bims-aditis Biomed News
on Adipose tissue, inflammation, immunometabolism
Issue of 2021–12–05
twelve papers selected by
Matthew C. Sinton, University of Glasgow
  1. Cysteine 253 of UCP1 regulates energy expenditure and sex-dependent adipose tissue inflammation.
  2. IL-17A and IFN-γ are Up-regulated in CD4 and γδ T Cells in Active Behcet's Disease Patients.
  3. A new immunometabolic perspective of intervertebral disc degeneration.
  4. Evidence That Hypothalamic Gliosis Is Related to Impaired Glucose Homeostasis in Adults With Obesity.
  5. β3-adrenergic receptor downregulation leads to adipocyte catecholamine resistance in obesity.
  6. Inter-Organ Crosstalk in the Development of Obesity-Associated Insulin Resistance.
  7. Local acetate inhibits brown adipose tissue function.
  8. The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β.
  9. Conditional Gene Targeting Using UCP1-Cre Mice Directly Targets the Central Nervous System Beyond Thermogenic Adipose Tissues.
  10. CD69 mediates the protective role of adipose tissue-derived mesenchymal stem cells against Pseudomonas aeruginosa pulmonary infection.
  11. Adipose Tissue Inflammation is Not Related to Adipose Insulin Resistance in Humans.
  12. The ATF3 inducer protects against diet-induced obesity via suppressing adipocyte adipogenesis and promoting lipolysis and browning.
  1. Cell Metab. 2021 Nov 24. pii: S1550-4131(21)00531-3. [Epub ahead of print]
    Cysteine 253 of UCP1 regulates energy expenditure and sex-dependent adipose tissue inflammation.
    Evanna L Mills, Cathal Harmon, Mark P Jedrychowski, Haopeng Xiao, Anja V Gruszczyk, Gary A Bradshaw, Nhien Tran, Ryan Garrity, Dina Laznik-Bogoslavski, John Szpyt, Hannah Prendeville, Lydia Lynch, Michael P Murphy, Steven P Gygi, Bruce M Spiegelman, Edward T Chouchani.
      Uncoupling protein 1 (UCP1) is a major regulator of brown and beige adipocyte energy expenditure and metabolic homeostasis. However, the widely employed UCP1 loss-of-function model has recently been shown to have a severe deficiency in the entire electron transport chain of thermogenic fat. As such, the role of UCP1 in metabolic regulation in vivo remains unclear. We recently identified cysteine-253 as a regulatory site on UCP1 that elevates protein activity upon covalent modification. Here, we examine the physiological importance of this site through the generation of a UCP1 cysteine-253-null (UCP1 C253A) mouse, a precise genetic model for selective disruption of UCP1 in vivo. UCP1 C253A mice exhibit significantly compromised thermogenic responses in both males and females but display no measurable effect on fat accumulation in an obesogenic environment. Unexpectedly, we find that a lack of C253 results in adipose tissue redox stress, which drives substantial immune cell infiltration and systemic inflammatory pathology in adipose tissues and liver of male, but not female, mice. Elevation of systemic estrogen reverses this male-specific pathology, providing a basis for protection from inflammation due to loss of UCP1 C253 in females. Together, our results establish the UCP1 C253 activation site as a regulator of acute thermogenesis and sex-dependent tissue inflammation.
    Keywords:  UCP1; cysteine; inflammation; metabolism; reactive oxygen species; sex differences
    DOI:  https://doi.org/10.1016/j.cmet.2021.11.003
  2. Immunol Lett. 2021 Nov 24. pii: S0165-2478(21)00180-2. [Epub ahead of print]
    IL-17A and IFN-γ are Up-regulated in CD4 and γδ T Cells in Active Behcet's Disease Patients.
    Vusala Abbasova, Ahmet Gul, Güher Saruhan-Direskeneli.
