bims-aditis Biomed News
on Adipose tissue, inflammation, immunometabolism
Issue of 2022–03–13
nine papers selected by
Matthew C. Sinton, University of Glasgow
  1. γδ T cells sense disturbance.
  2. Innate PD-L1 limits T cell-mediated adipose tissue inflammation and ameliorates diet-induced obesity.
  3. Adipose triglyceride lipase mediates lipolysis and lipid mobilization in response to iron-mediated negative energy balance.
  4. Interleukin-17 Contributes to Chikungunya Virus-Induced Disease.
  5. Isoform-specific functions of PPARγ in gene regulation and metabolism.
  6. Adipose-derived stem cells ameliorate atopic dermatitis by suppressing the IL-17 expression of Th17 cells in an ovalbumin-induced mouse model.
  7. Regulation of liver subcellular architecture controls metabolic homeostasis.
  8. A non-canonical tricarboxylic acid cycle underlies cellular identity.
  9. Perilipins at a glance.
  1. Nat Rev Immunol. 2022 Mar 08.
    γδ T cells sense disturbance.
    Lucy Bird.
      
    DOI:  https://doi.org/10.1038/s41577-022-00706-3
  2. Sci Transl Med. 2022 Mar 09. 14(635): eabj6879
    Innate PD-L1 limits T cell-mediated adipose tissue inflammation and ameliorates diet-induced obesity.
    Christian Schwartz, Viviane Schmidt, Andrea Deinzer, Heike C Hawerkamp, Emily Hams, Jasmin Bayerlein, Ole Röger, Moritz Bailer, Christian Krautz, Amr El Gendy, Moustafa Elshafei, Helen M Heneghan, Andrew E Hogan, Donal O'Shea, Padraic G Fallon.
      Obesity has become a major health problem in the industrialized world. Immune regulation plays an important role in adipose tissue homeostasis; however, the initial events that shift the balance from a noninflammatory homeostatic environment toward inflammation leading to obesity are poorly understood. Here, we report a role for the costimulatory molecule programmed death-ligand 1 (PD-L1) in the limitation of diet-induced obesity. Functional ablation of PD-L1 on dendritic cells (DCs) using conditional knockout mice increased weight gain and metabolic syndrome during diet-induced obesity, whereas PD-L1 expression on type 2 innate lymphoid cells (ILC2s), T cells, and macrophages was dispensable for obesity control. Using in vitro cocultures, DCs interacted with T cells and ILC2s via the PD-L1:PD-1 axis to inhibit T helper type 1 proliferation and promote type 2 polarization, respectively. A role for PD-L1 in adipose tissue regulation was also shown in humans, with a positive correlation between PD-L1 expression in visceral fat of people with obesity and elevated body weight. Thus, we define a mechanism of adipose tissue homeostasis controlled by the expression of PD-L1 by DCs, which may be a clinically relevant finding with regard to immune-related adverse events during immune checkpoint inhibitor therapy.
    DOI:  https://doi.org/10.1126/scitranslmed.abj6879
  3. iScience. 2022 Mar 18. 25(3): 103941
    Adipose triglyceride lipase mediates lipolysis and lipid mobilization in response to iron-mediated negative energy balance.
    Alicia R Romero, Andre Mu, Janelle S Ayres.
      Maintenance of energy balance is essential for overall organismal health. Mammals have evolved complex regulatory mechanisms that control energy intake and expenditure. Traditionally, studies have focused on understanding the role of macronutrient physiology in energy balance. In the present study, we examined the role of the essential micronutrient iron in regulating energy balance. We found that a short course of dietary iron caused a negative energy balance resulting in a severe whole body wasting phenotype. This disruption in energy balance was because of impaired intestinal nutrient absorption. In response to dietary iron-induced negative energy balance, adipose triglyceride lipase (ATGL) was necessary for wasting of subcutaneous white adipose tissue and lipid mobilization. Fat-specific ATGL deficiency protected mice from fat wasting, but caused a severe cachectic response in mice when fed iron. Our work reveals a mechanism for micronutrient control of lipolysis that is necessary for regulating mammalian energy balance.
    Keywords:  Cellular physiology; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2022.103941
  4. mBio. 2022 Mar 07. e0028922
    Interleukin-17 Contributes to Chikungunya Virus-Induced Disease.
    Xiang Liu, Yee-Suan Poo, Juliana C Alves, Roque P Almeida, Helen Mostafavi, Patrick Chun Hean Tang, Richard Bucala, Mauro M Teixeira, Adam Taylor, Ali Zaid, Suresh Mahalingam.
