bims-aditis Biomed News
on Adipose tissue, inflammation, immunometabolism
Issue of 2021–11–21
thirteen papers selected by
Matthew C. Sinton, University of Glasgow
  1. Slit3 secreted from M2-like macrophages increases sympathetic activity and thermogenesis in adipose tissue.
  2. SORLA is required for insulin-induced expansion of the adipocyte precursor pool in visceral fat.
  3. Insulin resistance rewires the metabolic gene program and glucose utilization in human white adipocytes.
  4. The role of the electron transport chain in immunity.
  5. IL-13 Controls IL-33 Activity through Modulation of ST2.
  6. Immunomodulatory role of Th17 pathway in experimental visceral leishmaniasis.
  7. BAd-CRISPR: inducible gene knockout in interscapular brown adipose tissue of adult mice.
  8. The role of mitochondrial reactive oxygen species in insulin resistance.
  9. Lipolysis: cellular mechanisms for lipid mobilization from fat stores.
  10. Dynamic CD4+ T cell heterogeneity defines subset-specific suppression and PD-L1-blockade-driven functional restoration in chronic infection.
  11. The links between Sleep Duration, Obesity and Type 2 Diabetes Mellitus.
  12. A novel cytokine consisting of the p40 and EBI3 subunits suppresses experimental autoimmune arthritis via reciprocal regulation of Th17 and Treg cells.
  13. Emerging technologies and infection models in cellular microbiology.
  1. Nat Metab. 2021 Nov;3(11): 1536-1551
    Slit3 secreted from M2-like macrophages increases sympathetic activity and thermogenesis in adipose tissue.
    Yi-Na Wang, Yan Tang, Zhihui He, Hong Ma, Linyuan Wang, Yang Liu, Qiqi Yang, Dongning Pan, Cuiqing Zhu, Shuwen Qian, Qi-Qun Tang.
      Beiging of white adipose tissue (WAT) is associated with an increase of anti-inflammatory M2-like macrophages in WAT. However, mechanisms through which M2-like macrophages affect beiging are incompletely understood. Here, we show that the macrophage cytokine Slit3 is secreted by adipose tissue macrophages and promotes cold adaptation by stimulating sympathetic innervation and thermogenesis in mice. Analysing the transcriptome of M2-like macrophages in murine inguinal WAT (iWAT) after cold exposure, we identify Slit3 as a secreted cytokine. Slit3 binds to the ROBO1 receptor on sympathetic neurons to stimulate Ca2+/calmodulin-dependent protein kinase II signalling and norepinephrine release, which enhances adipocyte thermogenesis. Adoptive transfer of Slit3-overexpressing M2 macrophages to iWAT promotes beiging and thermogenesis, whereas mice that lack Slit3 in myeloid cells are cold-intolerant and gain more weight. Our findings shed new light on the integral role of M2-like macrophages for adipose tissue homeostasis and uncover the macrophage-Slit3-sympathetic neuron-adipocyte signalling axis as a regulator of long-term cold adaptation.
    DOI:  https://doi.org/10.1038/s42255-021-00482-9
  2. J Cell Biol. 2021 Dec 06. pii: e202006058. [Epub ahead of print]220(12):
    SORLA is required for insulin-induced expansion of the adipocyte precursor pool in visceral fat.
    Vanessa Schmidt, Carla Horváth, Hua Dong, Matthias Blüher, Per Qvist, Christian Wolfrum, Thomas E Willnow.
      Visceral adipose tissue shows remarkable plasticity, constantly replacing mature adipocytes from an inherent pool of adipocyte precursors. The number of precursors is set in the juvenile organism and remains constant in adult life. Which signals drive precursor pool expansion in juveniles and why they operate in visceral but not in subcutaneous white adipose tissue (WAT) are unclear. Using mouse models, we identified the insulin-sensitizing receptor SORLA as a molecular factor explaining the distinct proliferative capacity of visceral WAT. High levels of SORLA activity in precursors of juvenile visceral WAT prime these cells for nutritional stimuli provided through insulin, promoting mitotic expansion of the visceral precursor cell pool in overfed juvenile mice. SORLA activity is low in subcutaneous precursors, blunting their response to insulin and preventing diet-induced proliferation of this cell type. Our findings provide a molecular explanation for the unique proliferative properties of juvenile visceral WAT, and for the genetic association of SORLA with visceral obesity in humans.