      Involvement of γδ T cells is implicated in the pathogenesis of Behçet's disease (BD) as a bridge between innate and adaptive responses. IL-17 and IL-22 have also been shown to participate in the BD pathogenesis in addition to IFN-γ. Mainly CD4+ T cells are investigated previously for the production of these inflammatory cytokines. In this study, the role of γδ T cells in cytokine-related mechanisms was evaluated in BD in comparison to CD4+ T cells. Surface expression of markers for functional states of both CD4+ and γδ T cells were compared in ex vivo samples collected from patients with BD and healthy controls (HC). Sixteen active BD (a-BD), 9 inactive BD (i-BD) patients and 25 HC were investigated. The expression of CD161, CCR6 as markers for IL-17 producing cells were analyzed on γδ and CD4+ T cells. IFN-γ, IL-17A, IL-22, as well as CD107a (LAMP1) and CD16 (FcγRIII) were evaluated in both cell subtypes after in vitro stimulation. Only IFN-γ production was increased in γδ T cells of a-BD patients. There was no difference in increase of CD107a or decrease of CD16 surface expression on γδ T cells upon stimulation between the groups. Ex vivo IL-17A and both IL-17A/IFN-γ production and expression of CD161, CCR6 by CD4+ T cells were increased in a-BD. Along with CD4+ T cells, γδ T cells have complementary roles in cytokine production in BD. Higher IFN-γ production of γδ T cells suggests the role of an environmental triggers in BD pathogenesis, whereas IL-17 related activity is mainly provided by CD4+ T cells.
    Keywords:  Behçet's disease; IL-17, IFN-γ; T helper cells; γδ T cell
    DOI:  https://doi.org/10.1016/j.imlet.2021.11.004
  3. Nat Rev Rheumatol. 2021 Nov 29.
    A new immunometabolic perspective of intervertebral disc degeneration.
    Vera Francisco, Jesús Pino, Miguel Ángel González-Gay, Francisca Lago, Jaro Karppinen, Osmo Tervonen, Ali Mobasheri, Oreste Gualillo.
      Intervertebral disc (IVD) degeneration is a common finding on spine imaging that increases in prevalence with age. IVD degeneration is a frequent cause of low back pain, which is a leading cause of disability. The process of IVD degeneration consists of gradual structural change accompanied by severe alterations in metabolic homeostasis. IVD degeneration, like osteoarthritis, is a common comorbidity in patients with obesity and type 2 diabetes mellitus, two metabolic syndrome pathological conditions in which adipokines are important promoters of low-grade inflammation, extracellular matrix degradation and fibrosis. Impairment in white adipose tissue function, due to the abnormal fat accumulation in obesity, is characterized by increased production of specific pro-inflammatory proteins such as adipokines by white adipose tissue and of cytokines such as TNF by immune cells of the stromal compartment. Investigations into the immunometabolic alterations in obesity and type 2 diabetes mellitus and their interconnections with IVD degeneration provide insights into how adipokines might affect the pathogenesis of IVD degeneration and impair IVD function and repair. Toll-like receptor-mediated signalling has also been implicated as a promoter of the inflammatory response in the metabolic alterations associated with IVD and is thus thought to have a role in IVD degeneration. Pathological starvation, obesity and adipokine dysregulation can result in immunometabolic alterations, which could be targeted for the development of new therapeutics.
    DOI:  https://doi.org/10.1038/s41584-021-00713-z
  4. Diabetes Care. 2021 Nov 30. pii: dc211535. [Epub ahead of print]
    Evidence That Hypothalamic Gliosis Is Related to Impaired Glucose Homeostasis in Adults With Obesity.
    Jennifer L Rosenbaum, Susan J Melhorn, Stefan Schoen, Mary F Webb, Mary Rosalynn B De Leon, Madelaine Humphreys, Kristina M Utzschneider, Ellen A Schur.
       OBJECTIVE: Preclinical research implicates hypothalamic glial cell responses in the pathogenesis of obesity and type 2 diabetes (T2D). In the current study we sought to translate such findings to humans by testing whether radiologic markers of gliosis in the mediobasal hypothalamus (MBH) were greater in individuals with obesity and impaired glucose homeostasis or T2D.
