bims-adipim 2023-05-14 papers

bims-adipim

Biomed News

on Adipose immunity and immunometabolism

Issue of 2023–05–14
seven papers selected by
Matthew C. Sinton, University of Glasgow

Adipose tissue macrophages as potential targets for obesity and metabolic diseases.
Lipid metabolism in dendritic cell biology.
Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils.
FoxO1 regulates adipose transdifferentiation and iron influx by mediating Tgfβ1 signaling pathway.
Diversity and heterogeneity in human breast cancer adipose tissue revealed at single-nucleus resolution.
Acetyl-CoA carboxylase 1 is a suppressor of the adipocyte thermogenic program.
The transcription factor Foxp1 regulates aerobic glycolysis in adipocytes and myocytes.

Front Immunol. 2023 ;14 1153915

Adipose tissue macrophages as potential targets for obesity and metabolic diseases.

Xirong Li, Yakun Ren, Kewei Chang, Wenlong Wu, Helen R Griffiths, Shemin Lu, Dan Gao.

  Macrophage infiltration into adipose tissue is a key pathological factor inducing adipose tissue dysfunction and contributing to obesity-induced inflammation and metabolic disorders. In this review, we aim to present the most recent research on macrophage heterogeneity in adipose tissue, with a focus on the molecular targets applied to macrophages as potential therapeutics for metabolic diseases. We begin by discussing the recruitment of macrophages and their roles in adipose tissue. While resident adipose tissue macrophages display an anti-inflammatory phenotype and promote the development of metabolically favorable beige adipose tissue, an increase in pro-inflammatory macrophages in adipose tissue has negative effects on adipose tissue function, including inhibition of adipogenesis, promotion of inflammation, insulin resistance, and fibrosis. Then, we presented the identities of the newly discovered adipose tissue macrophage subtypes (e.g. metabolically activated macrophages, CD9+ macrophages, lipid-associated macrophages, DARC+ macrophages, and MFehi macrophages), the majority of which are located in crown-like structures within adipose tissue during obesity. Finally, we discussed macrophage-targeting strategies to ameliorate obesity-related inflammation and metabolic abnormalities, with a focus on transcriptional factors such as PPARγ, KLF4, NFATc3, and HoxA5, which promote macrophage anti-inflammatory M2 polarization, as well as TLR4/NF-κB-mediated inflammatory pathways that activate pro-inflammatory M1 macrophages. In addition, a number of intracellular metabolic pathways closely associated with glucose metabolism, oxidative stress, nutrient sensing, and circadian clock regulation were examined. Understanding the complexities of macrophage plasticity and functionality may open up new avenues for the development of macrophage-based treatments for obesity and other metabolic diseases.

Keywords:  adipose tissue; macrophages; metabolic diseases; obesity; plasticity

DOI:  https://doi.org/10.3389/fimmu.2023.1153915
Immunol Rev. 2023 May 12.

Lipid metabolism in dendritic cell biology.

Zhiyuan You, Hongbo Chi.

  Dendritic cells (DCs) are innate immune cells that detect and process environmental signals and communicate them with T cells to bridge innate and adaptive immunity. Immune signals and microenvironmental cues shape the function of DC subsets in different contexts, which is associated with reprogramming of cellular metabolic pathways. In addition to integrating these extracellular cues to meet bioenergetic and biosynthetic demands, cellular metabolism interplays with immune signaling to shape DC-dependent immune responses. Emerging evidence indicates that lipid metabolism serves as a key regulator of DC responses. Here, we summarize the roles of fatty acid and cholesterol metabolism, as well as selective metabolites, in orchestrating the functions of DCs. Specifically, we highlight how different lipid metabolic programs, including de novo fatty acid synthesis, fatty acid β oxidation, lipid storage, and cholesterol efflux, influence DC function in different contexts. Further, we discuss how dysregulation of lipid metabolism shapes DC intracellular signaling and contributes to the impaired DC function in the tumor microenvironment. Finally, we conclude with a discussion on key future directions for the regulation of DC biology by lipid metabolism. Insights into the connections between lipid metabolism and DC functional specialization may facilitate the development of new therapeutic strategies for human diseases.

Keywords:  cholesterol; dendritic cells; fatty acid; innate immunity; lipid metabolism; lipid metabolites

DOI:  https://doi.org/10.1111/imr.13215
Elife. 2023 May 10. pii: e86001. [Epub ahead of print]12

Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils.

Jiang Li, Rebecca E Ruggiero-Ruff, Yuxin He, Xinru Qiu, Nancy Lainez, Pedro Villa, Adam Godzik, Djurdjica Coss, Meera G Nair.