    DOI:  https://doi.org/10.1083/jcb.202006058
  3. Int J Obes (Lond). 2021 Nov 19.
    Insulin resistance rewires the metabolic gene program and glucose utilization in human white adipocytes.
    Marie S Isidor, Wentao Dong, Rogelio I Servin-Uribe, Julia Villarroel, Ali Altıntaş, J Tonatiuh Ayala-Sumuano, Alfredo Varela-Echavarría, Romain Barrès, Gregory Stephanopoulos, Yazmín Macotela, Brice Emanuelli.
       BACKGROUND: In obesity, adipose tissue dysfunction resulting from excessive fat accumulation leads to systemic insulin resistance (IR), the underlying alteration of Type 2 Diabetes. The specific pathways dysregulated in dysfunctional adipocytes and the extent to which it affects adipose metabolic functions remain incompletely characterized.
    METHODS: We interrogated the transcriptional adaptation to increased adiposity in association with insulin resistance in visceral white adipose tissue from lean men, or men presenting overweight/obesity (BMI from 19 to 33) and discordant for insulin sensitivity. In human adipocytes in vitro, we investigated the direct contribution of IR in altering metabolic gene programming and glucose utilization using 13C-isotopic glucose tracing.
    RESULTS: We found that gene expression associated with impaired glucose and lipid metabolism and inflammation represented the strongest association with systemic insulin resistance, independently of BMI. In addition, we showed that inducing IR in mature human white adipocytes was sufficient to reprogram the transcriptional profile of genes involved in important metabolic functions such as glycolysis, the pentose phosphate pathway and de novo lipogenesis. Finally, we found that IR induced a rewiring of glucose metabolism, with higher incorporation of glucose into citrate, but not into downstream metabolites within the TCA cycle.
    CONCLUSIONS: Collectively, our data highlight the importance of obesity-derived insulin resistance in impacting the expression of key metabolic genes and impairing the metabolic processes of glucose utilization, and reveal a role for metabolic adaptation in adipose dysfunction in humans.
    DOI:  https://doi.org/10.1038/s41366-021-01021-y
  4. FASEB J. 2021 Dec;35(12): e21974
    The role of the electron transport chain in immunity.
    Maureen Yin, Luke A J O'Neill.
      The electron transport chain (ETC) couples oxidative phosphorylation (OXPHOS) with ATP synthase to drive the generation of ATP. In immune cells, research surrounding the ETC has drifted away from bioenergetics since the discovery of cytochrome c (Cyt c) release as a signal for programmed cell death. Complex I has been shown to generate reactive oxygen species (ROS), with key roles identified in inflammatory macrophages and T helper 17 cells (TH 17) cells. Complex II is the site of reverse electron transport (RET) in inflammatory macrophages and is also responsible for regulating fumarate levels linking to epigenetic changes. Complex III also produces ROS which activate hypoxia-inducible factor 1-alpha (HIF-1α) and can participate in regulatory T cell (Treg ) function. Complex IV is required for T cell activation and differentiation and the proper development of Treg subsets. Complex V is required for TH 17 differentiation and can be expressed on the surface of tumor cells where it is recognized by anti-tumor T and NK cells. In this review, we summarize these findings and speculate on the therapeutic potential of targeting the ETC as an anti-inflammatory strategy.
    Keywords:  T-lymphocytes; electron transport chain (ETC); immunometabolism; macrophage; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1096/fj.202101161R
  5. J Immunol. 2021 Nov 17. pii: ji2100655. [Epub ahead of print]
    IL-13 Controls IL-33 Activity through Modulation of ST2.
    Melvin Zhang, Jennifer L Duffen, Karl H Nocka, Marion T Kasaian.
