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

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.

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

Endocrinology ◽

10.1210/en.2013-1607 ◽

2014 ◽

Vol 155 (1) ◽

pp. 40-46 ◽

Cited By ~ 30

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.

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

Frontiers in Immunology ◽

10.3389/fimmu.2020.622468 ◽

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.

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NLRP3 Inflammasome Activation in Adipose Tissues and Its Implications on Metabolic Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21114184 ◽

2020 ◽

Vol 21 (11) ◽

pp. 4184 ◽

Cited By ~ 1

Author(s):

Kelvin Ka-Lok Wu ◽

Samson Wing-Ming Cheung ◽

Kenneth King-Yip Cheng

Keyword(s):

Adipose Tissue ◽

Nlrp3 Inflammasome ◽

Metabolic Disorders ◽

Immune Cell ◽

Diabetic Patients ◽

Inflammasome Activation ◽

Low Grade ◽

Adipose Tissues ◽

Adipose Tissue Dysfunction ◽

Nlrp3 Inflammasome Activation

Adipose tissue is an active endocrine and immune organ that controls systemic immunometabolism via multiple pathways. Diverse immune cell populations reside in adipose tissue, and their composition and immune responses vary with nutritional and environmental conditions. Adipose tissue dysfunction, characterized by sterile low-grade chronic inflammation and excessive immune cell infiltration, is a hallmark of obesity, as well as an important link to cardiometabolic diseases. Amongst the pro-inflammatory factors secreted by the dysfunctional adipose tissue, interleukin (IL)-1β, induced by the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, not only impairs peripheral insulin sensitivity, but it also interferes with the endocrine and immune functions of adipose tissue in a paracrine manner. Human studies indicated that NLRP3 activity in adipose tissues positively correlates with obesity and its metabolic complications, and treatment with the IL-1β antibody improves glycaemia control in type 2 diabetic patients. In mouse models, genetic or pharmacological inhibition of NLRP3 activation pathways or IL-1β prevents adipose tissue dysfunction, including inflammation, fibrosis, defective lipid handling and adipogenesis, which in turn alleviates obesity and its related metabolic disorders. In this review, we summarize both the negative and positive regulators of NLRP3 inflammasome activation, and its pathophysiological consequences on immunometabolism. We also discuss the potential therapeutic approaches to targeting adipose tissue inflammasome for the treatment of obesity and its related metabolic disorders.

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MicroRNA-Regulated Immune Cell Function in Obese Adipose Tissue

Handbook of Nutrition, Diet, and Epigenetics ◽

10.1007/978-3-319-31143-2_26-1 ◽

2017 ◽

pp. 1-18

Author(s):

Beiyan Zhou ◽

Wei Ying ◽

Chuan Li ◽

Anthony T. Vella

Keyword(s):

Adipose Tissue ◽

Cell Function ◽

Immune Cell ◽

Immune Cell Function

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Leukocyte Heterogeneity in Adipose Tissue, Including in Obesity

Circulation Research ◽

10.1161/circresaha.120.316203 ◽

2020 ◽

Vol 126 (11) ◽

pp. 1590-1612 ◽

Cited By ~ 6

Author(s):

Ada Weinstock ◽

Hernandez Moura Silva ◽

Kathryn J. Moore ◽

Ann Marie Schmidt ◽

Edward A. Fisher

Keyword(s):

Adipose Tissue ◽

Immune Cells ◽

Immune Cell ◽

Γδ T Cells ◽

The United States ◽

Low Grade ◽

Obesity Prevalence ◽

Cell Level ◽

Mortality And Morbidity ◽

Molecular Investigation

Adipose tissue (AT) plays a central role in both metabolic health and pathophysiology. Its expansion in obesity results in increased mortality and morbidity, with contributions to cardiovascular disease, diabetes mellitus, fatty liver disease, and cancer. Obesity prevalence is at an all-time high and is projected to be 50% in the United States by 2030. AT is home to a large variety of immune cells, which are critical to maintain normal tissue functions. For example, γδ T cells are fundamental for AT innervation and thermogenesis, and macrophages are required for recycling of lipids released by adipocytes. The expansion of visceral white AT promotes dysregulation of its immune cell composition and likely promotes low-grade chronic inflammation, which has been proposed to be the underlying cause for the complications of obesity. Interestingly, weight loss after obesity alters the AT immune compartment, which may account for the decreased risk of developing these complications. Recent technological advancements that allow molecular investigation on a single-cell level have led to the discovery of previously unappreciated heterogeneity in many organs and tissues. In this review, we will explore the heterogeneity of immune cells within the visceral white AT and their contributions to homeostasis and pathology.

