bims-aditis Biomed News
on Adipose tissue, inflammation, immunometabolism
Issue of 2021–10–24
twelve papers selected by
Matthew C. Sinton, University of Glasgow
  1. Type 3 Innate Lymphoid Cells as Regulators of the Host-Pathogen Interaction.
  2. Modulation of Adipocyte Metabolism by Microbial Short-Chain Fatty Acids.
  3. LETMD1 is required for mitochondrial structure and thermogenic function of brown adipocytes.
  4. Maternal high fructose diet exacerbates white adipose tissue thermogenic process in offspring upon exposure to cold temperature.
  5. Adipose-Tissue-Derived Mesenchymal Stem Cells Mediate PD-L1 Overexpression in the White Adipose Tissue of Obese Individuals, Resulting in T Cell Dysfunction.
  6. Functional diversity of human adipose tissue revealed by spatial mapping.
  7. New role for fatty acid receptor regulation of immune cells to control intestinal inflammation.
  8. Inflammatory arthritis increases the susceptibility to acute immune-mediated hepatitis in mice through enhancing leptin expression in T cells.
  9. Activation of the adipocyte CREB/CRTC pathway in obesity.
  10. The beta2 -adrenergic receptor - a re-emerging target to combat obesity and induce leanness?
  11. Mitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology.
  12. Hepatic progenitor cells promote the repair of schistosomiasis liver injury by inhibiting IL-33 secretion in mice.
  1. Front Immunol. 2021 ;12 748851
    Type 3 Innate Lymphoid Cells as Regulators of the Host-Pathogen Interaction.
    Ana Valle-Noguera, Anne Ochoa-Ramos, Maria José Gomez-Sánchez, Aranzazu Cruz-Adalia.
      Type 3 Innate lymphoid cells (ILC3s) have been described as tissue-resident cells and characterized throughout the body, especially in mucosal sites and classical first barrier organs such as skin, gut and lungs, among others. A significant part of the research has focused on their role in combating pathogens, mainly extracellular pathogens, with the gut as the principal organ. However, some recent discoveries in the field have unveiled their activity in other organs, combating intracellular pathogens and as part of the response to viruses. In this review we have compiled the latest studies on the role of ILC3s and the molecular mechanisms involved in defending against different microbes at the mucosal surface, most of these studies have made use of conditional transgenic mice. The present review therefore attempts to provide an overview of the function of ILC3s in infections throughout the body, focusing on their specific activity in different organs.
    Keywords:  IL-17; IL-22; ILC3s; host-pathogen interaction; infection; mucosa; pathogens; type 3 innate lymphoid cells
    DOI:  https://doi.org/10.3389/fimmu.2021.748851
  2. Nutrients. 2021 Oct 19. pii: 3666. [Epub ahead of print]13(10):
    Modulation of Adipocyte Metabolism by Microbial Short-Chain Fatty Acids.
    Karolline S May, Laura J den Hartigh.
      Obesity and its complications-including type 2 diabetes, cardiovascular disease, and certain cancers-constitute a rising global epidemic that has imposed a substantial burden on health and healthcare systems over the years. It is becoming increasingly clear that there is a link between obesity and the gut microbiota. Gut dysbiosis, characterized as microbial imbalance, has been consistently associated with obesity in both humans and animal models, and can be reversed with weight loss. Emerging evidence has shown that microbial-derived metabolites such as short-chain fatty acids (SCFAs)-including acetate, propionate, and butyrate-provide benefits to the host by impacting organs beyond the gut, including adipose tissue. In this review, we summarize what is currently known regarding the specific mechanisms that link gut-microbial-derived SCFAs with adipose tissue metabolism, such as adipogenesis, lipolysis, and inflammation. In addition, we explore indirect mechanisms by which SCFAs can modulate adipose tissue metabolism, such as via perturbation of gut hormones, as well as signaling to the brain and the liver. Understanding how the modulation of gut microbial metabolites such as SCFAs can impact adipose tissue function could lead to novel therapeutic strategies for the prevention and treatment of obesity.
    Keywords:  GLP-1; PYY; acetate; adipogenesis; butyrate; gut microbiota; host metabolism; lipolysis; obesity; propionate
    DOI:  https://doi.org/10.3390/nu13103666
  3. FASEB J. 2021 Nov;35(11): e21965
    LETMD1 is required for mitochondrial structure and thermogenic function of brown adipocytes.
    Madigan M Snyder, Feng Yue, Lijia Zhang, Renjie Shang, Jiamin Qiu, Jingjuan Chen, Kun Ho Kim, Ying Peng, Stephanie N Oprescu, Shawn S Donkin, Pengpeng Bi, Shihuan Kuang.