      IL-33 is a multifunctional cytokine that mediates local inflammation upon tissue damage. IL-33 is known to act on multiple cell types including group 2 innate lymphoid cells (ILC2s), Th2 cells, and mast cells to drive production of Th2 cytokines including IL-5 and IL-13. IL-33 signaling activity through transmembrane ST2L can be inhibited by soluble ST2 (sST2), which acts as a decoy receptor. Previous findings suggested that modulation of IL-13 levels in mice lacking decoy IL-13Rα2, or mice lacking IL-13, impacted responsiveness to IL-33. In this study, we used Il13 -/- mice to investigate whether IL-13 regulates IL-33 activity by modulating the transmembrane and soluble forms of ST2. In Il13 -/- mice, the effects of IL-33 administration were exacerbated relative to wild type (WT). Il13 -/- mice administered IL-33 i.p. had heightened splenomegaly, more immune cells in the peritoneum including an expanded ST2L+ ILC2 population, increased eosinophilia in the spleen and peritoneum, and reduced sST2 in the circulation and peritoneum. In the spleen, lung, and liver of mice given IL-33, gene expression of both isoforms of ST2 was increased in Il13 -/- mice relative to WT. We confirmed fibroblasts to be an IL-13-responsive cell type that can regulate IL-33 activity through production of sST2. This study elucidates the important regulatory activity that IL-13 exerts on IL-33 through induction of IL-33 decoy receptor sST2 and through modulation of ST2L+ ILC2s.
    DOI:  https://doi.org/10.4049/jimmunol.2100655
  6. Immunobiology. 2021 Oct 25. pii: S0171-2985(21)00096-6. [Epub ahead of print]226(6): 152148
    Immunomodulatory role of Th17 pathway in experimental visceral leishmaniasis.
    Rasmita Khatonier, Giasuddin Ahmed, Pallab Sarmah, Kanwar Narain, Abdul Mabood Khan.
      Visceral leishmaniasis (VL) or Kala-azar is a vector borne protozoan infection caused by Leishmania donovani in the Indian subcontinent mainly India, Nepal and Bangladesh. It is a major public health problem in these countries mostly affecting the socio-economically poor population. Leishmaniasis ranks the third most important disease after malaria and filariasis but is still considered as one of the neglected tropical diseases of the world. For development of better therapeutic agents and effective vaccine against VL, there is a need to understand host immunological changes that play a vital role during course of infection. Therefore, we investigated the role of Th17 pathway in Balb/c mice during Leishmania donovani infection and treatment with amphotericin B. Mice were divided in four groups i.e. Control, Infected, Uninfected treated and Infected treated. The cytokine levels were estimated in the spleen of Balb/c mice on days 1, 3, 7, 14, 17, 21, 28, 35, 45 and 60 post infection and during course of treatment. The mRNA levels of the Th17 pathway during active Leishmania donovani infection and after treatment were determined by real time polymerase chain reaction (RT-PCR) and protein levels by flow cytometry and ELISA. Results of our study revealed that active infection was associated with low levels of Th17 cytokines IL-17, IL-22 and IL-23 and elevated levels of IL-6, IL-1β and TGF-β. Amphotericin B treatment restored production of pro-inflammatory cytokines IL-17 and IL-22. The levels of transcription factor RORγt were found to correlate with the levels of IL-17 during infection and also after chemotherapy whereas STAT3 levels were elevated during infection and vice versa after treatment. The findings of this study suggest that Th17 cytokines IL-17 and IL-22 are associated with protection against VL infection and development of any interventions or chemotherapeutic agents targeting Th17 pathway could be an important approach for VL treatment.
    Keywords:  Amphotericin B; Cytokines; Immunotherapy; Leishmania donovani; Th17 pathway; Visceral leishmaniasis
    DOI:  https://doi.org/10.1016/j.imbio.2021.152148
  7. J Biol Chem. 2021 Nov 11. pii: S0021-9258(21)01209-6. [Epub ahead of print] 101402
    BAd-CRISPR: inducible gene knockout in interscapular brown adipose tissue of adult mice.