  Obesity incidence is increasing worldwide with the urgent need to identify new therapeutics. Sex differences in immune cell activation drive obesity-mediated pathologies where males are more susceptible to obesity comorbidities and exacerbated inflammation. Here, we demonstrate that the macrophage-secreted protein RELMα critically protects females against high-fat diet (HFD)-induced obesity. Compared to male mice, serum RELMα levels were higher in both control and HFD-fed females and correlated with frequency of adipose macrophages and eosinophils. RELMα-deficient females gained more weight and had proinflammatory macrophage accumulation and eosinophil loss in the adipose stromal vascular fraction (SVF), while RELMα treatment or eosinophil transfer rescued this phenotype. Single-cell RNA-sequencing of the adipose SVF was performed and identified sex and RELMα-dependent changes. Genes involved in oxygen sensing and iron homeostasis, including hemoglobin and lncRNA Gm47283/Gm21887, correlated with increased obesity, while eosinophil chemotaxis and response to amyloid-beta were protective. Monocyte-to-macrophage transition was also dysregulated in RELMα-deficient animals. Collectively, these studies implicate a RELMα-macrophage-eosinophil axis in sex-specific protection against obesity and uncover new therapeutic targets for obesity.

Keywords:  RELMα; adipose; eosinophil; immunology; inflammation; macrophage; mouse; obesity; sexual dimorphism

DOI:  https://doi.org/10.7554/eLife.86001
Redox Biol. 2023 May 02. pii: S2213-2317(23)00128-3. [Epub ahead of print]63 102727

FoxO1 regulates adipose transdifferentiation and iron influx by mediating Tgfβ1 signaling pathway.

Limin Shi, Zhipeng Tao, Louise Zheng, Jinying Yang, Xinran Hu, Karen Scott, Annette de Kloet, Eric Krause, James F Collins, Zhiyong Cheng.

Adipose plasticity is critical for metabolic homeostasis. Adipocyte transdifferentiation plays an important role in adipose plasticity, but the molecular mechanism of transdifferentiation remains incompletely understood. Here we show that the transcription factor FoxO1 regulates adipose transdifferentiation by mediating Tgfβ1 signaling pathway. Tgfβ1 treatment induced whitening phenotype in beige adipocytes, reducing UCP1 and mitochondrial capacity and enlarging lipid droplets. Deletion of adipose FoxO1 (adO1KO) dampened Tgfβ1 signaling by downregulating Tgfbr2 and Smad3 and induced browning of adipose tissue in mice, increasing UCP1 and mitochondrial content and activating metabolic pathways. Silencing FoxO1 also abolished the whitening effect of Tgfβ1 on beige adipocytes. The adO1KO mice exhibited a significantly higher energy expenditure, lower fat mass, and smaller adipocytes than the control mice. The browning phenotype in adO1KO mice was associated with an increased iron content in adipose tissue, concurrent with upregulation of proteins that facilitate iron uptake (DMT1 and TfR1) and iron import into mitochondria (Mfrn1). Analysis of hepatic and serum iron along with hepatic iron-regulatory proteins (ferritin and ferroportin) in the adO1KO mice revealed an adipose tissue-liver crosstalk that meets the increased iron requirement for adipose browning. The FoxO1-Tgfβ1 signaling cascade also underlay adipose browning induced by β3-AR agonist CL316243. Our study provides the first evidence of a FoxO1-Tgfβ1 axis in the regulation of adipose browning-whitening transdifferentiation and iron influx, which sheds light on the compromised adipose plasticity in conditions of dysregulated FoxO1 and Tgfβ1 signaling.

DOI: https://doi.org/10.1016/j.redox.2023.102727
Front Immunol. 2023 ;14 1158027

Diversity and heterogeneity in human breast cancer adipose tissue revealed at single-nucleus resolution.

Lina Tang, Tingting Li, Jing Xie, Yanping Huo.

   Introduction: There is increasing awareness of the role of adipose tissue in breast cancer occurrence and development, but no comparison of adipose adjacent to breast cancer tissues and adipose adjacent to normal breast tissues has been reported.
Methods: Single-nucleus RNA sequencing (snRNA-seq) was used to analyze cancer-adjacent and normal adipose tissues from the same breast cancer patient to characterize heterogeneity. SnRNA-seq was performed on 54513 cells from six samples of normal breast adipose tissue (N) distant from the tumor and tumor-adjacent adipose tissue (T) from the three patients (all surgically resected).
Results and discussion: Significant diversity was detected in cell subgroups, differentiation status and, gene expression profiles. Breast cancer induces inflammatory gene profiles in most adipose cell types, such as macrophages, endothelial cells, and adipocytes. Furthermore, breast cancer decreased lipid uptake and the lipolytic phenotype and caused a switch to lipid biosynthesis and an inflammatory state in adipocytes. The in vivo trajectory of adipogenesis revealed distinct transcriptional stages. Breast cancer induced reprogramming across many cell types in breast cancer adipose tissues. Cellular remodeling was investigated by alterations in cell proportions, transcriptional profiles and cell-cell interactions. Breast cancer biology and novel biomarkers and therapy targets may be exposed.

