scholarly journals Bone Marrow Leptin Signaling Mediates Obesity-Associated Adipose Tissue Inflammation in Male Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (1) ◽  
pp. 40-46 ◽  
Author(s):  
Lea H. Dib ◽  
M. Teresa Ortega ◽  
Sherry D. Fleming ◽  
Stephen K. Chapes ◽  
Tonatiuh Melgarejo
Keyword(s):  
Bone Marrow ◽  
Adipose Tissue ◽  
Systemic Inflammation ◽  
Leptin Receptor ◽  
Cell Function ◽  
Immune Cell ◽  
Metabolic Complications ◽  
Leptin Signaling ◽  
Lower Body Weight ◽  
Inflammatory Phenotype

Obesity is characterized by an increased recruitment of proinflammatory macrophages to the adipose tissue (AT), leading to systemic inflammation and metabolic disease. The pathogenesis of this AT inflammation, however, remains to be elucidated. The circulating adipokine leptin is increased in obesity and is involved in immune cell function and activation. In the present study, we investigated the role of leptin in the induction of obesity-associated inflammation. We generated radiation chimeric C57BL/6J mice reconstituted with either leptin receptor-deficient (db/db) or wild-type (WT) bone marrow and challenged them with a high-fat diet (HFD) for 16 weeks. Mice reconstituted with db/db bone marrow (WT/db), had significantly lower body weight and adiposity compared with mice with WT bone marrow (WT/WT). Gonadal AT in WT/db mice displayed a 2-fold lower expression of the inflammatory genes Tnfa, Il6, and Ccl2. In addition, gonadal fat of WT/db mice contained significantly fewer crown-like structures compared with WT/WT mice, and most of their AT macrophages expressed macrophage galactose-type C type lectin 1 (MGL1) and were C-C chemokine receptor type 2 (CCR2)-negative, indicative of an anti-inflammatory phenotype. Moreover, WT/db mice exhibited greater insulin sensitivity compared with WT/WT mice. These data show that disrupted leptin signaling in bone marrow-derived cells attenuates the proinflammatory conditions that mediate many of the metabolic complications that characterize obesity. Our findings establish a novel mechanism involved in the regulation of obesity-associated systemic inflammation and support the hypothesis that leptin is a proinflammatory cytokine.

scholarly journals The Role of the Adipokine Leptin in Immune Cell Function in Health and Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Kaitlin Kiernan ◽  
Nancie J. MacIver
Keyword(s):  
Adipose Tissue ◽  
Leptin Receptor ◽  
Cell Function ◽  
Immune Cell ◽  
Immune Cell Function ◽  
Tissue Mass ◽  
Inflammatory Phenotype ◽  
Health And Disease ◽  
Pleiotropic Actions

Leptin is a critical mediator of the immune response to changes in overall nutrition. Leptin is produced by adipocytes in proportion to adipose tissue mass and is therefore increased in obesity. Despite having a well-described role in regulating systemic metabolism and appetite, leptin displays pleiotropic actions, and it is now clear that leptin has a key role in influencing immune cell function. Indeed, many immune cells have been shown to respond to leptin directly via the leptin receptor, resulting in a largely pro-inflammatory phenotype. Understanding the role of adipose-tissue derived mediators in inflammation is critical to determining the pathophysiology of multiple obesity-associated diseases, such as type 2 diabetes, autoimmune disease, and infection. This review, therefore, focuses on the latest data regarding the role of leptin in modulating inflammation.

scholarly journals HIF1α activation in dendritic cells under sterile conditions promotes an anti-inflammatory phenotype through accumulation of intracellular lipids

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Elizabeth G. Wood ◽  
Claire E. Macdougall ◽  
Hazel Blythe ◽  
Marc Clément ◽  
Romain A. Colas ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cell Function ◽  
Immune Cell ◽  
Lipid Synthesis ◽  
Mortality And Morbidity ◽  
Intracellular Lipids ◽  
Adipose Tissue Dysfunction ◽  
Disease Mortality ◽  
Key Factor ◽  
Inflammatory Phenotype

AbstractObesity is among the leading causes of elevated cardiovascular disease mortality and morbidity. Adipose tissue dysfunction, insulin resistance and inflammation are recognized as important risk factors for the development of cardiovascular disorders in obesity. Hypoxia appears to be a key factor in adipose tissue dysfunction affecting not only adipocytes but also immune cell function. Here we examined the effect of hypoxia-induced transcription factor HIF1α activation on classical dendritic cell (cDCs) function during obesity. We found that deletion of Hif1α on cDCs results in enhanced adipose-tissue inflammation and atherosclerotic plaque formation in a mouse model of obesity. This effect is mediated by HIF1α-mediated increased lipid synthesis, accumulation of lipid droplets and alter synthesis of lipid mediators. Our findings demonstrate that HIF1α activation in cDCs is necessary to control vessel wall inflammation.

