bims-aditis 2021-12-26 papers

bims-aditis

Biomed News

on Adipose tissue, inflammation, immunometabolism

Issue of 2021–12–26
eleven papers selected by
Matthew C. Sinton, University of Glasgow

Novel insights into adipose tissue heterogeneity.
White Adipose Tissue Depots Respond to Chronic Beta-3 Adrenergic Receptor Activation in a Sexually Dimorphic and Depot Divergent Manner.
The New Role of AMP-Activated Protein Kinase in Regulating Fat Metabolism and Energy Expenditure in Adipose Tissue.
Susceptibility to diet-induced obesity at thermoneutral conditions is independent of UCP1.
Association Between Adipose Tissue Characteristics and Metabolic Flexibility in Humans: A Systematic Review.
Controlling TH17 cells.
m6A Regulators in Human Adipose Tissue - Depot-Specificity and Correlation With Obesity.
Costimulation of γδTCR and TLR7/8 promotes Vδ2 T-cell antitumor activity by modulating mTOR pathway and APC function.
Lipid Droplets, the Central Hub Integrating Cell Metabolism and the Immune System.
Glycolysis under Circadian Control.
Metabolic and Transcriptional Changes across Osteogenic Differentiation of Mesenchymal Stromal Cells.

Rev Endocr Metab Disord. 2021 Dec 21.

Novel insights into adipose tissue heterogeneity.

Tongtong Wang, Anand Kumar Sharma, Christian Wolfrum.

  When normalized to volume, adipose tissue is comprised mainly of large lipid metabolizing and storing cells called adipocytes. Strikingly, the numerical representation of non-adipocytes, composed of a wide variety of cell types found in the so-called stromal vascular fraction (SVF), outnumber adipocytes by far. Besides its function in energy storage, adipose tissue has emerged as a versatile organ that regulates systemic metabolism and has therefore constituted an attractive target for the treatment of metabolic diseases. Recent high-resolution single cells/nucleus RNA seq data exemplify an intriguingly profound diversity of both adipocytes and SVF cells in all adipose depots, and the current data, while limited, demonstrate the significance of the intra-tissue cell composition in shaping the overall functionality of this tissue. Due to the complexity of adipose tissue, our understanding of the biological relevance of this heterogeneity and plasticity is fractional. Therefore, establishing atlases of adipose tissue cell heterogeneity is the first step towards generating an understanding of these functionalities. In this review, we will describe the current knowledge on adipose tissue cell composition and the heterogeneity of single-cell RNA sequencing, including the technical limitations.

Keywords:  Adipose tissue; Heterogeneity; Mature adipocytes; Single cell RNA sequencing; Stromal vascular fraction

DOI:  https://doi.org/10.1007/s11154-021-09703-8
Cells. 2021 Dec 08. pii: 3453. [Epub ahead of print]10(12):

White Adipose Tissue Depots Respond to Chronic Beta-3 Adrenergic Receptor Activation in a Sexually Dimorphic and Depot Divergent Manner.

Eric D Queathem, Rebecca J Welly, Laura M Clart, Candace C Rowles, Hunter Timmons, Maggie Fitzgerald, Peggy A Eichen, Dennis B Lubahn, Victoria J Vieira-Potter.

  Beta-3 adrenergic receptor activation via exercise or CL316,243 (CL) induces white adipose tissue (WAT) browning, improves glucose tolerance, and reduces visceral adiposity. Our aim was to determine if sex or adipose tissue depot differences exist in response to CL. Daily CL injections were administered to diet-induced obese male and female mice for two weeks, creating four groups: male control, male CL, female control, and female CL. These groups were compared to determine the main and interaction effects of sex (S), CL treatment (T), and WAT depot (D). Glucose tolerance, body composition, and energy intake and expenditure were assessed, along with perigonadal (PGAT) and subcutaneous (SQAT) WAT gene and protein expression. CL consistently improved glucose tolerance and body composition. Female PGAT had greater protein expression of the mitochondrial uncoupling protein 1 (UCP1), while SQAT (S, p < 0.001) was more responsive to CL in increasing UCP1 (S×T, p = 0.011) and the mitochondrial biogenesis induction protein, PPARγ coactivator 1α (PGC1α) (S×T, p = 0.026). Females also displayed greater mitochondrial OXPHOS (S, p < 0.05) and adiponectin protein content (S, p < 0.05). On the other hand, male SQAT was more responsive to CL in increasing protein levels of PGC1α (S×T, p = 0.046) and adiponectin (S, p < 0.05). In both depots and in both sexes, CL significantly increased estrogen receptor beta (ERβ) and glucose-related protein 75 (GRP75) protein content (T, p < 0.05). Thus, CL improves systemic and adipose tissue-specific metabolism in both sexes; however, sex differences exist in the WAT-specific effects of CL. Furthermore, across sexes and depots, CL affects estrogen signaling by upregulating ERβ.