    Steven M Romanelli, Kenneth T Lewis, Akira Nishii, Alan C Rupp, Ziru Li, Hiroyuki Mori, Rebecca L Schill, Brian S Learman, Christopher J Rhodes, Ormond A MacDougald.
      CRISPR/Cas9 has enabled inducible gene knockout in numerous tissues; however, its use has not been reported in brown adipose tissue (BAT). Here we developed brown adipocyte CRISPR (BAd-CRISPR) methodology to rapidly interrogate function of one or multiple genes. With BAd-CRISPR, an adeno-associated virus (AAV8) expressing a single guide RNA (sgRNA) is administered directly to BAT of mice expressing Cas9 in brown adipocytes. We show that local administration of AAV8-sgRNA to interscapular BAT of adult mice robustly transduced brown adipocytes and ablated expression of adiponectin (Adipoq), adipose triglyceride lipase (Atgl), fatty acid synthase (Fasn), perilipin 1 (Plin1), or stearoyl-CoA desaturase 1 (Scd1) by >90%. Administration of multiple AAV8 sgRNAs led to simultaneous knockout of up to three genes. BAd-CRISPR induced frameshift mutations and suppressed target gene mRNA expression but did not lead to substantial accumulation of off-target mutations in BAT. We used BAd-CRISPR to create an inducible uncoupling protein 1 (Ucp1) knockout mouse to assess effects of UCP1 loss on adaptive thermogenesis in adult mice. Inducible Ucp1 knockout did not alter core body temperature; however, BAd-CRISPR Ucp1 mice had elevated circulating concentrations of fibroblast growth factor 21 (FGF21), and changes in BAT gene expression consistent with heat production through increased peroxisomal lipid oxidation. Other molecular adaptations predict additional cellular inefficiencies, with an increase in both protein synthesis and turnover, and mitochondria with reduced reliance on mitochondrial-encoded gene expression and increased expression of nuclear-encoded mitochondrial genes. These data suggest that BAd-CRISPR is an efficient tool to speed discoveries in adipose tissue biology.
    Keywords:  CRISPR/Cas; adipocyte; adiponectin; adipose tissue; adipose triglyceride lipase (ATGL); brown adipose tissue; fatty acid synthase (FASN); perilipin; stearoyl CoA desaturase I (SCD1); uncoupling protein
    DOI:  https://doi.org/10.1016/j.jbc.2021.101402
  8. Free Radic Biol Med. 2021 Nov 11. pii: S0891-5849(21)00794-2. [Epub ahead of print]
    The role of mitochondrial reactive oxygen species in insulin resistance.
    Anita Ayer, Daniel J Fazakerley, David E James, Roland Stocker.
      Insulin resistance is one of the earliest pathological features of a suite of diseases including type 2 diabetes collectively referred to as metabolic syndrome. There is a growing body of evidence from both pre-clinical studies and human cohorts indicating that reactive oxygen species, such as the superoxide radical anion and hydrogen peroxide are key players in the development of insulin resistance. Here we review the evidence linking mitochondrial reactive oxygen species generated within mitochondria with insulin resistance in adipose tissue and skeletal muscle, two major insulin sensitive tissues. We outline the relevant mitochondria-derived reactive species, how the mitochondrial redox state is regulated, and methodologies available to measure mitochondrial reactive oxygen species. Importantly, we highlight key experimental issues to be considered when studying the role of mitochondrial reactive oxygen species in insulin resistance. Evaluating the available literature on both mitochondrial reactive oxygen species/redox state and insulin resistance in a variety of biological systems, we conclude that the weight of evidence suggests a likely role for mitochondrial reactive oxygen species in the etiology of insulin resistance in adipose tissue and skeletal muscle. However, major limitations in the methods used to study reactive oxygen species in insulin resistance as well as the lack of data linking mitochondrial reactive oxygen species and cytosolic insulin signaling pathways are significant obstacles in proving the mechanistic link between these two processes. We provide a framework to guide future studies to provide stronger mechanistic information on the link between mitochondrial reactive oxygen species and insulin resistance as understanding the source, localization, nature, and quantity of mitochondrial reactive oxygen species, their targets and downstream signaling pathways may pave the way for important new therapeutic strategies.