      Obesity and metabolic disorders caused by energy surplus pose an increasing concern within the global population. Brown adipose tissue (BAT) dissipates energy through mitochondrial non-shivering thermogenesis, thus representing a powerful agent against obesity. Here we explore the novel role of a mitochondrial outer membrane protein, LETM1-domain containing 1 (LETMD1), in BAT. We generated a knockout (Letmd1KO ) mouse model and analyzed BAT morphology, function and gene expression under various physiological conditions. While the Letmd1KO mice are born normally and have normal morphology and body weight, they lose multilocular brown adipocytes completely and have diminished mitochondrial abundance, DNA copy number, cristae structure, and thermogenic gene expression in the intrascapular BAT, associated with elevated reactive oxidative stress. In consequence, the Letmd1KO mice fail to maintain body temperature in response to acute cold exposure without food and become hypothermic within 4 h. Although the cold-exposed Letmd1KO mice can maintain body temperature in the presence of food, they cannot upregulate expression of uncoupling protein 1 (UCP1) and convert white to beige adipocytes, nor can they respond to adrenergic stimulation. These results demonstrate that LETMD1 is essential for mitochondrial structure and function, and thermogenesis of brown adipocytes.
    Keywords:  LETM1 domain containing 1; brown adipose tissue; cold intolerance; mitochondria; thermogenesis
    DOI:  https://doi.org/10.1096/fj.202100597R
  4. Life Sci. 2021 Oct 19. pii: S0024-3205(21)01053-5. [Epub ahead of print] 120066
    Maternal high fructose diet exacerbates white adipose tissue thermogenic process in offspring upon exposure to cold temperature.
    A Alzamendi, I Miguel, M G Zubiría, S E Gambaro, E Spinedi, A Giovambattista.
       AIM: An adverse endogenous environment during early life predisposes to metabolic disorder development. We previously reported adverse metabolic and adipose tissue effects in adult male rats born to dams fed with a fructose-rich diet (FRD). The aim of this work was to determine the effect of a FRD consumed by the pregnant mother on the white adipose tissue (WAT) browning capacity of male offspring at adulthood.
    MAIN METHODS: Adult SD male offspring from control (C) and FRD-fed mothers were exposed during one week to a cold stimulus. WAT browning capacity was studied through in vivo and in vitro approaches.
    KEY FINDINGS: After cold exposure, WAT browning was higher in fructose-programmed animals as evidenced by an increase in ucp-1 gene expression, protein levels, and higher UCP-1 positive foci. Moreover, pgc1-α gene expression was increased. In vitro studies showed a lower adipogenic capacity in cells of prenatally fructose-exposed animals differentiated with a white differentiation cocktail, while a higher ucp-1 expression was noted when their cells were treated with a pro-beige differentiation cocktail.
    SIGNIFICANCE: For the first time we demonstrate that pre-natal fructose exposure predisposes programmed male rats to a higher WAT browning-induced response, under stimulated conditions, despite an apparent lower basal thermogenic capacity. These results should be considered in future studies to generate new therapeutic approaches to deal with adverse programming malnutrition effects.
    Keywords:  Beige adipocytes; Maternal fructose diet; Metabolic programming; UCP-1; White adipose tissue
    DOI:  https://doi.org/10.1016/j.lfs.2021.120066
  5. Cells. 2021 Oct 03. pii: 2645. [Epub ahead of print]10(10):
    Adipose-Tissue-Derived Mesenchymal Stem Cells Mediate PD-L1 Overexpression in the White Adipose Tissue of Obese Individuals, Resulting in T Cell Dysfunction.
    Assia Eljaafari, Julien Pestel, Brigitte Le Magueresse-Battistoni, Stephanie Chanon, Julia Watson, Maud Robert, Emmanuel Disse, Hubert Vidal.
      The PD-L1/PD-1 immune checkpoint axis is the strongest T cell exhaustion inducer. As immune dysfunction occurs during obesity, we analyzed the impact of obesity on PD-L1/PD-1 expression in white adipose tissue (WAT) in mice and in human white adipocytes. We found that PD-L1 was overexpressed in WAT of diet-induced obese mice and was associated with increased expression of PD-1 in visceral but not subcutaneous WAT. Human in vitro cocultures with adipose-tissue-derived mesenchymal stem cells (ASC) and mononuclear cells demonstrated that the presence of ASC harvested from obese WAT (i) enhanced PD-L1 expression as compared with ASC from lean WAT, (ii) decreased Th1 cell cytokine secretion, and (iii) resulted in decreased cytolytic activity towards adipocytes. Moreover, (iv) the implication of PD-L1 in obese ASC-mediated T cell dysfunction was demonstrated through PD-L1 blockade. Finally, (v) conditioned media gathered from these cocultures enhanced PD-L1 expression in freshly differentiated adipocytes, depending on IFNγ. Altogether, our results suggest that PD-L1 is overexpressed in the WAT of obese individuals during IFNγ secretion, leading to T cell dysfunction and notably reduced cytolytic activity. Such a mechanism could shed light on why adipose-tissue-infiltrating viruses, such as SARS-CoV-2, can worsen disease in obese individuals.