    RESEARCH DESIGN AND METHODS: Using cross-sectional and prospective cohort study designs, we applied a validated quantitative MRI approach to assess gliosis in 67 adults with obesity and normal glucose tolerance, impaired glucose tolerance (IGT), or T2D. Assessments of glucose homeostasis were conducted via oral glucose tolerance tests (OGTT) and β-cell modeling.
    RESULTS: We found significantly greater T2 relaxation times (a marker of gliosis by MRI), that were independent of adiposity, in the groups with IGT and T2D as compared with the group with normal glucose tolerance. Findings were present in the MBH, but not control regions. Moreover, positive linear associations were present in the MBH but not control regions between T2 relaxation time and glucose area under the curve during an OGTT, fasting glucose concentrations, hemoglobin A1c, and visceral adipose tissue mass, whereas negative linear relationships were present in the MBH for markers of insulin sensitivity and β-cell function. In a prospective cohort study, greater MBH T2 relaxation times predicted declining insulin sensitivity over 1 year.
    CONCLUSIONS: Findings support a role for hypothalamic gliosis in the progression of insulin resistance in obesity and thus T2D pathogenesis in humans.
    DOI:  https://doi.org/10.2337/dc21-1535
  5. J Clin Invest. 2021 Nov 30. pii: e153357. [Epub ahead of print]
    β3-adrenergic receptor downregulation leads to adipocyte catecholamine resistance in obesity.
    Joseph M Valentine, Maryam Ahmadian, Omer Keinan, Mohammad Abu-Odeh, Peng Zhao, Xin Zhou, Mark P Keller, Hui Gao, Ruth T Yu, Christopher Liddle, Michael Downes, Jin Zhang, Aldons J Lusis, Alan D Attie, Ronald M Evans, Mikael Rydén, Alan R Saltiel.
      The dysregulation of energy homeostasis in obesity involves multi-hormone resistance. Although leptin and insulin resistance have been well characterized, catecholamine resistance remains largely unexplored. Murine β3-adrenergic receptor expression in adipocytes is orders of magnitude higher compared to other isoforms. While resistant to classical desensitization pathways, its mRNA (Adrb3) and protein expression are dramatically downregulated after ligand exposure (homologous desensitization). β3-adrenergic receptor downregulation also occurs after high fat diet feeding, concurrent with catecholamine resistance and elevated inflammation. This downregulation is recapitulated in vitro by TNFα treatment (heterologous desensitization). Both homologous and heterologous desensitization of Adrb3 were triggered by induction of the pseudokinase TRIB1 downstream of the EPAC/RAP2A/PI-PLC pathway. TRIB1 in turn degraded the primary transcriptional activator of Adrb3, CEBPα. EPAC/RAP inhibition enhanced catecholamine-stimulated lipolysis and energy expenditure in obese mice. Moreover, adipose tissue expression of genes in this pathway correlated with body weight extremes in a cohort of genetically diverse mice, and with BMI in two independent cohorts of humans. These data implicate a new signaling axis that may explain reduced hormone-stimulated lipolysis in obesity and resistance to therapeutic interventions with β3-adrenergic receptor agonists.
    Keywords:  Adipose tissue; Cell Biology; G proteins; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI153357
  6. Handb Exp Pharmacol. 2021 Dec 02.
    Inter-Organ Crosstalk in the Development of Obesity-Associated Insulin Resistance.
    Megan Piquet, M Carmen Martínez, Tania Romacho.
      The epidemics of obesity and type 2 diabetes have led to intensive investigation of the underlying mechanisms of these diseases and their main complications such as cardiovascular diseases and non-alcoholic fatty liver disease. This search has contributed to better understand how organs and tissues communicate with each other in the so-called inter-organ crosstalk. Adipose tissue, the liver, or skeletal muscle can actively release secreted factors termed "organokines" which can interact with other distant targets in complex networks. More recently, other novel mediators of inter-organ crosstalk such as extracellular vesicles and their non-traditional cargoes as miRNAs and lncRNAs are gaining importance and represent potential therapeutic targets. In the present chapter we summarize some of the current knowledge on inter-organ communication with a focus on adipose tissue-released factors and their modulation on other organs and tissues like pancreas, liver, skeletal muscle, the cardiovascular system, and the gut in the context of obesity and its progression to insulin resistance. We also provide a perspective on mediators of inter-organ crosstalk as potential therapeutic targets.