Keywords:  adipose tissue; breast cancer; diversity; heterogeneity; single-cell RNA sequencing

DOI:  https://doi.org/10.3389/fimmu.2023.1158027
Cell Rep. 2023 May 08. pii: S2211-1247(23)00499-0. [Epub ahead of print]42(5): 112488

Acetyl-CoA carboxylase 1 is a suppressor of the adipocyte thermogenic program.

Adilson Guilherme, Leslie A Rowland, Nicole Wetoska, Emmanouela Tsagkaraki, Kaltinaitis B Santos, Alexander H Bedard, Felipe Henriques, Mark Kelly, Sean Munroe, David J Pedersen, Olga R Ilkayeva, Timothy R Koves, Lauren Tauer, Meixia Pan, Xianlin Han, Jason K Kim, Christopher B Newgard, Deborah M Muoio, Michael P Czech.

  Disruption of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) in mice induces browning in inguinal white adipose tissue (iWAT). However, adipocyte FASN knockout (KO) increases acetyl-coenzyme A (CoA) and malonyl-CoA in addition to depletion of palmitate. We explore which of these metabolite changes triggers adipose browning by generating eight adipose-selective KO mouse models with loss of ATP-citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), ACC2, malonyl-CoA decarboxylase (MCD) or FASN, or dual KOs ACLY/FASN, ACC1/FASN, and ACC2/FASN. Preventing elevation of acetyl-CoA and malonyl-CoA by depletion of adipocyte ACLY or ACC1 in combination with FASN KO does not block the browning of iWAT. Conversely, elevating malonyl-CoA levels in MCD KO mice does not induce browning. Strikingly, adipose ACC1 KO induces a strong iWAT thermogenic response similar to FASN KO while also blocking malonyl-CoA and palmitate synthesis. Thus, ACC1 and FASN are strong suppressors of adipocyte thermogenesis through promoting lipid synthesis rather than modulating the DNL intermediates acetyl-CoA or malonyl-CoA.

Keywords:  ACC1; CP: Metabolism; FASN; UCP1; acetyl-CoA; adipose tissue; browning; fatty acids; lipogenesis; malonyl-CoA; thermogenesis

DOI:  https://doi.org/10.1016/j.celrep.2023.112488
J Biol Chem. 2023 May 05. pii: S0021-9258(23)01823-9. [Epub ahead of print] 104795

The transcription factor Foxp1 regulates aerobic glycolysis in adipocytes and myocytes.

Haixia Ma, Valentina Sukonina, Wei Zhang, Fang Meng, Santhilal Subhash, Henrik Palmgren, Ida Alexandersson, Huiming Han, Shuping Zhou, Stefano Bartesaghi, Chandrasekhar Kanduri, Sven Enerbäck.

  In recent years, lactate has been recognized as an important circulating energy substrate rather than only a dead-end metabolic waste product generated during glucose oxidation at low levels of oxygen. The term "aerobic glycolysis" has been coined to denote increased glucose uptake and lactate production despite normal oxygen levels and functional mitochondria. Hence, in "aerobic glycolysis" lactate production is a metabolic choice, whereas in "anaerobic glycolysis" it is a metabolic necessity based on inadequate levels of oxygen. Interestingly, lactate can be taken up by cells and oxidized to pyruvate and thus constitutes a source of pyruvate that is independent of insulin. Here, we show that the transcription factor Foxp1 regulates glucose uptake and lactate production in adipocytes and myocytes. Over-expression of Foxp1 leads to increased glucose uptake and lactate production. In addition, protein levels of several enzymes in the glycolytic pathway are upregulated, such as hexokinase 2, phosphofructokinase, aldolase, and lactate dehydrogenase. Using chromatin immunoprecipitation and real-time quantitative PCR (ChIP-qPCR) assays, we demonstrate that Foxp1 directly interacts with promoter consensus cis-elements that regulate expression of several of these target genes. Conversely, knock-down of Foxp1 suppresses these enzyme levels and lowers glucose uptake and lactate production. Moreover, mice with a targeted deletion of Foxp1 in muscle display systemic glucose intolerance with decreased muscle glucose uptake. In primary human adipocytes with induced expression of Foxp1, we find increased glycolysis and glycolytic capacity. Our results indicate Foxp1 may play an important role as a regulator of aerobic glycolysis in adipose tissue and muscle.

Keywords:  Foxp1; Glucose tolerance test; aerobic glycolysis; glucose uptake; lactate production

DOI:  https://doi.org/10.1016/j.jbc.2023.104795