bims-aditis Biomed News
on Adipose tissue, inflammation, immunometabolism
Issue of 2022‒04‒24
thirteen papers selected by
Matthew C. Sinton, University of Glasgow
  1. Multilayered omics reveal sex- and depot-dependent adipose progenitor cell heterogeneity.
  2. The Role of Metabolic Dysfunction in T-Cell Exhaustion During Chronic Viral Infection.
  3. When fat meets the gut-focus on intestinal lipid handling in metabolic health and disease.
  4. Gamma delta T cells in hepatocellular carcinoma: Sunrise of new therapy based on Vδ2 T cells?
  5. Serum Amyloid A is not obligatory for high-fat, high-sucrose, cholesterol-fed diet-induced obesity and its metabolic and inflammatory complications.
  6. The central melanocortin system as a treatment target for obesity and diabetes: A brief overview.
  7. Regulating metabolism to shape immune function: Lessons from Drosophila.
  8. PD-1 Targeted Nanoparticles Inhibit Activated T Cells and Alleviate Autoimmunity via Suppression of Cellular Energy Metabolism Mediated by PKM2.
  9. Interleukin 17, the double-edged sword in atherosclerosis.
  10. Complexity of subcellular metabolism: strategies for compartment-specific profiling.
  11. Tetracycline response element driven Cre causes ectopic recombinase activity independent of transactivator element.
  12. A Ménage à Trois of Cytotoxic Effector Cells: γδ T Cells Suppress NK Cells but Not CTLs.
  13. A chromatin accessibility landscape during early adipogenesis of human adipose-derived stem cells.
  1. Cell Metab. 2022 Apr 14. pii: S1550-4131(22)00126-7. [Epub ahead of print]
    Multilayered omics reveal sex- and depot-dependent adipose progenitor cell heterogeneity.
    Bo Shan, Clive S Barker, Mengle Shao, Qianbin Zhang, Rana K Gupta, Yibo Wu.
      Single-cell RNA sequencing (scRNA-seq) has revealed that adult white adipose tissue (WAT) harbors functionally diverse subpopulations of mesenchymal stromal cells that differentially impact tissue plasticity. To date, the molecular basis of this cellular heterogeneity has not been fully defined. Here, we describe a multilayered omics approach to dissect adipose progenitor cell heterogeneity in three dimensions: progenitor subpopulation, sex, and anatomical localization. We applied state-of-the-art mass spectrometry methods to quantify 4,870 proteins in eight different stromal cell populations from perigonadal and inguinal WAT of male and female mice and acquired transcript expression levels of 15,477 genes using RNA-seq. Our data unveil molecular signatures defining sex differences in preadipocyte differentiation and identify regulatory pathways that functionally distinguish adipose progenitor subpopulations. This multilayered omics analysis, freely accessible at http://preadprofiler.net/, provides unprecedented insights into adipose stromal cell heterogeneity and highlights the benefit of complementary proteomics to support findings from scRNA-seq studies.
    Keywords:  PPARγ; adipocyte precursor cells; adipogenesis; adipose tissue; cellular heterogeneity; inflammation; multilayered omics; sex difference
    DOI:  https://doi.org/10.1016/j.cmet.2022.03.012
  2. Front Immunol. 2022 ;13 843242
    The Role of Metabolic Dysfunction in T-Cell Exhaustion During Chronic Viral Infection.
    Kehong Zheng, Xiaojun Zheng, Wei Yang.
      T cells are important components of adaptive immunity that protect the host against invading pathogens during infection. Upon recognizing the activation signals, naïve and/or memory T cells will initiate clonal expansion, trigger differentiation into effector populations and traffic to the inflamed sites to eliminate pathogens. However, in chronic viral infections, such as those caused by human immunodeficiency virus (HIV), hepatitis B and C (HBV and HCV), T cells exhibit impaired function and become difficult to clear pathogens in a state known as T-cell exhaustion. The activation and function persistence of T cells demand for dynamic changes in cellular metabolism to meet their bioenergetic and biosynthetic demands, especially the augmentation of aerobic glycolysis, which not only provide efficient energy generation, but also fuel multiple biochemical intermediates that are essential for nucleotide, amino acid, fatty acid synthesis and mitochondria function. Changes in cellular metabolism also affect the function of effectors T cells through modifying epigenetic signatures. It is widely accepted that the dysfunction of T cell metabolism contributes greatly to T-cell exhaustion. Here, we reviewed recent findings on T cells metabolism under chronic viral infection, seeking to reveal the role of metabolic dysfunction played in T-cell exhaustion.