    Keywords:  Coenzyme Q; Hydrogen peroxide; Insulin resistance; Mitochondria; Redox signaling; Superoxide radical anion
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.11.007
  9. Nat Metab. 2021 Nov;3(11): 1445-1465
    Lipolysis: cellular mechanisms for lipid mobilization from fat stores.
    Gernot F Grabner, Hao Xie, Martina Schweiger, Rudolf Zechner.
      The perception that intracellular lipolysis is a straightforward process that releases fatty acids from fat stores in adipose tissue to generate energy has experienced major revisions over the last two decades. The discovery of new lipolytic enzymes and coregulators, the demonstration that lipophagy and lysosomal lipolysis contribute to the degradation of cellular lipid stores and the characterization of numerous factors and signalling pathways that regulate lipid hydrolysis on transcriptional and post-transcriptional levels have revolutionized our understanding of lipolysis. In this review, we focus on the mechanisms that facilitate intracellular fatty-acid mobilization, drawing on canonical and noncanonical enzymatic pathways. We summarize how intracellular lipolysis affects lipid-mediated signalling, metabolic regulation and energy homeostasis in multiple organs. Finally, we examine how these processes affect pathogenesis and how lipolysis may be targeted to potentially prevent or treat various diseases.
    DOI:  https://doi.org/10.1038/s42255-021-00493-6
  10. Nat Immunol. 2021 Nov 18.
    Dynamic CD4+ T cell heterogeneity defines subset-specific suppression and PD-L1-blockade-driven functional restoration in chronic infection.
    Laura M Snell, Wenxi Xu, Diala Abd-Rabbo, Giselle Boukhaled, Mengdi Guo, Bethany L Macleod, Heidi J Elsaesser, Kebria Hezaveh, Nirmin Alsahafi, Sabelo Lukhele, Sara Nejat, Ramanandan Prabhakaran, Slava Epelman, Tracy L McGaha, David G Brooks.
      Inhibiting PD-1:PD-L1 signaling has transformed therapeutic immune restoration. CD4+ T cells sustain immunity in chronic infections and cancer, yet little is known about how PD-1 signaling modulates CD4+ helper T (TH) cell responses or the ability to restore CD4+ TH-mediated immunity by checkpoint blockade. We demonstrate that PD-1:PD-L1 specifically suppressed CD4+ TH1 cell amplification, prevents CD4+ TH1 cytokine production and abolishes CD4+ cytotoxic killing capacity during chronic infection in mice. Inhibiting PD-L1 rapidly restored these functions, while simultaneously amplifying and activating TH1-like T regulatory cells, demonstrating a system-wide CD4-TH1 recalibration. This effect coincided with decreased T cell antigen receptor signaling, and re-directed type I interferon (IFN) signaling networks towards dominant IFN-γ-mediated responses. Mechanistically, PD-L1 blockade specifically targeted defined populations with pre-established, but actively suppressed proliferative potential, with limited impact on minimally cycling TCF-1+ follicular helper T cells, despite high PD-1 expression. Thus, CD4+ T cells require unique differentiation and functional states to be targets of PD-L1-directed suppression and therapeutic restoration.
    DOI:  https://doi.org/10.1038/s41590-021-01060-7
  11. J Endocrinol. 2021 Nov 01. pii: JOE-21-0155.R1. [Epub ahead of print]
    The links between Sleep Duration, Obesity and Type 2 Diabetes Mellitus.
    Christina Antza, Georgios Kostopoulos, Samiul Mostafa, Krishnarajah Nirantharakumar, Abd Tahrani.
      Global rates of obesity and Type 2 diabetes mellitus (T2DM) are increasing globally concomitant with a rising prevalence of sleep deprivation and sleep disorders. Understanding the links between sleep, obesity and T2DM might offer an opportunity to develop better prevention and treatment strategies for these epidemics. Experimental studies have shown that sleep restriction is associated with changes in energy homeostasis, insulin resistance and β-cell function. Epidemiological cohort studies established short sleep duration as a risk factor for developing obesity and T2DM. In addition, small studies suggested that short sleep duration was associated less weight loss following lifestyle interventions or bariatric surgery. In this article, we review the epidemiological evidence linking sleep duration to obesity and T2DM and plausible mechanisms. In addition, we review the impact of changes in sleep duration on obesity and T2DM.
