bims-aditis 2021-11-28 papers

Issue of 2021–11–28
six papers selected by
Matthew C. Sinton, University of Glasgow

Cell Mol Immunol. 2021 Nov 26.

Resident and migratory adipose immune cells control systemic metabolism and thermogenesis.

Kevin Man, Axel Kallies, Ajithkumar Vasanthakumar.

Glucose is a vital source of energy for all mammals. The balance between glucose uptake, metabolism and storage determines the energy status of an individual, and perturbations in this balance can lead to metabolic diseases. The maintenance of organismal glucose metabolism is a complex process that involves multiple tissues, including adipose tissue, which is an endocrine and energy storage organ that is critical for the regulation of systemic metabolism. Adipose tissue consists of an array of different cell types, including specialized adipocytes and stromal and endothelial cells. In addition, adipose tissue harbors a wide range of immune cells that play vital roles in adipose tissue homeostasis and function. These cells contribute to the regulation of systemic metabolism by modulating the inflammatory tone of adipose tissue, which is directly linked to insulin sensitivity and signaling. Furthermore, these cells affect the control of thermogenesis. While lean adipose tissue is rich in type 2 and anti-inflammatory cytokines such as IL-10, obesity tips the balance in favor of a proinflammatory milieu, leading to the development of insulin resistance and the dysregulation of systemic metabolism. Notably, anti-inflammatory immune cells, including regulatory T cells and innate lymphocytes, protect against insulin resistance and have the characteristics of tissue-resident cells, while proinflammatory immune cells are recruited from the circulation to obese adipose tissue. Here, we review the key findings that have shaped our understanding of how immune cells regulate adipose tissue homeostasis to control organismal metabolism.

Keywords: adipose tissue; immune cells; metabolism

DOI: https://doi.org/10.1038/s41423-021-00804-7

Trends Cell Biol. 2021 Nov 19. pii: S0962-8924(21)00221-X. [Epub ahead of print]

Mitochondrial regulation and white adipose tissue homeostasis.

Qingzhang Zhu, Yu A An, Philipp E Scherer.

The important role of mitochondria in the regulation of white adipose tissue (WAT) remodeling and energy balance is increasingly appreciated. The remarkable heterogeneity of the adipose tissue stroma provides a cellular basis to enable adipose tissue plasticity in response to various metabolic stimuli. Regulating mitochondrial function at the cellular level in adipocytes, in adipose progenitor cells (APCs), and in adipose tissue macrophages (ATMs) has a profound impact on adipose homeostasis. Moreover, mitochondria facilitate the cell-to-cell communication within WAT, as well as the crosstalk with other organs, such as the liver, the heart, and the pancreas. A better understanding of mitochondrial regulation in the diverse adipose tissue cell types allows us to develop more specific and efficient approaches to improve adipose function and achieve improvements in overall metabolic health.

DOI: https://doi.org/10.1016/j.tcb.2021.10.008

J Inflamm Res. 2021 ;14 5981-5998

IL-33/ST2 Axis Deficiency Exacerbates Hepatic Pathology by Regulating Treg and Th17 Cells in Murine Schistosomiasis Japonica.

Yang Bai, Fei Guan, Feifan Zhu, Chunjie Jiang, XiaoXiao Xu, Fang Zheng, Wenqi Liu, Jiahui Lei.

Purpose: Schistosoma japonicum-infected IL-33 and ST2 gene deficiency (IL-33 -/- and ST2-/- , respectively) mice were used to explore the role of the IL-33/ST2 axis in liver pathology targeting regulatory T cells (Treg)/T helper 17 cells (Th17).
Materials and Methods: Each mouse was infected percutaneously with 20 S. japonicum cercariae. Hepatic mass index (HMI), liver egg granulomas, hepatic fibrosis biomarkers and serum levels of alanine aminotransferase (ALT) were investigated. Treg and Th17 frequency was determined by flow cytometry. Expressions of Foxp3, ST2, TGF-β1, IL-10, RORγt, and IL-17A were measured via quantitative real-time polymerase chain reaction (qRT-PCR). Concentrations of TGF-β1, IL-10 and IL-17A were tested with ELISA. In vitro experiments, mRNA expressions of Foxp3, TGF-β1, IL-10, Atg5, Beclin-1 and p62 associated with polarization of Treg by recombinant mouse IL-33 (rmIL-33) were detected by qRT-PCR.
Results: An increased expression of IL-33/ST2 was shown in S. japonicum-infected mice. Deficiency of IL-33 or ST2 gene led to an aggravated liver pathology, which was evidenced by elevated hepatic granuloma volume, HMI and ALT levels and fibrosis, which was demonstrated by increased hepatic collagen deposition in the infected mice. Injection of rmIL-33 into the infected IL-33-/- mice strongly abrogated the liver pathology and fibrosis, whereas no detectable effect with injecting rmIL-33 into the infected ST2-/- mice. Furthermore, depletion of the IL-33/ST2 axis inhibited Treg, accompanied by increased Th17. rmIL-33 treatment upregulated Treg and downregulated Th17 in the infected IL-33-/- mice, while no effect in the infected ST2-/- mice. rmIL-33 led to elevated expressions of Atg5, Beclin-1 and inhibited expression of p62 in expansion of Treg.
Conclusion: The IL-33/ST2 axis plays a protective role in S. japonicum infected mice, which is closely related to increasing Treg responses as well as suppressing Th17 responses. Expansion of Treg by IL-33 may be associated with its regulation of autophagy.

