, the third and relatively new type of adipocyte, can emerge in white adipose tissue (WAT) under thermogenic stimulations that is termed as browning of WAT. Recent studies suggest that browning of WAT deserves more attention and therapies targeting browning of WAT can be helpful for reducing obesity. Beyond the major inducers of browning, namely cold and β3-adrenergic stimulation, beige adipocytes are affected by several factors, and excess adiposity per se may also influence the browning process. The objective of the present review is to provide an overview of recent clinical and preclinical studies on the hormonal and non-hormonal factors that affect the browning of WAT. This review further focuses on the role of obesity per se on browning process.
    Keywords:  Beige; Beigeing; Brown Adipose Tissue; Browning; Obesity; Thermogenesis
    DOI:  https://doi.org/10.1210/clinem/dgab921
  2. Epigenomes. 2021 Jan 12. pii: 3. [Epub ahead of print]5(1):
    Epigenetic Regulators of White Adipocyte Browning.
    Ravikanth Nanduri.
      Adipocytes play an essential role in maintaining energy homeostasis in mammals. The primary function of white adipose tissue (WAT) is to store energy; for brown adipose tissue (BAT), primary function is to release fats in the form of heat. Dysfunctional or excess WAT can induce metabolic disorders such as dyslipidemia, obesity, and diabetes. Preadipocytes or adipocytes from WAT possess sufficient plasticity as they can transdifferentiate into brown-like beige adipocytes. Studies in both humans and rodents showed that brown and beige adipocytes could improve metabolic health and protect from metabolic disorders. Brown fat requires activation via exposure to cold or β-adrenergic receptor (β-AR) agonists to protect from hypothermia. Considering the fact that the usage of β-AR agonists is still in question with their associated side effects, selective induction of WAT browning is therapeutically important instead of activating of BAT. Hence, a better understanding of the molecular mechanisms governing white adipocyte browning is vital. At the same time, it is also essential to understand the factors that define white adipocyte identity and inhibit white adipocyte browning. This literature review is a comprehensive and focused update on the epigenetic regulators crucial for differentiation and browning of white adipocytes.
    Keywords:  WAT browning; beige adipocytes; epigenetic regulators; white adipocytes
    DOI:  https://doi.org/10.3390/epigenomes5010003
  3. PLoS One. 2021 ;16(12): e0261681
    A systems biology analysis of lipolysis and fatty acid release from adipocytes in vitro and from adipose tissue in vivo.
    William Lövfors, Jona Ekström, Cecilia Jönsson, Peter Strålfors, Gunnar Cedersund, Elin Nyman.
      Lipolysis and the release of fatty acids to supply energy fuel to other organs, such as between meals, during exercise, and starvation, are fundamental functions of the adipose tissue. The intracellular lipolytic pathway in adipocytes is activated by adrenaline and noradrenaline, and inhibited by insulin. Circulating fatty acids are elevated in type 2 diabetic individuals. The mechanisms behind this elevation are not fully known, and to increase the knowledge a link between the systemic circulation and intracellular lipolysis is key. However, data on lipolysis and knowledge from in vitro systems have not been linked to corresponding in vivo data and knowledge in vivo. Here, we use mathematical modelling to provide such a link. We examine mechanisms of insulin action by combining in vivo and in vitro data into an integrated mathematical model that can explain all data. Furthermore, the model can describe independent data not used for training the model. We show the usefulness of the model by simulating new and more challenging experimental setups in silico, e.g. the extracellular concentration of fatty acids during an insulin clamp, and the difference in such simulations between individuals with and without type 2 diabetes. Our work provides a new platform for model-based analysis of adipose tissue lipolysis, under both non-diabetic and type 2 diabetic conditions.
    DOI:  https://doi.org/10.1371/journal.pone.0261681
  4. Cell Rep. 2021 Dec 28. pii: S2211-1247(21)01653-3. [Epub ahead of print]37(13): 110157
    NAD kinase sustains lipogenesis and mitochondrial metabolismthrough fatty acid synthesis.
    Mengyao Xu, Long Ding, Jingjing Liang, Xiao Yang, Yuan Liu, Yingchun Wang, Mei Ding, Xun Huang.