    Keywords:  Crosstalk; Insulin resistance; Obesity; Organokines; Type 2 diabetes
    DOI:  https://doi.org/10.1007/164_2021_564
  7. Proc Natl Acad Sci U S A. 2021 Dec 07. pii: e2116125118. [Epub ahead of print]118(49):
    Local acetate inhibits brown adipose tissue function.
    Wenfei Sun, Hua Dong, Christian Wolfrum.
      Brown adipose tissue has been extensively studied in the last decade for its potential to counteract the obesity pandemic. However, the paracrine regulation within brown tissue is largely unknown. Here, we show that local acetate directly inhibits brown fat thermogenesis, without changing acetate levels in the circulation. We demonstrate that modulating acetate within brown tissue at physiological levels blunts its function and systemically decreases energy expenditure. Using a series of transcriptomic analyses, we identified genes related to the tricarboxylic acid cycle and brown adipocyte formation, which are down-regulated upon local acetate administration. Overall, these findings demonstrate that local acetate inhibits brown fat function.
    Keywords:  RNA-seq; acetate; brown adipose tissue; obesity
    DOI:  https://doi.org/10.1073/pnas.2116125118
  8. Front Immunol. 2021 ;12 700431
    The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1β.
    George A Timmons, Richard G Carroll, James R O'Siorain, Mariana P Cervantes-Silva, Lauren E Fagan, Shannon L Cox, Eva Palsson-McDermott, David K Finlay, Emma E Vincent, Nicholas Jones, Annie M Curtis.
      The transcription factor BMAL1 is a clock protein that generates daily or circadian rhythms in physiological functions including the inflammatory response of macrophages. Intracellular metabolic pathways direct the macrophage inflammatory response, however whether the clock is impacting intracellular metabolism to direct this response is unclear. Specific metabolic reprogramming of macrophages controls the production of the potent pro-inflammatory cytokine IL-1β. We now describe that the macrophage molecular clock, through Bmal1, regulates the uptake of glucose, its flux through glycolysis and the Krebs cycle, including the production of the metabolite succinate to drive Il-1β production. We further demonstrate that BMAL1 modulates the level and localisation of the glycolytic enzyme PKM2, which in turn activates STAT3 to further drive Il-1β mRNA expression. Overall, this work demonstrates that BMAL1 is a key metabolic sensor in macrophages, and its deficiency leads to a metabolic shift of enhanced glycolysis and mitochondrial respiration, leading to a heightened pro-inflammatory state. These data provide insight into the control of macrophage driven inflammation by the molecular clock, and the potential for time-based therapeutics against a range of chronic inflammatory diseases.
    Keywords:  IL-1β; macrophage inflammation; metabolism; molecular clock; pSTAT3
    DOI:  https://doi.org/10.3389/fimmu.2021.700431
  9. Mol Metab. 2021 Nov 26. pii: S2212-8778(21)00263-5. [Epub ahead of print] 101405
    Conditional Gene Targeting Using UCP1-Cre Mice Directly Targets the Central Nervous System Beyond Thermogenic Adipose Tissues.
    Kristin E Claflin, Kyle H Flippo, Andrew I Sullivan, Meghan C Naber, Bolu Zhou, Tate J Neff, Sharon O Jensen-Cody, Matthew J Potthoff.
       OBJECTIVE: Uncoupling protein 1 (UCP1) is a mitochondrial protein critical for adaptive thermogenesis in adipose tissues, and as such, is typically believed to be restricted to thermogenic adipose tissues. UCP1-Cre transgenic mice are utilized in numerous studies to provide "brown adipose-specific" conditional gene targeting. Here, we examine the distribution of Cre and UCP1 throughout the body in UCP1-Cre reporter mice.