      Alphaviral arthritides caused by mosquito-borne arboviruses such as chikungunya virus (CHIKV) can persist for months after the initial acute disease. Here, we investigated the contribution of interleukin-17 (IL-17), a cytokine involved in chronic autoimmune arthropathies such as rheumatoid arthritis, to the development of alphaviral arthropathy. Sera from CHIKV-infected patients who displayed both acute and chronic disease showed high levels of IL-17, IL-6, IL-21, IL-22, and IL-23, especially during the chronic phase of disease. We sought to validate these findings using a mouse model of CHIKV infection and disease using wild-type and IL-17A-deficient mice. Mice were infected with CHIKV, and joint and muscle tissues were harvested at designated time points. Tissue infiltrates were examined by immunohistochemistry, and tissue mRNA and protein expression of cytokines was assessed. Joint and muscle pathology was assessed using histology. CHIKV-infected mice lacking IL-17A showed reduced tissue inflammation and neutrophil infiltration, compared to wild-type mice. These investigations showed a role for IL-17 in the acute phase of CHIKV infection and also during the postacute disease resolution phase. IMPORTANCE CHIKV has been prevalent in Africa, Asia, and the Indian Ocean Islands for decades. There are currently no clinically approved vaccines or specific antiviral drugs targeting CHIKV. The upregulation of IL-17 detected in CHIKV disease patients and the reduced disease seen in IL-17-deficient mice suggest a correlation between IL-17 signaling pathways and CHIKV-induced arthritic inflammation. With an established role in contributing to the pathogenesis of immune-mediated diseases, such as psoriatic arthritis and rheumatoid arthritis, IL-17 signaling plays an important role in alphavirus arthritides.
    Keywords:  alphavirus; chikungunya; interleukin-17
    DOI:  https://doi.org/10.1128/mbio.00289-22
  5. Genes Dev. 2022 Mar 10.
    Isoform-specific functions of PPARγ in gene regulation and metabolism.
    Wenxiang Hu, Chunjie Jiang, Mindy Kim, Yang Xiao, Hannah J Richter, Dongyin Guan, Kun Zhu, Brianna M Krusen, Arielle N Roberts, Jessica Miller, David J Steger, Mitchell A Lazar.
      Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is a vital regulator of adipogenesis, insulin sensitivity, and lipid metabolism. Activation of PPARγ by antidiabetic thiazolidinediones (TZD) reverses insulin resistance but also leads to weight gain that limits the use of these drugs. There are two main PPARγ isoforms, but the specific functions of each are not established. Here we generated mouse lines in which endogenous PPARγ1 and PPARγ2 were epitope-tagged to interrogate isoform-specific genomic binding, and mice deficient in either PPARγ1 or PPARγ2 to assess isoform-specific gene regulation. Strikingly, although PPARγ1 and PPARγ2 contain identical DNA binding domains, we uncovered isoform-specific genomic binding sites in addition to shared sites. Moreover, PPARγ1 and PPARγ2 regulated a different set of genes in adipose tissue depots, suggesting distinct roles in adipocyte biology. Indeed, mice with selective deficiency of PPARγ1 maintained body temperature better than wild-type or PPARγ2-deficient mice. Most remarkably, although TZD treatment improved glucose tolerance in mice lacking either PPARγ1 or PPARγ2, the PPARγ1-deficient mice were protected from TZD-induced body weight gain compared with PPARγ2-deficient mice. Thus, PPARγ isoforms have specific and separable metabolic functions that may be targeted to improve therapy for insulin resistance and diabetes.
    Keywords:  PPARγ; adipocyte; diabetes; gene regulation; nuclear receptor; obesity
    DOI:  https://doi.org/10.1101/gad.349232.121
  6. Stem Cell Res Ther. 2022 Mar 07. 13(1): 98
    Adipose-derived stem cells ameliorate atopic dermatitis by suppressing the IL-17 expression of Th17 cells in an ovalbumin-induced mouse model.
    Jingyan Guan, Yibao Li, Feng Lu, Jingwei Feng.
       BACKGROUND: Mesenchymal stem cells (MSCs) have therapeutic potential for atopic dermatitis (AD) owing to their immunoregulatory effects. However, the underlying mechanisms associated with the therapeutic efficacy of MSCs on AD are diverse and related to both cell type and delivery method.
    OBJECTIVES: This study investigated the therapeutic effect and mechanisms of adipose-derived stem cells (ADSCs) on AD using an ovalbumin (OVA)-induced AD mouse model.
    METHODS: AD mice were subcutaneously injected with mouse ADSCs, cortisone, or PBS, and the therapeutic effects were determined by gross and histological examinations and serum IgE levels. Additionally, qPCR, RNA-sequencing analyses of skin samples and co-culture of ADSCs and Th17 cells were conducted to explore the underlying therapeutic mechanisms.
    RESULTS: ADSCs treatment attenuated the AD pathology, decreased the serum IgE levels, and decreased mast cells infiltration in the skin of the model mice. Moreover, tissue levels of IL-4R and Th17-relevant products (IL-17A, CCL20, and MMP12) were suppressed in the ADSC- and cortisone-treated groups. Genomics and bioinformatics analyses demonstrated significant enrichment of inflammation-related pathways in the downregulated genes of the ADSC- and cortisone-treated groups, specifically the IL-17 signaling pathway. Co-culture experiments revealed that ADSCs significantly suppressed the proliferation of Th17 cells and the expression of proinflammatory cytokines (IL-17A and RORγT). Furthermore, expression levels of PD-L1, TGF-β, and PGE2 were significantly upregulated in co-cultured ADSCs relative to those in monocultured ADSCs.