scholarly journals Erratum: Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo: Role in osteoclast-mediated NK cell activation

Oncotarget ◽  
2015 ◽  
Vol 6 (38) ◽  
pp. 41398-41398 ◽  
Author(s):  
Han-Ching Tseng ◽  
Keiichi Kanayama ◽  
Kawaljit Kaur ◽  
So-Hyun Park ◽  
Sil Park ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Nk Cell ◽  
Differential Modulation ◽  
Immune Cell Function

scholarly journals Activation of Bone Marrow Adaptive Immunity in Type 2 Diabetes: Rescue by Co-stimulation Modulator Abatacept

2021 ◽  
Vol 12 ◽  
Author(s):  
Marianna Santopaolo ◽  
Niall Sullivan ◽  
Anita Coral Thomas ◽  
Valeria Vincenza Alvino ◽  
Lindsay B. Nicholson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bone Marrow ◽  
T Cells ◽  
Insulin Sensitivity ◽  
Adaptive Immunity ◽  
Cell Function ◽  
Immune Cell ◽  
Low Grade ◽  
Cardiac Damage

Background: Chronic low-grade inflammation and alterations in innate and adaptive immunity were reported in Type 2 diabetes (T2D). Here, we investigated the abundance and activation of T cells in the bone marrow (BM) of patients with T2D. We then verified the human data in a murine model and tested if the activation of T cells can be rescued by treating mice with abatacept, an immunomodulatory drug employed for the treatment of rheumatoid arthritis. Clinical evidence indicated abatacept can slow the decline in beta-cell function.Methods: A cohort of 24 patients (12 with T2D) undergoing hip replacement surgery was enrolled in the study. Flow cytometry and cytokine analyses were performed on BM leftovers from surgery. We next compared the immune profile of db/db and control wt/db mice. In an additional study, db/db mice were randomized to receive abatacept or vehicle for 4 weeks, with endpoints being immune cell profile, indices of insulin sensitivity, and heart performance.Results: Patients with T2D showed increased frequencies of BM CD4+ (2.8-fold, p = 0.001) and CD8+ T cells (1.8-fold, p = 0.01), with the upregulation of the activation marker CD69 and the homing receptor CCR7 in CD4+ (1.64-fold, p = 0.003 and 2.27-fold, p = 0.01, respectively) and CD8+ fractions (1.79-fold, p = 0.05 and 1.69-fold, p = 0.02, respectively). These differences were confirmed in a multivariable regression model. CCL19 (CCR7 receptor ligand) and CXCL10/11 (CXCR3 receptor ligands), implicated in T-cell migration and activation, were the most differentially modulated chemokines. Studies in mice confirmed the activation of adaptive immunity in T2D. Abatacept reduced the activation of T cells and the levels of proinflammatory cytokines and improved cardiac function but not insulin sensitivity.Conclusions: Results provide proof-of-concept evidence for the activation of BM adaptive immunity in T2D. In mice, treatment with abatacept dampens the activation of adaptive immunity and protects from cardiac damage.

scholarly journals Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo: Role in osteoclast-mediated NK cell activation

Oncotarget ◽  
2015 ◽  
Vol 6 (24) ◽  
pp. 20002-20025 ◽  
Author(s):  
Han-Ching Tseng ◽  
Keiichi Kanayama ◽  
Kawaljit Kaur ◽  
So-Hyun Park ◽  
Sil Park ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Nk Cell ◽  
Differential Modulation ◽  
Immune Cell Function

scholarly journals The Crosstalk Between Leptin Receptor Activation and iNKT Mediated Anti-Tumor Immunity in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2075-2075
Author(s):  
Mérédis Favreau ◽  
Eline Menu ◽  
Karin Vanderkerken ◽  
Sylvia Faict ◽  
Ken Maes ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Adipose Tissue ◽  
Tumor Immunity ◽  
Leptin Receptor ◽  
Receptor Activation ◽  
Newly Diagnosed ◽  
Inkt Cells ◽  
Bone Marrow Adipose Tissue ◽  
Bone Marrow Adipocytes