Keywords: IL-33; ST2; Th17; Treg; autophagy; fibrosis; liver pathology

DOI: https://doi.org/10.2147/JIR.S336404

Nature. 2021 Nov 24.

IL-27 signalling promotes adipocyte thermogenesis and energy expenditure.

Thermogenesis in brown and beige adipose tissue has important roles in maintaining body temperature and countering the development of metabolic disorders such as obesity and type 2 diabetes1,2. Although much is known about commitment and activation of brown and beige adipose tissue, its multiple and abundant immunological factors have not been well characterized3-6. Here we define a critical role of IL-27-IL-27Rα signalling in improving thermogenesis, protecting against diet-induced obesity and ameliorating insulin resistance. Mechanistic studies demonstrate that IL-27 directly targets adipocytes, activating p38 MAPK-PGC-1α signalling and stimulating the production of UCP1. Notably, therapeutic administration of IL-27 ameliorated metabolic morbidities in well-established mouse models of obesity. Consistently, individuals with obesity show significantly decreased levels of serum IL-27, which can be restored after bariatric surgery. Collectively, these findings show that IL-27 has an important role in orchestrating metabolic programs, and is a highly promising target for anti-obesity immunotherapy.

DOI: https://doi.org/10.1038/s41586-021-04127-5

Cells. 2021 Nov 08. pii: 3073. [Epub ahead of print]10(11):

Multidimensional Single-Nuclei RNA-Seq Reconstruction of Adipose Tissue Reveals Adipocyte Plasticity Underlying Thermogenic Response.

Carlos Alberto Oliveira Biagi, Sarah Santiloni Cury, Cleidson Pádua Alves, Nabil Rabhi, Wilson Araujo Silva, Stephen R Farmer, Robson Francisco Carvalho, Miguel Luiz Batista.

Adipose tissue has been classified based on its morphology and function as white, brown, or beige/brite. It plays an essential role as a regulator of systemic metabolism through paracrine and endocrine signals. Recently, multiple adipocyte subtypes have been revealed using RNA sequencing technology, going beyond simply defined morphology but also by their cellular origin, adaptation to metabolic stress, and plasticity. Here, we performed an in-depth analysis of publicly available single-nuclei RNAseq from adipose tissue and utilized a workflow template to characterize adipocyte plasticity, heterogeneity, and secretome profiles. The reanalyzed dataset led to the identification of different subtypes of adipocytes including three subpopulations of thermogenic adipocytes, and provided a characterization of distinct transcriptional profiles along the adipocyte trajectory under thermogenic challenges. This study provides a useful resource for further investigations regarding mechanisms related to adipocyte plasticity and trans-differentiation.

Keywords: adipocyte subpopulations; cellular compartment prediction; mature adipocyte plasticity; thermogenic treatment; transcriptional factors

DOI: https://doi.org/10.3390/cells10113073

Nat Commun. 2021 Nov 26. 12(1): 6931

CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease.

Obesity and type 2 diabetes are associated with disturbances in insulin-regulated glucose and lipid fluxes and severe comorbidities including cardiovascular disease and steatohepatitis. Whole body metabolism is regulated by lipid-storing white adipocytes as well as "brown" and "brite/beige" adipocytes that express thermogenic uncoupling protein 1 (UCP1) and secrete factors favorable to metabolic health. Implantation of brown fat into obese mice improves glucose tolerance, but translation to humans has been stymied by low abundance of primary human beige adipocytes. Here we apply methods to greatly expand human adipocyte progenitors from small samples of human subcutaneous adipose tissue and then disrupt the thermogenic suppressor gene NRIP1 by CRISPR. Ribonucleoprotein consisting of Cas9 and sgRNA delivered ex vivo are fully degraded by the human cells following high efficiency NRIP1 depletion without detectable off-target editing. Implantation of such CRISPR-enhanced human or mouse brown-like adipocytes into high fat diet fed mice decreases adiposity and liver triglycerides while enhancing glucose tolerance compared to implantation with unmodified adipocytes. These findings advance a therapeutic strategy to improve metabolic homeostasis through CRISPR-based genetic enhancement of human adipocytes without exposing the recipient to immunogenic Cas9 or delivery vectors.

DOI: https://doi.org/10.1038/s41467-021-27190-y