      Lipid storage in fat tissue is important for energy homeostasis and cellular functions. Through RNAi screening in Drosophila fat body, we found that knockdown of a Drosophila NAD kinase (NADK), which phosphorylates NAD to synthesize NADP de novo, causes lipid storage defects. NADK sustains lipogenesis by maintaining the pool of NADPH. Promoting NADPH production rescues the lipid storage defect in the fat body of NADK RNAi animals. Furthermore, NADK and fatty acid synthase 1 (FASN1) regulate mitochondrial mass and function by altering the levels of acetyl-CoA and fatty acids. Reducing the level of acetyl-CoA or increasing the synthesis of cardiolipin (CL), a mitochondrion-specific phospholipid, partially rescues the mitochondrial defects of NADK RNAi. Therefore, NADK- and FASN1-mediated fatty acid synthesis coordinates lipid storage and mitochondrial function.
    Keywords:  Drosophila; FASN; NADK; lipogenesis; mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2021.110157
  5. Mol Metab. 2021 Dec 22. pii: S2212-8778(21)00282-9. [Epub ahead of print] 101424
    Glucocorticoids Coordinate Macrophage Metabolism Through Regulation of the Tricarboxylic Acid Cycle.
    Ulrich Stifel, Eva-Maria Wolfschmitt, Josef Vogt, Ulrich Wachter, Sabine Vettorazzi, Daniel Tews, Melanie Hogg, Fabian Zink, Nora Maria Koll, Sandra Winning, Rémi Mounier, Bénédicte Chazaud, Peter Radermacher, Pamela Fischer-Posovszky, Giorgio Caratti, Jan Tuckermann.
      Glucocorticoids (GCs) are one of the most widely prescribed anti-inflammatory drugs. By acting through their cognate receptor, the glucocorticoid receptor (GR), GCs down-regulate the expression of pro-inflammatory genes, and up-regulate anti-inflammatory genes. Metabolic pathways have recently been identified as key parts of both the inflammatory activation and anti-inflammatory polarization of macrophages, immune cells responsible for acute inflammation and tissue repair. It is currently unknown whether GCs control macrophage metabolism, and if so, to what extent metabolic regulation by GCs confers anti-inflammatory activity. Using transcriptomic and metabolomic profiling of macrophages, we identified GC controlled pathways involved in metabolism, especially in mitochondrial function. Metabolic analyses revealed that GCs repress glycolysis in inflammatory myeloid cells and promote tricarboxylic acid (TCA) cycle flux, promoting succinate metabolism and preventing intracellular accumulation of succinate. Inhibition of ATP synthase attenuated GC induced transcriptional changes, likely through stalling of TCA cycle anaplerosis. We further identified a glycolytic regulatory transcription factor, HIF1α, as regulated by GCs, and as a key regulator of GC responsiveness during inflammatory challenge, further linking metabolism to GC action in macrophages.
    Keywords:  Glucocorticoids; Succinate; TCA Cycle; immunometabolism; macrophage
    DOI:  https://doi.org/10.1016/j.molmet.2021.101424
  6. Viruses. 2021 Nov 26. pii: 2372. [Epub ahead of print]13(12):
    The Contribution of Human Herpes Viruses to γδ T Cell Mobilisation in Co-Infections.
    Fanny Martini, Eric Champagne.
      γδ T cells are activated in viral, bacterial and parasitic infections. Among viruses that promote γδ T cell mobilisation in humans, herpes viruses (HHVs) occupy a particular place since they infect the majority of the human population and persist indefinitely in the organism in a latent state. Thus, other infections should, in most instances, be considered co-infections, and the reactivation of HHV is a serious confounding factor in attributing γδ T cell alterations to a particular pathogen in human diseases. We review here the literature data on γδ T cell mobilisation in HHV infections and co-infections, and discuss the possible contribution of HHVs to γδ alterations observed in various infectious settings. As multiple infections seemingly mobilise overlapping γδ subsets, we also address the concept of possible cross-protection.
    Keywords:  CMV; HHV; co-infections; gamma delta T cells; herpes virus; lymphocytes
    DOI:  https://doi.org/10.3390/v13122372
  7. J Immunol. 2021 Dec 29. pii: ji2100047. [Epub ahead of print]
    IL-17/IL-17 Receptor Pathway-Mediated Inflammatory Response in Apostichopus japonicus Supports the Conserved Functions of Cytokines in Invertebrates.
    Zhimeng Lv, Ming Guo, Xuelin Zhao, Yina Shao, Weiwei Zhang, Chenghua Li.