    CONCLUSION: ADSCs ameliorate OVA-induced AD in mice mainly by downregulating IL-17 secretion of Th17 cells.
    Keywords:  Adipose-derived stem cells; Atopic dermatitis; IL-17 signaling pathway; Mouse model; Ovalbumin; Th17 cells
    DOI:  https://doi.org/10.1186/s13287-022-02774-7
  7. Nature. 2022 Mar 09.
    Regulation of liver subcellular architecture controls metabolic homeostasis.
    Güneş Parlakgül, Ana Paula Arruda, Song Pang, Erika Cagampan, Nina Min, Ekin Güney, Grace Yankun Lee, Karen Inouye, Harald F Hess, C Shan Xu, Gökhan S Hotamışlıgil.
      Cells display complex intracellular organization by compartmentalization of metabolic processes into organelles, yet the resolution of these structures in the native tissue context and their functional consequences are not well understood. Here we resolved the three-dimensional structural organization of organelles in large (more than 2.8 × 105 µm3) volumes of intact liver tissue (15 partial or full hepatocytes per condition) at high resolution (8 nm isotropic pixel size) using enhanced focused ion beam scanning electron microscopy1,2 imaging followed by deep-learning-based automated image segmentation and 3D reconstruction. We also performed a comparative analysis of subcellular structures in liver tissue of lean and obese mice and found substantial alterations, particularly in hepatic endoplasmic reticulum (ER), which undergoes massive structural reorganization characterized by marked disorganization of stacks of ER sheets3 and predominance of ER tubules. Finally, we demonstrated the functional importance of these structural changes by monitoring the effects of experimental recovery of the subcellular organization on cellular and systemic metabolism. We conclude that the hepatic subcellular organization of the ER architecture are highly dynamic, integrated with the metabolic state and critical for adaptive homeostasis and tissue health.
    DOI:  https://doi.org/10.1038/s41586-022-04488-5
  8. Nature. 2022 Mar 09.
    A non-canonical tricarboxylic acid cycle underlies cellular identity.
    Paige K Arnold, Benjamin T Jackson, Katrina I Paras, Julia S Brunner, Madeleine L Hart, Oliver J Newsom, Sydney P Alibeckoff, Jennifer Endress, Esther Drill, Lucas B Sullivan, Lydia W S Finley.
      The tricarboxylic acid (TCA) cycle is a central hub of cellular metabolism, oxidizing nutrients to generate reducing equivalents for energy production and critical metabolites for biosynthetic reactions. Despite the importance of the products of the TCA cycle for cell viability and proliferation, mammalian cells display diversity in TCA-cycle activity1,2. How this diversity is achieved, and whether it is critical for establishing cell fate, remains poorly understood. Here we identify a non-canonical TCA cycle that is required for changes in cell state. Genetic co-essentiality mapping revealed a cluster of genes that is sufficient to compose a biochemical alternative to the canonical TCA cycle, wherein mitochondrially derived citrate exported to the cytoplasm is metabolized by ATP citrate lyase, ultimately regenerating mitochondrial oxaloacetate to complete this non-canonical TCA cycle. Manipulating the expression of ATP citrate lyase or the canonical TCA-cycle enzyme aconitase 2 in mouse myoblasts and embryonic stem cells revealed that changes in the configuration of the TCA cycle accompany cell fate transitions. During exit from pluripotency, embryonic stem cells switch from canonical to non-canonical TCA-cycle metabolism. Accordingly, blocking the non-canonical TCA cycle prevents cells from exiting pluripotency. These results establish a context-dependent alternative to the traditional TCA cycle and reveal that appropriate TCA-cycle engagement is required for changes in cell state.
    DOI:  https://doi.org/10.1038/s41586-022-04475-w
  9. J Cell Sci. 2022 Mar 01. pii: jcs259501. [Epub ahead of print]135(5):
    Perilipins at a glance.
    Charles P Najt, Mahima Devarajan, Douglas G Mashek.
      Lipid droplets (LDs) are ubiquitous organelles that store and supply lipids for energy metabolism, membrane synthesis and production of lipid-derived signaling molecules. While compositional differences in the phospholipid monolayer or neutral lipid core of LDs impact their metabolism and function, the proteome of LDs has emerged as a major influencer in all aspects of LD biology. The perilipins (PLINs) are the most studied and abundant proteins residing on the LD surface. This Cell Science at a Glance and the accompanying poster summarize our current knowledge of the common and unique features of the mammalian PLIN family of proteins, the mechanisms through which they affect cell metabolism and signaling, and their links to disease.
    Keywords:  Lipid droplets; Lipid metabolism; Lipid signaling; Perilipins
    DOI:  https://doi.org/10.1242/jcs.259501
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