    Keywords:  IFNγ; PD-1/PD-L1 immune checkpoints; T cell dysfunction; adipose-tissue-derived mesenchymal stem cells; inflammation; obesity; white adipose tissue
    DOI:  https://doi.org/10.3390/cells10102645
  6. Nat Rev Endocrinol. 2021 Oct 19.
    Functional diversity of human adipose tissue revealed by spatial mapping.
    Camilla Scheele, Christian Wolfrum.
      
    DOI:  https://doi.org/10.1038/s41574-021-00582-2
  7. Gastroenterology. 2021 Oct 18. pii: S0016-5085(21)03647-7. [Epub ahead of print]
    New role for fatty acid receptor regulation of immune cells to control intestinal inflammation.
    Michael J Rosen.
      
    DOI:  https://doi.org/10.1053/j.gastro.2021.09.072
  8. Mol Immunol. 2021 Oct 19. pii: S0161-5890(21)00290-X. [Epub ahead of print]140 97-105
    Inflammatory arthritis increases the susceptibility to acute immune-mediated hepatitis in mice through enhancing leptin expression in T cells.
    Youyi Wang, Ping Wang, Qishan Xu, Lijun Dong, Yunzhi Liu, Yu Chen, Jia Zhou, Xiao Lu, Daming Zuo, Qingyun Chen.
      Liver function abnormalities are common in patients with inflammatory arthritis. However, the precise mechanism is still unclear. In this study, inflammatory arthritis was established in mice by subcutaneous injection of complete Freund's adjuvant, and the intravenous injection of concanavalin A (Con A) was employed to induce acute immune-mediated hepatitis in mice. The result showed that the arthritis mice were more susceptible to ConA-induced hepatitis than the control mice, as evidenced by increased hepatic necrosis, elevated serum alanine aminotransferase activity, and raised inflammatory cytokines. Besides, the in vitro assay demonstrated that the T cells from arthritis mice were more sensitive to the Con A stimulation than those from control mice. Moreover, we determined that the level of leptin, a kind of adipokine, was significantly increased in the serum and hepatic T cells of arthritis mice. Interestingly, the data indicated that the enhanced expression of leptin in hepatic T cells is responsible for the hypersensitivity of arthritis mice-derived T cells to Con A challenge. Collectively, our findings demonstrate an unexpected role of leptin in the connection between inflammatory arthritis and acute immune-mediated hepatitis, thus providing new insight into the clinical therapy of arthritis-related liver dysfunction.
    Keywords:  Concanavalin A; Immune-mediated hepatitis; Inflammatory arthritis; Leptin; T cells
    DOI:  https://doi.org/10.1016/j.molimm.2021.09.015
  9. Commun Biol. 2021 Oct 22. 4(1): 1214
    Activation of the adipocyte CREB/CRTC pathway in obesity.
    Young-Sil Yoon, Weiyi Liu, Sam Van de Velde, Shigenobu Matsumura, Ezra Wiater, Ling Huang, Marc Montminy.
      Obesity is a major risk factor for the development of type II diabetes. Increases in adipose tissue mass trigger insulin resistance via the release of pro-inflammatory cytokines from adipocytes and macrophages. CREB and the CRTC coactivators have been found to promote insulin resistance in obesity, although the mechanism is unclear. Here we show that high fat diet feeding activates the CREB/CRTC pathway in adipocytes by decreasing the expression of SIK2, a Ser/Thr kinase that phosphorylates and inhibits CRTCs. SIK2 levels are regulated by the adipogenic factor C/EBPα, whose expression is reduced in obesity. Exposure to PPARγ agonist rescues C/EBPα expression and restores SIK2 levels. CRTC2/3 promote insulin resistance via induction of the chemokines CXCL1/2. Knockout of CRTC2/3 in adipocytes reduces CXCL1/2 expression and improves insulin sensitivity. As administration of CXCL1/2 reverses salutary effects of CRTC2/3 depletion, our results demonstrate the importance of the CREB/CRTC pathway in modulating adipose tissue function.
    DOI:  https://doi.org/10.1038/s42003-021-02735-5
  10. J Physiol. 2021 Oct 22.
    The beta2 -adrenergic receptor - a re-emerging target to combat obesity and induce leanness?
    Morten Hostrup, Johan Onslev.