    Keywords:  PD-1; T-cell exhaustion; chronic viral infection; glycolysis; metabolism
    DOI:  https://doi.org/10.3389/fimmu.2022.843242
  3. EMBO Mol Med. 2022 Apr 19. e14742
    When fat meets the gut-focus on intestinal lipid handling in metabolic health and disease.
    Magdalena Wit, Jonathan Trujillo-Viera, Akim Strohmeyer, Martin Klingenspor, Mohammed Hankir, Grzegorz Sumara.
      The regular overconsumption of energy-dense foods (rich in lipids and sugars) results in elevated intestinal nutrient absorption and consequently excessive accumulation of lipids in the liver, adipose tissue, skeletal muscles, and other organs. This can eventually lead to obesity and obesity-associated diseases such as type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, and certain types of cancer, as well as aggravate inflammatory bowel disease (IBD). Therefore, targeting the pathways that regulate intestinal nutrient absorption holds significant therapeutic potential. In this review, we discuss the molecular and cellular mechanisms controlling intestinal lipid handling, their relevance to the development of metabolic diseases, and emerging therapeutic strategies.
    Keywords:  enterocyte; fat absorption; intestine; metabolic diseases; triglycerides
    DOI:  https://doi.org/10.15252/emmm.202114742
  4. Clin Transl Med. 2022 Apr;12(4): e834
    Gamma delta T cells in hepatocellular carcinoma: Sunrise of new therapy based on Vδ2 T cells?
    Zuzana Macek Jilkova.
      
    Keywords:  Hepatocellular carcinoma; tumour microenvironment; γδ T cells
    DOI:  https://doi.org/10.1002/ctm2.834
  5. PLoS One. 2022 ;17(4): e0266688
    Serum Amyloid A is not obligatory for high-fat, high-sucrose, cholesterol-fed diet-induced obesity and its metabolic and inflammatory complications.
    Ailing Ji, Andrea C Trumbauer, Victoria P Noffsinger, Hayce Jeon, Avery C Patrick, Frederick C De Beer, Nancy R Webb, Lisa R Tannock, Preetha Shridas.
      Several studies in the past have reported positive correlations between circulating Serum amyloid A (SAA) levels and obesity. However, based on limited number of studies involving appropriate mouse models, the role of SAA in the development of obesity and obesity-related metabolic consequences has not been established. Accordingly, herein, we have examined the role of SAA in the development of obesity and its associated metabolic complications in vivo using mice deficient for all three inducible forms of SAA: SAA1.1, SAA2.1 and SAA3 (TKO). Male and female mice were rendered obese by feeding a high fat, high sucrose diet with added cholesterol (HFHSC) and control mice were fed rodent chow diet. Here, we show that the deletion of SAA does not affect diet-induced obesity, hepatic lipid metabolism or adipose tissue inflammation. However, there was a modest effect on glucose metabolism. The results of this study confirm previous findings that SAA levels are elevated in adipose tissues as well as in the circulation in diet-induced obese mice. However, the three acute phase SAAs do not play a causative role in the development of obesity or obesity-associated adipose tissue inflammation and dyslipidemia.
    DOI:  https://doi.org/10.1371/journal.pone.0266688
  6. Eur J Pharmacol. 2022 Apr 14. pii: S0014-2999(22)00217-5. [Epub ahead of print]924 174956
    The central melanocortin system as a treatment target for obesity and diabetes: A brief overview.
    Rajesh Kumar Goit, Andrew W Taylor, Amy Cheuk Yin Lo.