Keywords:  UCP1; adipose tissue metabolism; adrenergic activity; browning; estrogen signaling; insulin resistance; sex differences

DOI:  https://doi.org/10.3390/cells10123453
Biomolecules. 2021 Nov 24. pii: 1757. [Epub ahead of print]11(12):

The New Role of AMP-Activated Protein Kinase in Regulating Fat Metabolism and Energy Expenditure in Adipose Tissue.

Qun Wang, Jiayi Sun, Mengyu Liu, Yaqi Zhou, Lei Zhang, Yanzhang Li.

  Obesity is characterized by excessive accumulation of fat in the body, which is triggered by a body energy intake larger than body energy consumption. Due to complications such as cardiovascular diseases, type 2 diabetes (T2DM), obstructive pneumonia and arthritis, as well as high mortality, morbidity and economic cost, obesity has become a major health problem. The global prevalence of obesity, and its comorbidities is escalating at alarming rates, demanding the development of additional classes of therapeutics to reduce the burden of disease further. As a central energy sensor, the AMP-activated protein kinase (AMPK) has recently been elucidated to play a paramount role in fat synthesis and catabolism, especially in regulating the energy expenditure of brown/beige adipose tissue and the browning of white adipose tissue (WAT). This review discussed the role of AMPK in fat metabolism in adipose tissue, emphasizing its role in the energy expenditure of brown/beige adipose tissue and browning of WAT. A deeper understanding of the role of AMPK in regulating fat metabolism and energy expenditure can provide new insights into obesity research and treatment.

Keywords:  AMPK; brown/beige adipose tissue; browning; energy expenditure; obesity

DOI:  https://doi.org/10.3390/biom11121757
Am J Physiol Endocrinol Metab. 2021 Dec 20.

Susceptibility to diet-induced obesity at thermoneutral conditions is independent of UCP1.

Sebastian Dieckmann, Akim Strohmeyer, Monja Willershäuser, Stefanie F Maurer, Wolfgang Wurst, Susan Marschall, Martin Hrabě de Angelis, Ralf Kühn, Anna Worthmann, Marceline M Fuh, Joerg Heeren, Nikolai Köhler, Josch K Pauling, Martin Klingenspor.

  Objective Activation of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) upon cold stimulation leads to substantial increase in energy expenditure to defend body temperature. Increases in energy expenditure after a high caloric food intake, termed diet-induced thermogenesis, are also attributed to BAT. These properties render BAT a potential target to combat diet-induced obesity. However, studies investigating the role of UCP1 to protect against diet-induced obesity are controversial and rely on the phenotyping of a single constitutive UCP1-knockout model. To address this issue, we generated a novel UCP1-knockout model by Cre-mediated deletion of Exon 2 in the UCP1 gene. We studied the effect of constitutive UCP1 knockout on metabolism and the development of diet-induced obesity. Methods UCP1 knockout and wildtype mice were housed at 30°C and fed a control diet for 4-weeks followed by 8-weeks of high-fat diet. Body weight and food intake were monitored continuously over the course of the study and indirect calorimetry was used to determine energy expenditure during both feeding periods. Results Based on Western blot analysis, thermal imaging and noradrenaline test, we confirmed the lack of functional UCP1 in knockout mice. However, body weight gain, food intake and energy expenditure were not affected by deletion of UCP1 gene function during both feeding periods. Conclusion We introduce a novel UCP1-KO mouse enabling the generation of conditional UCP1-knockout mice to scrutinize the contribution of UCP1 to energy metabolism in different cell types or life stages. Our results demonstrate that UCP1 does not protect against diet-induced obesity at thermoneutrality.