Abstract In recent years, researchers have showed a growing interest in the mechanistic relationship between bone marrow adipose tissue and adjacent tumors. However, the impact of bone marrow adipocytes on development of hematological malignancies, particularly multiple myeloma is unknown. With aging, bone marrow changes occur and fatty deposits can occupy up to 70% of the BM cavity. Interactions of bone marrow adipose tissue with bone cells and other immune cells, possibly suggest indirect ways in which bone marrow adipocytes may affect MM disease progression. Leptin, an adipokine released by adipocytes and crucial in energy homeostasis, displays immune modulatory properties but its role in anti-tumor immunity remains unclear. In this study we aimed to investigate the intriguing relationship between leptin receptor activation and invariant natural killer T (iNKT) cell mediated anti-tumor immunity in multiple myeloma. The murine immunocompetent 5T33MM model, mimicking the human disease closely, and human samples of newly diagnosed patients were used to investigate this research topic. A marked increase in serum leptin levels and an upregulation of the leptin receptor expression on iNKT cells was observed in multiple myeloma, in both mice and newly diagnosed patients. In vitro functional analysis demonstrated a direct role for leptin in the downmodulation of the iNKT cell function and an indirect role by acting on the MM cells itself, potentiating the immunosuppressive effect on iNKT cells. We next evaluated the in vivo effects of blocking the leptin receptor together with activating iNKT cells with the prototypic glycolipid a-galactosylceramide (a-GalCer), in the 5T33 myeloma model. Remarkably, strong protection was seen in the combined regimen (a-GalCer and leptin receptor blockade), which was found to be linked to an amplified and sustained activation of iNKT cells, preventing them to become hypoactive. These findings suggest that leptin has a crucial immune suppressive role in myeloma development. Overall, our data reveal the leptin receptor axis as a novel target to treat multiple myeloma. Disclosures Leleu: TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria.

scholarly journals Inhibiting LXRα Phosphorylation in Hematopoietic Cells Reduces Inflammation and Attenuates Atherosclerosis and Obesity

2020 ◽  
Author(s):  
Maud Voisin ◽  
Elina Shrestha ◽  
Claire Rollet ◽  
Tatjana Josefs ◽  
Tessa J Barrett ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Hematopoietic Cells ◽  
High Cholesterol Diet ◽  
Knock Out ◽  
Adaptive Immune Cells ◽  
Adipose Tissue Macrophages ◽  
Lower Body Weight ◽  
Inflammatory Phenotype ◽  
Functional Consequences ◽  
Knock Out Mice

Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα, a nuclear receptor, plays a central role in the transcription of inflammatory and lipid metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the functional consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRa phosphorylation, bone marrow from LXRaWT and S196A mice was transplanted into Ldlr knock out mice, which were fed a high fat, high cholesterol diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68 cells from S196A mouse plaques revealed downregulation of proinflammatory genes and upregulation of mitochondrial genes characteristic of antiinflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue. This was associated with transcriptional reprograming of the adipose tissue macrophages and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXRα pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXRα to an anti-inflammatory phenotype.

scholarly journals Obesity and Fat Metabolism in Human Immunodeficiency Virus–Infected Individuals: Immunopathogenic Mechanisms and Clinical Implications

2019 ◽  
Vol 220 (3) ◽  
pp. 420-431 ◽  
Author(s):  
Catherine Godfrey ◽  
Andrew Bremer ◽  
Diana Alba ◽  
Caroline Apovian ◽  
John R Koethe ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Adipose Tissue ◽  
Immune Cell ◽  
Clinical Care ◽  
Fat Metabolism ◽  
Visceral Obesity ◽  
Ectopic Fat ◽  
Metabolic Complications ◽  
Fat Accumulation ◽  
Immunodeficiency Virus

Abstract Metabolic complications relating to complex effects of viral and immune-mediated mechanisms are now a focus of clinical care among persons living with human immunodeficiency virus (PLHIV), and obesity is emerging as a critical problem. To address knowledge gaps, the US National Institutes of Health sponsored a symposium in May 2018 entitled “Obesity and Fat Metabolism in HIV-infected Individuals.” Mechanisms relating to adipose dysfunction and fibrosis, immune function, inflammation, and gastrointestinal integrity were highlighted as contributors to obesity among PLHIV. Fibrotic subcutaneous adipose tissue is metabolically dysfunctional and loses its capacity to expand, leading to fat redistribution, including visceral obesity and ectopic fat accumulation, promoting insulin resistance. Viral proteins, including viral protein R and negative regulatory factor, have effects on adipogenic pathways and cellular metabolism in resident macrophages and T cells. HIV also affects immune cell trafficking into the adipose compartments, with effects on adipogenesis, lipolysis, and ectopic fat accumulation. Key cellular metabolic functions are likely to be affected in PLHIV by gut-derived cytokines and altered microbiota. There are limited strategies to reduce obesity specifically in PLHIV. Enhancing our understanding of critical pathogenic mechanisms will enable the development of novel therapeutics that may normalize adipose tissue function and distribution, reduce inflammation, and improve insulin sensitivity in PLHIV.

Sign in / Sign up

Export Citation Format

Share Document