Lipocalin-2 counteracts metabolic dysregulation in obesity and diabetes

Mosialou, Ioanna; Shikhel, Steven; Luo, Na; Πετροπούλου, Περιστέρα-Ιωάννα; Panitsas, Konstantinos; Bisikirska, Brygida; Rothman, Nyanza J.; Τέντα, Ρωξάνη; Cariou, Bertrand; Wargny, Matthieu; Sornay‐Rendu, Elisabeth; Nickolas, Thomas L.; Rubin, Mishaela R.; Confavreux, Cyrille; Kousteni, Stavroula

doi:10.1084/jem.20191261

Cited by 57 publications

(53 citation statements)

References 58 publications

(87 reference statements)

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“…Several, smaller clusters of genes of interest were identified. Cluster A includes genes involved in fatty acid synthesis ( Fasn, Elovl6 , and Me1 ) while the other clusters (B-D) included genes known to control appetite and fatty acid uptake and synthesis/oxidation ( Lipocalin-2, Vanin1, Hadha, Hadhb , and Hsdl2 ) [ 31 – 34 ]. The most interesting changes occurred when the diets were switched (CHFD-THFD-D85 (II) and THFD-CHFD-D85 (II)) since at this point the weights of the animal (and the i-WF) were very close in both groups (35 grams, Fig.…”

Section: Resultsmentioning

confidence: 99%

The antioxidant tempol transforms gut microbiome to resist obesity in female C3H mice fed a high fat diet

Choudhuri

Sowers

Chandramouli³

et al. 2022

Free Radical Biology and Medicine

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The nitroxide, Tempol, prevents obesity related changes in mice fed a high fat diet (HFD). The purpose of this study was to gain insight into the mechanisms that result in such changes by Tempol in female C3H mice. Microarray methodology, Western blotting, bile acid analyses, and gut microbiome sequencing were used to identify multiple genes, proteins, bile acids, and bacteria that are regulated by Tempol in female C3H mice on HFD. The effects of antibiotics in combination with Tempol on the gut microflora were also studied. Adipose tissue, from Tempol treated mice, was analyzed using targeted gene microarrays revealing up-regulation of fatty acid metabolism genes ( Acadm and Acadl > 4-fold, and Acsm3 and Acsm5 > 10-fold). Gene microarray studies of liver tissue from mice switched from HFD to Tempol HFD showed down-regulation of fatty acid synthesis genes and up-regulation of fatty acid oxidation genes. Analyses of proteins involved in obesity revealed that the expression of aldehyde dehydrogenase 1A1 (ALDH1A1) and fasting induced adipose factor/angiopoietin-like protein 4 (FIAF/ANGPTL4) was altered by Tempol HFD. Bile acid studies revealed increases in cholic acid (CA) and deoxycholic acid (DCA) in both the liver and serum of Tempol treated mice. Tempol HFD effect on the gut microbiome composition showed an increase in the population of Akkermansia muciniphila , a bacterial species known to be associated with a lean, anti-inflammatory phenotype. Antibiotic treatment significantly reduced the total level of bacterial numbers, however, Tempol was still effective in reducing the HFD weight gain. Even after antibiotic treatment Tempol still positively influenced several bacterial species such as as Akkermansia muciniphila and Bilophila wadsworthia . The positive effects of Tempol moderating weight gain in female mice fed a HFD involves changes to the gut microbiome, bile acids composition, and finally to changes in genes and proteins involved in fatty acid metabolism and storage.

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Section: Resultsmentioning

confidence: 99%

The antioxidant tempol transforms gut microbiome to resist obesity in female C3H mice fed a high fat diet

Choudhuri

Sowers

Chandramouli³

et al. 2022

Free Radical Biology and Medicine

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“…For instance, decreased LCN2 levels might identify patients at risk of exaggerated responses to inflammatory triggers such as viral infections, and, on the other hand, supraphysiological LCN2 levels might prevent proper function of the adaptive immune system. Recent evidence suggests a beneficial effect of chronically increased LCN2 levels in patients with obesity or type 2 diabetes [ 48 , 49 ], as it assists in counteracting obesity-induced glucose intolerance by reducing appetite and driving beta-cell proliferation [ 50 ]. Interestingly, diabetes and obesity are also associated with increased susceptibility to severe influenza infection [ 51 , 52 ], but the potential correlation between LCN2 levels and disease outcome in humans is not known.…”