      The melanocortins are derived from proopiomelanocortin (POMC) and include three forms of melanocyte-stimulating hormone (α-, β-, γ-, MSH) and adrenocorticotropic hormone. α-MSH, a potent POMC-derived neuropeptide, binds to melanocortin 4 receptor (MC4R) in the brain to reduce food intake (via appetite suppression) and increase energy expenditure (via sympathetic nervous system) after integration of central neuronal signal (e.g. serotonin, glutamate) and peripheral signals such as anorexigenic hormones (e.g. leptin, insulin) and nutrient (e.g. glucose). Mutations in POMC or MC4R can cause increase in food intake and body weight. Weight gain and obesity in turn result in a phenotypic switch of white adipose tissue, which then secretes proinflammatory cytokines that play a role in the development of insulin resistance and type 2 diabetes. Besides α-MSH's effects in decreasing food intake and body weight, α-MSH also carries protective anti-inflammatory properties in both immune cells and non-immune cells (e.g. adipocyte) that express melanocortin receptors. Since type 2 diabetic patients who have overweight or obese are recommended to lose body weight while current available anti-obesity drugs have various side effects, α-MSH-based therapeutics might be hopeful for the management of both obesity and type 2 diabetes.
    Keywords:  Diabetes; Melanocortin receptor; Melanocyte-stimulating hormone; Obesity; Proopiomelanocortin
    DOI:  https://doi.org/10.1016/j.ejphar.2022.174956
  7. Semin Cell Dev Biol. 2022 Apr 16. pii: S1084-9521(22)00127-6. [Epub ahead of print]
    Regulating metabolism to shape immune function: Lessons from Drosophila.
    Michelle L Bland.
      Infection with pathogenic microbes is a severe threat that hosts manage by activating the innate immune response. In Drosophila melanogaster, the Toll and Imd signaling pathways are activated by pathogen-associated molecular patterns to initiate cellular and humoral immune processes that neutralize and kill invaders. The Toll and Imd signaling pathways operate in organs such as fat body and gut that control host nutrient metabolism, and infections or genetic activation of Toll and Imd signaling also induce wide-ranging changes in host lipid, carbohydrate and protein metabolism. Metabolic regulation by immune signaling can confer resistance to or tolerance of infection, but it can also lead to pathology and susceptibility to infection. These immunometabolic phenotypes are described in this review, as are changes in endocrine signaling and gene regulation that mediate survival during infection. Future work in the field is anticipated to determine key variables such as sex, dietary nutrients, life stage, and pathogen characteristics that modify immunometabolic phenotypes and, importantly, to uncover the mechanisms used by the immune system to regulate metabolism.
    Keywords:  Drosophila; Infection; Innate immunity; Metabolism
    DOI:  https://doi.org/10.1016/j.semcdb.2022.04.002
  8. Int J Nanomedicine. 2022 ;17 1711-1724
    PD-1 Targeted Nanoparticles Inhibit Activated T Cells and Alleviate Autoimmunity via Suppression of Cellular Energy Metabolism Mediated by PKM2.
    Zhangluxi Liu, Jing Xu, Hongxi Li, Jia Shu, Guannan Su, Chunjiang Zhou, Peizeng Yang.
      Background: Effector T cells, especially T helper 1 (Th1) cells and T helper 17 (Th17) cells, are involved in the pathogenesis of many autoimmune diseases such as uveitis. Under hyperactive immune conditions, these effector T cells pathologically maintain a high expression level of programmed cell death protein 1 (PD-1) receptors and distinctively engage aerobic glycolysis via cellular energy metabolism mediated by pyruvate kinase M2 (PKM2). Therefore, we proposed that the synergy of metabolic inhibition and receptor guidance might target and down-regulate these hyperactive effector T cells to achieve anti-immune effects.Methods: PD-1 antibody and TEPP-46 were integrated by polyethylene glycol (PEG) modified poly (lactic-co-glycolic acid) (PLGA) as a nanoplatform (TPP). Characteristics of TPP were basically detected. The biosafety of TPP was evaluated in vitro and in vivo. The targeting effect of TPP was detected by laser scanning confocal microscopy and flow cytometry (FCM). Interleukin-2 (IL-2)/interleukin-17A (IL-17A)/interferon-gamma (IFN-γ) producing cells were detected by FCM. Experimental autoimmune uveoretinitis (EAU) was induced in C57BL/6J mice as the inflammatory model.