    DOI:  https://doi.org/10.1530/JOE-21-0155
  12. Cell Mol Immunol. 2021 Nov 15.
    A novel cytokine consisting of the p40 and EBI3 subunits suppresses experimental autoimmune arthritis via reciprocal regulation of Th17 and Treg cells.
    Seon-Yeong Lee, Su-Jin Moon, Young-Mee Moon, Hyeon-Beom Seo, Jun-Geol Ryu, A Ram Lee, Chae Rim Lee, Da-Som Kim, Yang-Mi Her, Jeong Won Choi, Seung-Ki Kwok, Sung-Hwan Park, Mi-La Cho.
       OBJECTIVE: The interleukin (IL)-12 cytokine family is closely related to the development of T helper cells, which are responsible for autoimmune disease enhancement or suppression. IL-12 family members are generally heterodimers and share three α-subunits (p35, p19, and p28) and two β-subunits (p40 and EBI3). However, a β-sheet p40 homodimer has been shown to exist and antagonize IL-12 and IL-23 signaling 1. Therefore, we assumed the existence of a p40-EBI3 heterodimer in nature and sought to investigate its role in immune regulation.
    METHODS: The presence of the p40-EBI3 heterodimer was confirmed by ELISA, immunoprecipitation, and western blotting. A p40-EBI3 vector and p40-EBI3-Fc protein were synthesized to confirm the immunological role of this protein in mice with collagen-induced arthritis (CIA). The anti-inflammatory effects of p40-EBI3 were analyzed with regard to clinical, histological, and immune cell-regulating features in mice with CIA.
    RESULTS: Clinical arthritis scores and the expression levels of proinflammatory cytokines (e.g., IL-17, IL-1β, IL-6, and TNF-α) were significantly attenuated in p40-EBI3-overexpressing and p40-EBI3-Fc-treated mice with CIA compared to vehicle-treated mice with CIA. Structural joint damage and vessel formation-related gene expression were also reduced by p40-EBI3 heterodimer treatment. In vitro, the p40-EBI3-Fc protein significantly suppressed the differentiation of Th17 cells and reciprocally induced CD4+CD25+Foxp3+ (regulatory T) cells. p40-EBI3 also inhibited osteoclast formation in a concentration-dependent manner.
    CONCLUSION: In this study, p40-EBI3 ameliorated proinflammatory conditions both in vivo and in vitro. We propose that p40-EBI3 is a novel anti-inflammatory cytokine involved in suppressing the immune response through the expansion of Treg cells and suppression of Th17 cells and osteoclastogenesis.
    Keywords:  Autoimmune disease; Rheumatoid arthritis; cytokine; p40-EBI3; regulatory T cell
    DOI:  https://doi.org/10.1038/s41423-021-00798-2
  13. Nat Commun. 2021 Nov 19. 12(1): 6764
    Emerging technologies and infection models in cellular microbiology.
    Ana Teresa López-Jiménez, Serge Mostowy.
      The field of cellular microbiology, rooted in the co-evolution of microbes and their hosts, studies intracellular pathogens and their manipulation of host cell machinery. In this review, we highlight emerging technologies and infection models that recently promoted opportunities in cellular microbiology. We overview the explosion of microscopy techniques and how they reveal unprecedented detail at the host-pathogen interface. We discuss the incorporation of robotics and artificial intelligence to image-based screening modalities, biochemical mapping approaches, as well as dual RNA-sequencing techniques. Finally, we describe chips, organoids and animal models used to dissect biophysical and in vivo aspects of the infection process. As our knowledge of the infected cell improves, cellular microbiology holds great promise for development of anti-infective strategies with translational applications in human health.
    DOI:  https://doi.org/10.1038/s41467-021-26641-w
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