    METHODS: UCP1-Cre mice crossed to Ai14-tdTomato and Ai9-tdTomato reporter mice were used to explore the tissue distribution of Cre recombinase and Ucp1 mRNA in various tissues. UCP1-Cre mice were independently infected with either a Cre-dependent PHP.eB-tdTomato virus or a Cre-dependent AAV-tdTomato virus to determine if and where UCP1 is actively expressed in the adult central nervous system. In situ analysis of deposited single cell RNA sequencing data was used to evaluate Ucp1 expression in the hypothalamus.
    RESULTS: As expected, Ucp1 expression was detected in both brown and inguinal adipose tissues. Ucp1 expression was also detected in the kidney, adrenal glands, thymus and the hypothalamus. Consistent with detectable Ucp1 expression, tdTomato expression was also observed in brown adipose tissue, inguinal white adipose tissue, kidney, adrenal glands and the hypothalamus of both male and female UCP1-Cre;Ai14-tdTomato and UCP1-Cre;Ai9-tdTomato mice by fluorescent imaging and qPCR. Critically, expression of tdTomato, and thus UCP1, within the central nervous system was observed in regions of the brain critical for the regulation of energy homeostasis, including the ventromedial hypothalamus (VMH).
    CONCLUSIONS: TdTomato expression in UCP1-Cre;tdTomato mice is not restricted to thermogenic adipose tissues. TdTomato was also expressed in the kidneys, adrenal glands and throughout the brain, including brain regions and cell types which are critical for multiple aspects of central regulation of energy homeostasis. Collectively, these data have important implications for the utility of UCP1-Cre mice as genetic tools to investigate gene function specifically in brown adipose tissue.
    Keywords:  VMH; adipose; beige; brain; brown; brown adipose tissue
    DOI:  https://doi.org/10.1016/j.molmet.2021.101405
  10. Clin Transl Med. 2021 11;11(11): e563
    CD69 mediates the protective role of adipose tissue-derived mesenchymal stem cells against Pseudomonas aeruginosa pulmonary infection.
    Yanshan Jiang, Fan Li, Yanan Li, Jielin Duan, Caixia Di, Yinggang Zhu, Jingya Zhao, Xinming Jia, Jieming Qu.
       BACKGROUND: Our previous study shows that Adipose tissue-derived mesenchymal stem cells (ASCs) are a promising strategy for cell-based therapy against pulmonary infection with Pseudomonas aeruginosa (P. aeruginosa), but the underlying mechanisms remain unclear.
    METHODS: cDNA microarray assay was performed to explore the transcriptome of ASCs primed by P. aeruginosa. Small interfering RNA (siRNA) was constructed to select the receptor candidates for P. aeruginosa recognition and granulocyte-macrophage colony-stimulating factor (GM-CSF) production in ASCs. The soluble protein chimeras containing the extracellular domain of human CD69 fused to the Fc region of human immunoglobulin IgG1 were used as a probe to validate the recognition of P. aeruginosa. The association between CD69 and extracellular regulated protein kinases 1/2 (ERK1/2) was explored via co-immunoprecipitation, siRNA, and inhibitor. The murine models of P. aeruginosa pneumonia treated with WT-ASCs, GM-CSF-/- -ASCs Cd69-/- -ASCs or Erk1-/- -ASCs were used to determine the role of GM-CSF, CD69, and ERK1 in ASCs against P. aeruginosa infection.
    RESULTS: We showed that C-type lectin receptor CD69 mediated the protective effects of ASCs partly through GM-CSF. CD69 could specifically recognize P. aeruginosa and regulate GM-CSF secretion of ASCs. CD69 regulated the production of GM-CSF via ERK1 in ASCs after P. aeruginosa infection. Moreover, the Administration of ASCs with deficiency of CD69 or ERK1 completely blocked its protective effects in a murine model of P. aeruginosa pneumonia.
    CONCLUSIONS: CD69 recognizes P. aeruginosa and further facilitates ERK1 activation, which plays a crucial role in ASCs-based therapy against P. aeruginosa pneumonia. CD69 may be a novel target molecule to improve ASCs-based therapy against P. aeruginosa infection.