      Treatment of obesity with repurposed or novel drugs is an expanding research field. One approach is to target beta2 -adrenergic receptors because they regulate the metabolism and phenotype of adipose and skeletal muscle tissue. Several observations support a role of the beta2 -adrenergic receptor in obesity. Specific human beta2 -adrenergic receptor polymorphisms are associated with body composition and obesity, for which the Gln27Glu polymorphism is associated with obesity, while the Arg16Gly polymorphism is associated with lean mass in men and the development of obesity in specific populations. Individuals with obesity also have lower abundancy of beta2 -adrenergic receptors in adipose tissue and are less sensitive to catecholamines. In addition, studies in livestock and rodents demonstrate that selective beta2 -agonists induce a so-called "repartitioning effect" characterized by muscle accretion and reduced fat deposition. In humans, beta2 -agonists dose-dependently increase resting metabolic rate by 10-50%. And like that observed in other mammals, only a few weeks of treatment with beta2 -agonists increases muscle mass and reduces fat mass in young healthy individuals. Beta2 -agonists also exert beneficial effects on body composition when used concomitantly with training and work additively to increase muscle strength and mass during periods with resistance training. Thus, the beta2 -adrenergic receptor seems like an attractive target in the development of anti-obesity drugs. However, the long-term efficacy and safety of beta2 -agonists should be assessed in individuals with obesity - particularly in those with comorbidities. This article is protected by copyright. All rights reserved.
    Keywords:  adrenoceptor; beta agonist; clenbuterol; hypertrophy; salbutamol; thermogenesis
    DOI:  https://doi.org/10.1113/JP281819
  11. Nat Immunol. 2021 Oct 22.
    Mitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology.
    Hideaki Fujiwara, Keisuke Seike, Michael D Brooks, Anna V Mathew, Ilya Kovalenko, Anupama Pal, Ho-Joon Lee, Daniel Peltier, Stephanie Kim, Chen Liu, Katherine Oravecz-Wilson, Lu Li, Yaping Sun, Jaeman Byun, Yoshinobu Maeda, Max S Wicha, Thomas L Saunders, Alnawaz Rehemtulla, Costas A Lyssiotis, Subramaniam Pennathur, Pavan Reddy.
      Intestinal epithelial cell (IEC) damage by T cells contributes to graft-versus-host disease, inflammatory bowel disease and immune checkpoint blockade-mediated colitis. But little is known about the target cell-intrinsic features that affect disease severity. Here we identified disruption of oxidative phosphorylation and an increase in succinate levels in the IECs from several distinct in vivo models of T cell-mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses, identified disruption of IEC-intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations. The relevance of IEC-intrinsic SDHA in mediating disease severity was confirmed by complementary chemical and genetic experimental approaches and validated in human clinical samples. These data identify a critical role for the alteration of the IEC-specific mitochondrial complex II component SDHA in the regulation of the severity of T cell-mediated intestinal diseases.
    DOI:  https://doi.org/10.1038/s41590-021-01048-3
  12. Stem Cell Res Ther. 2021 Oct 21. 12(1): 546
    Hepatic progenitor cells promote the repair of schistosomiasis liver injury by inhibiting IL-33 secretion in mice.
    Beibei Zhang, Xiaoying Wu, Jing Li, An Ning, Bo Zhang, Jiahua Liu, Langui Song, Chao Yan, Xi Sun, Kuiyang Zheng, Zhongdao Wu.
       BACKGROUND: Hepatic schistosomiasis, a chronic liver injury induced by long-term Schistosoma japonicum (S. japonicum) infection, is characterized by egg granulomas and fibrotic pathology. Hepatic progenitor cells (HPCs), which are nearly absent or quiescent in normal liver, play vital roles in chronic and severe liver injury. But their role in the progression of liver injury during infection remains unknown.
    METHODS: In this study, the hepatic egg granulomas, fibrosis and proliferation of HPCs were analyzed in the mice model of S. japonicum infection at different infectious stages. For validating the role of HPCs in hepatic injury, tumor necrosis factor-like-weak inducer of apoptosis (TWEAK) and TWEAK blocking antibody were used to manipulate the proliferation of HPCs in wild-type and IL-33-/- mice infected with S. japonicum.
    RESULTS: We found that the proliferation of HPCs was accompanied by inflammatory granulomas and fibrosis formation. HPCs expansion promoted liver regeneration and inhibited inflammatory egg granulomas, as well as the deposition of fibrotic collagen. Interestingly, the expression of IL-33 was negatively associated with HPCs' expansion. There were no obvious differences of liver injury caused by infection between wild-type and IL-33-/- mice with HPCs' expansion. However, liver injury was more attenuated in IL-33-/- mice than wild-type mice when the proliferation of HPCs was inhibited by anti-TWEAK.
    CONCLUSIONS: Our data uncovered a protective role of HPCs in hepatic schistosomiasis in an IL-33-dependent manner, which might provide a promising progenitor cell therapy for hepatic schistosomiasis.
    Keywords:  Hepatic progenitor cells; Hepatic schistosomiasis; IL-33
    DOI:  https://doi.org/10.1186/s13287-021-02589-y
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