      Inflammation participates in host defenses against infectious agents and contributes to the pathophysiology of many diseases. IL-17 is a well-known proinflammatory cytokine that contributes to various aspects of inflammation in vertebrates. However, the functional role of invertebrate IL-17 in inflammatory regulation is not well understood. In this study, we first established an inflammatory model in the Vibrio splendidus-challenged sea cucumber Apostichopus japonicus (Echinodermata). Typical inflammatory symptoms, such as increased coelomocyte infiltration, tissue vacuoles, and tissue fractures, were observed in the V. splendidus-infected and diseased tissue of the body wall. Interestingly, A. japonicus IL-17 (AjIL-17) expression in the body wall and coelomocytes was positively correlated with the development of inflammation. The administration of purified recombinant AjIL-17 protein also directly promoted inflammation in A. japonicus Through genome searches and ZDOCK prediction, a novel IL-17R counterpart containing FNIII and hypothetical TIR domains was identified in the sea cucumber genome. Coimmunoprecipitation, far-Western blotting, and laser confocal microscopy confirmed that AjIL-17R could bind AjIL-17. A subsequent cross-linking assay revealed that the AjIL-17 dimer mediates the inflammatory response by the specific binding of dimeric AjIL-17R upon pathogen infection. Moreover, silencing AjIL-17R significantly attenuated the LPS- or exogenous AjIL-17-mediated inflammatory response. Functional analysis revealed that AjIL-17/AjIL-17R modulated inflammatory responses by promoting A. japonicus TRAF6 ubiquitination and p65 nuclear translocation and evenly mediated coelomocyte proliferation and migration. Taken together, our results provide functional evidence that IL-17 is a conserved cytokine in invertebrates and vertebrates associated with inflammatory regulation via the IL-17-IL-17R-TRAF6 axis.
    DOI:  https://doi.org/10.4049/jimmunol.2100047
  8. Nutrients. 2021 Dec 15. pii: 4487. [Epub ahead of print]13(12):
    Circadian Clock Component BMAL1 in the Paraventricular Nucleus Regulates Glucose Metabolism.
    Masanori Nakata, Parmila Kumari, Rika Kita, Nanako Katsui, Yuriko Takeuchi, Tomoki Kawaguchi, Toshiya Yamazaki, Boyang Zhang, Shigeki Shimba, Toshihiko Yada.
      It is suggested that clock genes link the circadian rhythm to glucose and lipid metabolism. In this study, we explored the role of the clock gene Bmal1 in the hypothalamic paraventricular nucleus (PVN) in glucose metabolism. The Sim1-Cre-mediated deletion of Bmal1 markedly reduced insulin secretion, resulting in impaired glucose tolerance. The pancreatic islets' responses to glucose, sulfonylureas (SUs) and arginine vasopressin (AVP) were well maintained. To specify the PVN neuron subpopulation targeted by Bmal1, the expression of neuropeptides was examined. In these knockout (KO) mice, the mRNA expression of Avp in the PVN was selectively decreased, and the plasma AVP concentration was also decreased. However, fasting suppressed Avp expression in both KO and Cre mice. These results demonstrate that PVN BMAL1 maintains Avp expression in the PVN and release to the circulation, possibly providing islet β-cells with more AVP. This action helps enhance insulin release and, consequently, glucose tolerance. In contrast, the circadian variation of Avp expression is regulated by feeding, but not by PVN BMAL1.
    Keywords:  BMAL1; circadian; glucose metabolism; insulin release; paraventricular nucleus; vasopressin
    DOI:  https://doi.org/10.3390/nu13124487
  9. Front Immunol. 2021 ;12 779534
    Association of IL-9, IL-10, and IL-17 Cytokines With Hepatic Fibrosis in Human Schistosoma mansoni Infection.
    Karine Garcez Schuster Franco, Fabio Jorge Ramalho de Amorim, Mário Adriano Santos, Carla Virgínia Vieira Rollemberg, Fabricia Alvisi de Oliveira, Alex Vianey Callado França, Camilla Natália Oliveira Santos, Lucas Sousa Magalhães, Rodrigo Anselmo Cazzaniga, Frederico Santana de Lima, Luciana Benevides, Vanessa Carregaro, João Santana Silva, Hugo Leite de Farias Brito, Daniel Alvarenga Fernandes, Ângela Maria da Silva, Roque Pacheco de Almeida, Márcio Bezerra-Santos, Amélia Ribeiro de Jesus.