Keywords:  Uncoupling protein 1; adipose tissue; diet induced obesity; thermogenesis

DOI:  https://doi.org/10.1152/ajpendo.00278.2021
Front Nutr. 2021 ;8 744187

Association Between Adipose Tissue Characteristics and Metabolic Flexibility in Humans: A Systematic Review.

Alice Glaves, Francisco Díaz-Castro, Javiera Farías, Rodrigo Ramírez-Romero, Jose E Galgani, Rodrigo Fernández-Verdejo.

  Adipose tissue total amount, distribution, and phenotype influence metabolic health. This may be partially mediated by the metabolic effects that these adipose tissue characteristics exert on the nearby and distant tissues. Thus, adipose tissue may influence the capacity of cells, tissues, and the organism to adapt fuel oxidation to fuel availability, i.e., their metabolic flexibility (MetF). Our aim was to systematically review the evidence for an association between adipose tissue characteristics and MetF in response to metabolic challenges in human adults. We searched in PubMed (last search on September 4, 2021) for reports that measured adipose tissue characteristics (total amount, distribution, and phenotype) and MetF in response to metabolic challenges (as a change in respiratory quotient) in humans aged 18 to <65 years. Any study design was considered, and the risk of bias was assessed with a checklist for randomized and non-randomized studies. From 880 records identified, 22 remained for the analysis, 10 of them measured MetF in response to glucose plus insulin stimulation, nine in response to dietary challenges, and four in response to other challenges. Our main findings were that: (a) MetF to glucose plus insulin stimulation seems inversely associated with adipose tissue total amount, waist circumference, and visceral adipose tissue; and (b) MetF to dietary challenges does not seem associated with adipose tissue total amount or distribution. In conclusion, evidence suggests that adipose tissue may directly or indirectly influence MetF to glucose plus insulin stimulation, an effect probably explained by skeletal muscle insulin sensitivity. Systematic Review Registration: PROSPERO [CRD42020167810].

Keywords:  body composition; fuel oxidation; metabolic health; obesity; respiratory quotient

DOI:  https://doi.org/10.3389/fnut.2021.744187
Nat Immunol. 2022 Jan;23(1): 2

Controlling TH17 cells.

Nicholas J Bernard.

DOI: https://doi.org/10.1038/s41590-021-01112-y
Front Endocrinol (Lausanne). 2021 ;12 778875

m6A Regulators in Human Adipose Tissue - Depot-Specificity and Correlation With Obesity.

Torunn Rønningen, Mai Britt Dahl, Tone Gretland Valderhaug, Akin Cayir, Maria Keller, Anke Tönjes, Matthias Blüher, Yvonne Böttcher.

   Background: N6-methyladenosine (m6A) is one of the most abundant post-transcriptional modifications on mRNA influencing mRNA metabolism. There is emerging evidence for its implication in metabolic disease. No comprehensive analyses on gene expression of m6A regulators in human adipose tissue, especially in paired adipose tissue depots, and its correlation with clinical variables were reported so far. We hypothesized that inter-depot specific gene expression of m6A regulators may differentially correlate with clinical variables related to obesity and fat distribution.
Methods: We extracted intra-individually paired gene expression data (omental visceral adipose tissue (OVAT) N=48; subcutaneous adipose tissue (SAT) N=56) of m6A regulators from an existing microarray dataset. We also measured gene expression in another sample set of paired OVAT and SAT (N=46) using RT-qPCR. Finally, we extracted existing gene expression data from peripheral mononuclear blood cells (PBMCs) and single nucleotide polymorphisms (SNPs) in METTL3 and YTHDF3 from genome wide data from the Sorbs population (N=1049). The data were analysed for differential gene expression between OVAT and SAT; and for association with obesity and clinical variables. We further tested for association of SNP markers with gene expression and clinical traits.
Results: In adipose tissue we observed that several m6A regulators (WTAP, VIRMA, YTHDC1 and ALKBH5) correlate with obesity and clinical variables. Moreover, we found adipose tissue depot specific gene expression for METTL3, WTAP, VIRMA, FTO and YTHDC1. In PBMCs, we identified ALKBH5 and YTHDF3 correlated with obesity. Genetic markers in METTL3 associate with BMI whilst SNPs in YTHDF3 are associated with its gene expression.
Conclusions: Our data show that expression of m6A regulators correlates with obesity, is adipose tissue depot-specific and related to clinical traits. Genetic variation in m6A regulators adds an additional layer of variability to the functional consequences.