Section: Discussionmentioning

confidence: 99%

Lipocalin 2 modulates dendritic cell activity and shapes immunity to influenza in a microbiome dependent manner

et al. 2021

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Lipocalin 2 (LCN2) is a secreted glycoprotein with roles in multiple biological processes. It contributes to host defense by interference with bacterial iron uptake and exerts immunomodulatory functions in various diseases. Here, we aimed to characterize the function of LCN2 in lung macrophages and dendritic cells (DCs) using Lcn2-/- mice. Transcriptome analysis revealed strong LCN2-related effects in CD103+ DCs during homeostasis, with differential regulation of antigen processing and presentation and antiviral immunity pathways. We next validated the relevance of LCN2 in a mouse model of influenza infection, wherein LCN2 protected from excessive weight loss and improved survival. LCN2-deficiency was associated with enlarged mediastinal lymph nodes and increased lung T cell numbers, indicating a dysregulated immune response to influenza infection. Depletion of CD8+ T cells equalized weight loss between WT and Lcn2-/- mice, proving that LCN2 protects from excessive disease morbidity by dampening CD8+ T cell responses. In vivo T cell chimerism and in vitro T cell proliferation assays indicated that improved antigen processing by CD103+ DCs, rather than T cell intrinsic effects of LCN2, contribute to the exacerbated T cell response. Considering the antibacterial potential of LCN2 and that commensal microbes can modulate antiviral immune responses, we speculated that LCN2 might cause the observed influenza phenotype via the microbiome. Comparing the lung and gut microbiome of WT and Lcn2-/- mice by 16S rRNA gene sequencing, we observed profound effects of LCN2 on gut microbial composition. Interestingly, antibiotic treatment or co-housing of WT and Lcn2-/- mice prior to influenza infection equalized lung CD8+ T cell counts, suggesting that the LCN2-related effects are mediated by the microbiome. In summary, our results highlight a novel regulatory function of LCN2 in the modulation of antiviral immunity.

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“…Furthermore, an LCN2 transgenic mouse model driven by bone-specific type 1 collagen, an osteolineage-specific promoter, showed expansion of long-term HSCs with higher clonogenic capacity due to elevated levels of CXCL12, SCF and matrix metalloproteinase inhibitors released by the BM niche ( Costa et al, 2017 ). It has also been shown that osteoblasts, which decrease during aging, are the major source for blood circulating LCN2 in the body ( Mosialou et al, 2020 ). Taken together, these findings suggest a beneficial effect of LCN2 supplementation on promoting hematopoieisis and stabilizing the aging BM microenvironment that would require further investigation for potential therapeutic applications.…”

Section: Msc Changes In Aging Bone Marrowmentioning

confidence: 99%

Dynamic Changes of the Bone Marrow Niche: Mesenchymal Stromal Cells and Their Progeny During Aging and Leukemia

Woods

Guezguez

2021

Front. Cell Dev. Biol.

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Mesenchymal stromal cells (MSCs) are a heterogenous cell population found in a wide range of tissues in the body, known for their nutrient-producing and immunomodulatory functions. In the bone marrow (BM), these MSCs are critical for the regulation of hematopoietic stem cells (HSC) that are responsible for daily blood production and functional immunity throughout an entire organism’s lifespan. Alongside other stromal cells, MSCs form a specialized microenvironment BM tissue called “niche” that tightly controls HSC self-renewal and differentiation. In addition, MSCs are crucial players in maintaining bone integrity and supply of hormonal nutrients due to their capacity to differentiate into osteoblasts and adipocytes which also contribute to cellular composition of the BM niche. However, MSCs are known to encompass a large heterogenous cell population that remains elusive and poorly defined. In this review, we focus on deciphering the BM-MSC biology through recent advances in single-cell identification of hierarchical subsets with distinct functionalities and transcriptional profiles. We also discuss the contribution of MSCs and their osteo-adipo progeny in modulating the complex direct cell-to-cell or indirect soluble factors-mediated interactions of the BM HSC niche during homeostasis, aging and myeloid malignancies. Lastly, we examine the therapeutic potential of MSCs for rejuvenation and anti-tumor remedy in clinical settings.

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Lipocalin-2 counteracts metabolic dysregulation in obesity and diabetes

Cited by 57 publications

References 58 publications

The antioxidant tempol transforms gut microbiome to resist obesity in female C3H mice fed a high fat diet

The antioxidant tempol transforms gut microbiome to resist obesity in female C3H mice fed a high fat diet

Lipocalin 2 modulates dendritic cell activity and shapes immunity to influenza in a microbiome dependent manner

Dynamic Changes of the Bone Marrow Niche: Mesenchymal Stromal Cells and Their Progeny During Aging and Leukemia

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