    Results: TPP had homogeneous distribution, good stability in vitro, and high biosafety in vitro and in vivo. Encapsulated TEPP-46 showed a sustained release profile with burst, steady and slow release periods. Early activation and proliferation of effector T cells was inhibited by TPP treatment in vitro. Th1 and Th17 cells were suppressed by TPP in vitro and in vivo. EAU was alleviated in mice by systemic administration of TPP.
    Conclusion: The novel nanoplatform TPP could suppress Th1 and Th17 cells and exhibited an anti-inflammatory effect on EAU, providing an alternative approach to ameliorate autoimmune diseases mediated by these cells.
    Keywords:  Th1 and Th17 cells; aerobic glycolysis; anti-inflammation; biomaterial; experimental autoimmune uveitis; sustained release
    DOI:  https://doi.org/10.2147/IJN.S349360
  9. Immunobiology. 2022 Apr 18. pii: S0171-2985(22)00046-8. [Epub ahead of print]227(3): 152220
    Interleukin 17, the double-edged sword in atherosclerosis.
    Aysan Moeinafshar, Sepideh Razi, Nima Rezaei.
      Cardiovascular diseases, including atherosclerosis, are the number one cause of death worldwide. These diseases have taken the place of pneumonia and other infectious diseases in the epidemiological charts. Thus, their importance should not be underestimated. Atherosclerosis is an inflammatory disease. Therefore, immunological signaling molecules and immune cells carry out a central role in its etiology. One of these signaling molecules is interleukin (IL)-17. This relatively newly discovered signaling molecule might have a dual role as acting both pro-atherogenic and anti-atherogenic depending on the situation. The majority of articles have discussed IL-17 and its action in atherosclerosis, and it may be a new target for the treatment of patients with this disease. In this review, the immunological basis of atherosclerosis with an emphasis on the role of IL-17 and a brief explanation of the role of IL-17 on atherosclerogenic disorders will be discussed.
    Keywords:  Atherosclerosis; Cytokines; IL-17; Macrophage; T helper cells
    DOI:  https://doi.org/10.1016/j.imbio.2022.152220
  10. Curr Opin Biotechnol. 2022 Apr 13. pii: S0958-1669(22)00044-1. [Epub ahead of print]75 102711
    Complexity of subcellular metabolism: strategies for compartment-specific profiling.
    Tushar H More, Karsten Hiller.
      Subcellular compartmentalization provides cells with tremendous advantages for the operation of cellular metabolism. Spatial separation of metabolism generates microenvironments with distinct concentrations of metabolites and cofactors allowing the cell to execute otherwise thermodynamically exclusive reactions simultaneously. Moreover, compartmentalization is also involved in the fine-tuned regulation of gene expression. Thus, the elucidation of compartment-specific metabolic processes has become essential for a thorough understanding of cellular metabolism. The limited availability of reliable methods to inspect metabolic activities in subcellular compartments has been a major impediment in this field. During the last decade, progress has been greatly extended through methodological advances in subcellular metabolic profiling. This review summarizes recent strategies applied for the direct and indirect assessment of compartment-specific metabolism. We review contemporary techniques, recent advances, limitations, and future trends in the field of subcellular metabolomics.
    DOI:  https://doi.org/10.1016/j.copbio.2022.102711
  11. Mol Metab. 2022 Apr 19. pii: S2212-8778(22)00070-9. [Epub ahead of print] 101501
    Tetracycline response element driven Cre causes ectopic recombinase activity independent of transactivator element.
    Kenneth T Lewis, Lily R Oles, Ormond A MacDougald.