      This is a case series study to evaluate immunological markers associated with schistosomiasis advanced fibrosis, including 69 patients from an endemic area from the State of Sergipe and from the Hepatology Service of the University Hospital in Sergipe, Brazil. Hepatic fibrosis was classified based on Niamey protocol for ultrasonography (US). Immune response to Schistosoma mansoni antigens was evaluated by stimulating peripheral blood mononuclear cells (PBMCs) from these patients with either adult worm (SWAP-10 μg/ml) or egg (SEA-10 μg/ml) antigens or purified protein derivative of turberculin (PPD-10 μg/ml) or phytohemagglutinin (PHA-1 μg/ml) for 72 h. The levels of IFN-γ, TNF-α, IL-5, IL-10, and IL-17 were measured in these supernatants by ELISA and IL-9 by Luminex. Single nucleotide polymorphisms in IL-17, IL10, and CD209 genes were genotyped using TaqMan probe by qPCR. Higher levels of IL-9, IL-10, and IL-17 were found in PBMC supernatants of patients with advanced hepatic fibrosis. Direct correlations were detected between IL-9 and IL-17 levels with US spleen sizes, portal vein diameters, and periportal thickening. The CD209 rs2287886 AG polymorphism patients produce higher IL-17 levels. Together, these data suggest a role of these cytokines in the immunopathogenesis of advanced fibrosis in human schistosomiasis.
    Keywords:  IL-10; IL-17; IL-9; hepatic fibrosis; schistosomiasis
    DOI:  https://doi.org/10.3389/fimmu.2021.779534
  10. Front Nutr. 2021 ;8 783164
    The Pyruvate Dehydrogenase Complex in Sepsis: Metabolic Regulation and Targeted Therapy.
    Zhenhua Zeng, Qiaobing Huang, Liangfeng Mao, Jie Wu, Sheng An, Zhongqing Chen, Weijin Zhang.
      Anaerobic glycolysis is the process by which glucose is broken down into pyruvate and lactate and is the primary metabolic pathway in sepsis. The pyruvate dehydrogenase complex (PDHC) is a multienzyme complex that serves as a critical hub in energy metabolism. Under aerobic conditions, pyruvate translocates to mitochondria, where it is oxidized into acetyl-CoA through the activation of PDHC, thereby accelerating aerobic oxidation. Both phosphorylation and acetylation affect PDHC activity and, consequently, the regulation of energy metabolism. The mechanisms underlying the protective effects of PDHC in sepsis involve the regulation on the balance of lactate, the release of inflammatory mediators, the remodeling of tricarboxylic acid (TCA) cycle, as well as on the improvement of lipid and energy metabolism. Therapeutic drugs that target PDHC activation for sepsis treatment include dichloroacetate, thiamine, amrinone, TNF-binding protein, and ciprofloxacin. In this review, we summarize the recent findings regarding the metabolic regulation of PDHC in sepsis and the therapies targeting PDHC for the treatment of this condition.
    Keywords:  glycolysis; metabolism; pyruvate dehydrogenase complex; sepsis; therapy
    DOI:  https://doi.org/10.3389/fnut.2021.783164
  11. J Lipid Res. 2021 Dec 21. pii: S0022-2275(21)00148-6. [Epub ahead of print] 100165
    Cholesterol metabolism: from lipidomics to immunology.
    William J Griffiths, Yuqin Wang.
      Oxysterols, the oxidized forms of cholesterol or of its precursors, are formed in the first steps of cholesterol metabolism. Oxysterols have interested chemists, biologists, and physicians for many decades, but their exact biological relevance in vivo, other than as intermediates in bile acid biosynthesis, has long been debated. However, in first quarter of this century, a role for side-chain oxysterols and their C-7 oxidized metabolites has been convincingly established in the immune system. 25-Hydroxycholesterol has been shown to be synthesized by macrophages in response to the activation of Toll-like receptors and to offer protection against microbial pathogens, while 7α,25-dihydroxycholesterol has been shown to act as a chemoattractant to lymphocytes expressing the G protein-coupled receptor EBI2 and to be important in coordinating the action of B, T, and dendritic cells in secondary lymphoid tissue. There is a growing body of evidence that not only these two oxysterols but also many of their isomers are of importance to the proper function of the immune system. Here, we review recent findings related to the roles of oxysterols in immunology.
    Keywords:  B cell; T cell; accessible cholesterol; bacterial infection; dendritic cell; hydroxycholesterol; macrophage; membrane fusion; oxysterol; virus
    DOI:  https://doi.org/10.1016/j.jlr.2021.100165
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