Keywords:  RNA methylome; epitranscriptome; fat distribution; m6A methylation; obesity; transcription

DOI:  https://doi.org/10.3389/fendo.2021.778875
J Immunother Cancer. 2021 Dec;pii: e003339. [Epub ahead of print]9(12):

Costimulation of γδTCR and TLR7/8 promotes Vδ2 T-cell antitumor activity by modulating mTOR pathway and APC function.

Huaishan Wang, Hui Chen, Shujing Liu, Jie Zhang, Hezhe Lu, Rajasekharan Somasundaram, Robin Choi, Gao Zhang, Lingling Ou, John Scholler, Shifu Tian, Liyun Dong, Guo Yeye, Lili Huang, Thomas Connelly, Ling Li, Alexander Huang, Tara C Mitchell, Yi Fan, Carl H June, Gordon B Mills, Wei Guo, Meenhard Herlyn, Xiaowei Xu.

   BACKGROUND: Gamma delta (γδ) T cells are attractive effector cells for cancer immunotherapy. Vδ2 T cells expanded by zoledronic acid (ZOL) are the most commonly used γδ T cells for adoptive cell therapy. However, adoptive transfer of the expanded Vδ2 T cells has limited clinical efficacy.
METHODS: We developed a costimulation method for expansion of Vδ2 T cells in PBMCs by activating γδ T-cell receptor (γδTCR) and Toll-like receptor (TLR) 7/8 using isopentenyl pyrophosphate (IPP) and resiquimod, respectively, and tested the functional markers and antitumoral effects in vitro two-dimensional two-dimensional and three-dimensional spheroid models and in vivo models. Single-cell sequencing dataset analysis and reverse-phase protein array were employed for mechanistic studies.
RESULTS: We find that Vδ2 T cells expanded by IPP plus resiquimod showed significantly increased cytotoxicity to tumor cells with lower programmed cell death protein 1 (PD-1) expression than Vδ2 T cells expanded by IPP or ZOL. Mechanistically, the costimulation enhanced the activation of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/Akt)-the mammalian target of rapamycin (mTOR) pathway and the TLR7/8-MyD88 pathway. Resiquimod stimulated Vδ2 T-cell expansion in both antigen presenting cell dependent and independent manners. In addition, resiquimod decreased the number of adherent inhibitory antigen-presenting cells (APCs) and suppressed the inhibitory function of APCs by decreasing PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in these cells during in vitro Vδ2 T-cell expansion. Finally, we showed that human Vδ2 T cells can be expanded from PBMCs and spleen of humanized NSG mice using IPP plus resiquimod or ZOL, demonstrating that humanized mice are a promising preclinical model for studying human γδ T-cell development and function.
CONCLUSIONS: Vδ2 T cells expanded by IPP and resiquimod demonstrate improved anti-tumor function and have the potential to increase the efficacy of γδ T cell-based therapies.

Keywords:  adjuvants; adoptive; costimulatory and inhibitory T-cell receptors; immunological; immunotherapy; melanoma

DOI:  https://doi.org/10.1136/jitc-2021-003339
Front Physiol. 2021 ;12 746749

Lipid Droplets, the Central Hub Integrating Cell Metabolism and the Immune System.

Wei Zhang, Linyong Xu, Ling Zhu, Yifan Liu, Siwei Yang, Mingyi Zhao.