      OBJECTIVE: Tamoxifen is widely used for inducible Cre-LoxP systems but has several undesirable side effects for researchers investigating metabolism or energy balance, including weight loss, lipoatrophy, and drug incorporation into lipid stores. For this reason, we sought to determine whether a doxycycline-inducible system would be more advantageous for adipocyte-specific Cre mouse models, but serendipitously discovered widespread ectopic tetracycline response element Cre (TRE-Cre) recombinase activity.METHODS: Adipocyte-specific tamoxifen- and doxycycline-inducible Cre mice were crossed to fluorescent Cre reporter mice and visualized by confocal microscopy to assess efficiency and background activity. TRE-Cre mice were crossed to stop-floxed diphtheria toxin mice to selectively ablate cells with background Cre activity.
    RESULTS: Tamoxifen- and doxycycline-inducible systems performed similarly in adipose tissues, but ectopic Cre recombination was evident in numerous other cell types of the latter, most notably neurons. The source of ectopic Cre activity was isolated to the TRE-Cre transgene, driven by the pTet (tetO7) tetracycline-inducible promoter. Ablation of cells with ectopic recombination in mice led to stunted growth, diminished survival, and reduced brain mass.
    CONCLUSIONS: These results indicate that tamoxifen- and doxycycline-inducible adipocyte-specific Cre mouse models are similarly efficient, but the TRE-Cre component of the latter is inherently leaky. TRE-Cre background activity is especially pronounced in the brain and peripheral nerve fibers, and selective ablation of these cells impairs mouse development and survival. Caution should be taken when pairing TRE-Cre with floxed alleles that have defined roles in neural function, and additional controls should be included when using this model system.
    Keywords:  AdipoChaser; Ectopic Cre activity; TRE-Cre; pTet; tetO7-Cre; tetracycline response element
    DOI:  https://doi.org/10.1016/j.molmet.2022.101501
  12. Cancer Immunol Res. 2022 Apr 18. OF1
    A Ménage à Trois of Cytotoxic Effector Cells: γδ T Cells Suppress NK Cells but Not CTLs.
    Dieter Kabelitz.
      Three types of cytotoxic effector cells can kill tumor cells: innate natural killer (NK) cells, CD8+ CTL, and γδ T cells. In this issue, Walwyn-Brown and colleagues report new insights into the interplay between these three cell types that are integral to antitumor immunity, finding that γδ T cells can specifically suppress NK cells but not CD8+ CTLs. These results are relevant in view of the so far limited efficacy of γδ T-cell immunotherapy. See related article by Walwyn-Brown et al., (3) .
    DOI:  https://doi.org/10.1158/2326-6066.CIR-22-0148
  13. Adipocyte. 2022 Dec;11(1): 239-249
    A chromatin accessibility landscape during early adipogenesis of human adipose-derived stem cells.
    Sen Li, Xiaolin Zong, Liheng Zhang, Luya Li, Jianxin Wu.
      Obesity has become a serious global public health problem; a deeper understanding of systemic change of chromatin accessibility during human adipogenesis contributes to conquering obesity and its related diseases. Here, we applied the ATAC-seq method to depict a high-quality genome-wide time-resolved accessible chromatin atlas during adipogenesis of human adipose-derived stem cells (hASCs). Our data indicated that the chromatin accessibility drastic dynamically reformed during the adipogenesis of hASCs and 8 h may be the critical transition node of adipogenesis chromatin states from commitment phase to determination phase. Moreover, upon adipogenesis, we also found that the chromatin accessibility of regions related to anti-apoptotic, angiogenic and immunoregulatory gradually increased, which is beneficial to maintaining the health of adipose tissue (AT). Finally, the chromatin accessibility changed significantly in intronic regions of peroxisome proliferator-activated receptor γ during adipogenesis, and these regions were rich in transcription factors binding motifs that were exposed for further regulation. Overall, we systematically analysed the complex change of chromatin accessibility occurring in the early stage of adipogenesis and deepened our understanding of human adipogenesis. Furthermore, we also provided a good reference data resource of genome-wide chromatin accessibility for future studies on human adipogenesis.
    Keywords:  ATAC-seq; Obesity; adipogenesis; chromatin accessibility; human adipose-derived stem cells
    DOI:  https://doi.org/10.1080/21623945.2022.2063015
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