    Keywords:  CD69; ERK1; GM-CSF; Pseudomonas aeruginosa; adipose tissue-derived mesenchymal stem cells
    DOI:  https://doi.org/10.1002/ctm2.563
  11. Diabetes. 2021 Dec 02. pii: db210609. [Epub ahead of print]
    Adipose Tissue Inflammation is Not Related to Adipose Insulin Resistance in Humans.
    Ana Elena Espinosa De Ycaza, Esben Søndergaard, Maria Morgan-Bathke, Kelli Lytle, Danae A Delivanis, Paola Ramos, Barbara Gisella Carranza Leon, Michael D Jensen.
      The role of adipose tissue (AT) inflammation on AT function in humans is unclear. We tested whether AT macrophage (ATM) content, cytokine gene expression and senescent cell burden (markers of AT inflammation) predict AT insulin resistance measured as the insulin concentration that suppresses lipolysis by 50% (IC5). We studied 86 volunteers with normal weight or obesity at baseline, and a subgroup of 25 volunteers with obesity before and after weight loss. There was a strong, positive relationship between IC50 and abdominal subcutaneous and femoral fat cell size (FCS). The positive, univariate relationships between IC50 and abdominal AT inflammatory markers: CD68, CD14, CD206 ATM/100 adipocytes, senescent cells, IL-6 and TNF-- mRNA were not significant after adjustment for FCS. A 10% weight loss significantly reduced IC50, however, there was no reduction in adipose ATM content, senescent cells or cytokine gene expression. Our study suggests that commonly used markers of AT inflammation are not causally linked to AT insulin resistance, whereas FCS is a strong predictor of AT insulin resistance with respect to lipolysis.
    DOI:  https://doi.org/10.2337/db21-0609
  12. Biomed Pharmacother. 2021 Nov 25. pii: S0753-3322(21)01226-9. [Epub ahead of print]145 112440
    The ATF3 inducer protects against diet-induced obesity via suppressing adipocyte adipogenesis and promoting lipolysis and browning.
    Hui-Chen Ku, Tsai-Yun Chan, Jia-Fang Chung, Yung-Hsi Kao, Ching-Feng Cheng.
      In this study, we investigated whether the activating transcription factor 3 (ATF3) inducer ST32db, a synthetic compound with a chemical structure similar to that of native Danshen compounds, exerts an anti-obesity effect in 3T3-L1 white preadipocytes, D16 beige cells, and mice with obesity induced by a high-fat diet (HFD). The results showed that ST32db inhibited 3T3-L1 preadipocyte differentiation by inhibiting adipogenesis/lipogenesis-related gene (and protein levels) and enhancing lipolysis-related gene (and protein levels) via the activation of β3-adrenoceptor (β3-AR)/PKA/p38, AMPK, and ERK pathways. Furthermore, ST32db inhibited triacylglycerol accumulation in D16 adipocytes by suppressing adipogenesis/lipogenesis-related gene (and protein levels) and upregulating browning gene expression by suppressing the β3-AR/PKA/p38, and AMPK pathways. Intraperitoneally injected ST32db (1 mg kg-1 twice weekly) inhibited body weight gain and reduced the weight of inguinal white adipose tissue (iWAT), epididymal WAT (eWAT), and mesenteric WAT, with no effects on food intake by the obese mice. The adipocyte diameter and area of iWAT and eWAT were decreased in obese mice injected with ST32db compared with those administered only HFD. In addition, ST32db significantly suppressed adipogenesis and activated lipolysis, browning, mitochondrial oxidative phosphorylation, and β-oxidation-related pathways by suppressing the p38 pathway in the iWAT of the obese mice. These results indicated that the ATF3 inducer ST32db has therapeutic potential for reducing obesity.
    Keywords:  activating transcription factor 3 inducer; adipocyte; adipogenesis; anti-obesity; browning; lipolysis
    DOI:  https://doi.org/10.1016/j.biopha.2021.112440
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