  Lipid droplets (LDs) are commonly found in various biological cells and are organelles related to cell metabolism. LDs, the number and size of which are heterogeneous across cell type, are primarily composed of polar lipids and proteins on the surface with neutral lipids in the core. Neutral lipids stored in LDs can be degraded by lipolysis and lipophagocytosis, which are regulated by various proteins. The process of LD formation can be summarized in four steps. In addition to energy production, LDs play an extremely pivotal role in a variety of physiological and pathological processes, such as endoplasmic reticulum stress, lipid toxicity, storage of fat-soluble vitamins, regulation of oxidative stress, and reprogramming of cell metabolism. Interestingly, LDs, the hub of integration between metabolism and the immune system, are involved in antitumor immunity, anti-infective immunity (viruses, bacteria, parasites, etc.) and some metabolic immune diseases. Herein, we summarize the role of LDs in several major immune cells as elucidated in recent years, including T cells, dendritic cells, macrophages, mast cells, and neutrophils. Additionally, we analyze the role of the interaction between LDs and immune cells in two typical metabolic immune diseases: atherosclerosis and Mycobacterium tuberculosis infection.

Keywords:  atherosclerosis; immune cells; immunity; lipid droplets; metabolism

DOI:  https://doi.org/10.3389/fphys.2021.746749
Int J Mol Sci. 2021 Dec 20. pii: 13666. [Epub ahead of print]22(24):

Glycolysis under Circadian Control.

Jana Zlacká, Michal Zeman.

  Glycolysis is considered a main metabolic pathway in highly proliferative cells, including endothelial, epithelial, immune, and cancer cells. Although oxidative phosphorylation (OXPHOS) is more efficient in ATP production per mole of glucose, proliferative cells rely predominantly on aerobic glycolysis, which generates ATP faster compared to OXPHOS and provides anabolic substrates to support cell proliferation and migration. Cellular metabolism, including glucose metabolism, is under strong circadian control. Circadian clocks control a wide array of metabolic processes, including glycolysis, which exhibits a distinct circadian pattern. In this review, we discuss circadian regulations during metabolic reprogramming and key steps of glycolysis in activated, highly proliferative cells. We suggest that the inhibition of metabolic reprogramming in the circadian manner can provide some advantages in the inhibition of oxidative glycolysis and a chronopharmacological approach is a promising way to treat diseases associated with up-regulated glycolysis.

Keywords:  circadian; clock genes; glycolysis; metabolic reprogramming; oxidative phosphorylation

DOI:  https://doi.org/10.3390/ijms222413666
Bioengineering (Basel). 2021 Dec 10. pii: 208. [Epub ahead of print]8(12):

Metabolic and Transcriptional Changes across Osteogenic Differentiation of Mesenchymal Stromal Cells.

Thora Bjorg Sigmarsdottir, Sarah McGarrity, Adrián López García de Lomana, Aristotelis Kotronoulas, Snaevar Sigurdsson, James T Yurkovich, Ottar Rolfsson, Olafur Eysteinn Sigurjonsson.

  Mesenchymal stromal cells (MSCs) are multipotent post-natal stem cells with applications in tissue engineering and regenerative medicine. MSCs can differentiate into osteoblasts, chondrocytes, or adipocytes, with functional differences in cells during osteogenesis accompanied by metabolic changes. The temporal dynamics of these metabolic shifts have not yet been fully characterized and are suspected to be important for therapeutic applications such as osteogenesis optimization. Here, our goal was to characterize the metabolic shifts that occur during osteogenesis. We profiled five key extracellular metabolites longitudinally (glucose, lactate, glutamine, glutamate, and ammonia) from MSCs from four donors to classify osteogenic differentiation into three metabolic stages, defined by changes in the uptake and secretion rates of the metabolites in cell culture media. We used a combination of untargeted metabolomic analysis, targeted analysis of 13C-glucose labelled intracellular data, and RNA-sequencing data to reconstruct a gene regulatory network and further characterize cellular metabolism. The metabolic stages identified in this proof-of-concept study provide a framework for more detailed investigations aimed at identifying biomarkers of osteogenic differentiation and small molecule interventions to optimize MSC differentiation for clinical applications.

Keywords:  gene regulatory network; glycolysis; mesenchymal stromal cells (MSCs); metabolic changes; metabolism; metabolites; osteogenic differentiation; oxidative phosphorylation

DOI:  https://doi.org/10.3390/bioengineering8120208