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Mechanistic Links Between Obesity, Diabetes, and Blood Pressure: Role of Perivascular Adipose Tissue

Physiological Reviews ◽

10.1152/physrev.00034.2018 ◽

2019 ◽

Vol 99 (4) ◽

pp. 1701-1763 ◽

Cited By ~ 27

Author(s):

Sophie N. Saxton ◽

Ben J. Clark ◽

Sarah B. Withers ◽

Etto C. Eringa ◽

Anthony M. Heagerty

Keyword(s):

Adipose Tissue ◽

Cell Population ◽

Cardiovascular Health ◽

Inflammatory Cell ◽

Immune Cell ◽

Disease Process ◽

Immune Cell Population ◽

Perivascular Adipose Tissue ◽

Key Factor

Obesity is increasingly prevalent and is associated with substantial cardiovascular risk. Adipose tissue distribution and morphology play a key role in determining the degree of adverse effects, and a key factor in the disease process appears to be the inflammatory cell population in adipose tissue. Healthy adipose tissue secretes a number of vasoactive adipokines and anti-inflammatory cytokines, and changes to this secretory profile will contribute to pathogenesis in obesity. In this review, we discuss the links between adipokine dysregulation and the development of hypertension and diabetes and explore the potential for manipulating adipose tissue morphology and its immune cell population to improve cardiovascular health in obesity.

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Physiological Aging: Links Among Adipose Tissue Dysfunction, Diabetes, and Frailty

Physiology ◽

10.1152/physiol.00012.2016 ◽

2017 ◽

Vol 32 (1) ◽

pp. 9-19 ◽

Cited By ~ 57

Author(s):

Michael B. Stout ◽

Jamie N. Justice ◽

Barbara J. Nicklas ◽

James L. Kirkland

Keyword(s):

Adipose Tissue ◽

Chronic Disease ◽

Immune Cell ◽

Sterile Inflammation ◽

Metabolic Dysfunction ◽

Adverse Health Outcomes ◽

Cytokines And Chemokines ◽

Inflammatory Status ◽

Adipose Tissue Dysfunction ◽

Age Related

Advancing age is associated with progressive declines in physiological function that lead to overt chronic disease, frailty, and eventual mortality. Importantly, age-related physiological changes occur in cellularity, insulin-responsiveness, secretory profiles, and inflammatory status of adipose tissue, leading to adipose tissue dysfunction. Although the mechanisms underlying adipose tissue dysfunction are multifactorial, the consequences result in secretion of proinflammatory cytokines and chemokines, immune cell infiltration, an accumulation of senescent cells, and an increase in senescence-associated secretory phenotype (SASP). These processes synergistically promote chronic sterile inflammation, insulin resistance, and lipid redistribution away from subcutaneous adipose tissue. Without intervention, these effects contribute to age-related systemic metabolic dysfunction, physical limitations, and frailty. Thus adipose tissue dysfunction may be a fundamental contributor to the elevated risk of chronic disease, disability, and adverse health outcomes with advancing age.

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Adipose tissue: an endocrine organ playing a role in metabolic regulation

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2015-0073 ◽

2016 ◽

Vol 26 (1) ◽

Cited By ~ 25

Author(s):

Andrea Booth ◽

Aaron Magnuson ◽

Josephine Fouts ◽

Michelle T. Foster

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Glucose Homeostasis ◽

Insulin Signaling ◽

Metabolic Regulation ◽

Cell Function ◽

Immune Cell ◽

Whole Body ◽

Endocrine Organ

AbstractAdipose tissue is a complex endocrine organ with an intricate role in whole body homeostasis. Beyond storing energy, adipose tissue is fundamental in numerous processes including, but not limited to, metabolism, food intake and immune cell function. Adipokines and cytokines are the signaling factors from adipose tissue. These factors play a role in maintaining health, but are also candidates for pathologies associated with obesity. Indeed excessive adiposity causes dysregulation of these factors which negatively affect health and contribute to numerous obesity-induced co-morbidities. In particular, adipokines are fundamental in regulation of glucose homeostasis and insulin signaling, thus aberrant production of these adipose derived hormones correlates with the development and progression of type 2 diabetes. Therefore, elucidation of adipose regulation is crucial for understanding the pathophysiological basis of obesity and metabolic diseases such as type 2 diabetes. In the present review, we summarize current data on the relation between adipokines and adipose depot derived cytokines in the maintenance of glucose homeostasis. Specifically, physiological and molecular functions of several adipokines are defined with particular focus on interactions within the insulin-signaling pathway and subsequent regulation of glucose uptake in both standard and obesity-induced dysregulated conditions. This same relation will be discussed for cytokines and inflammation as well.

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Peritoneal macrophages have an impaired immune response in obesity which can be reversed by subsequent weight loss

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000751 ◽

2019 ◽

Vol 7 (1) ◽

pp. e000751 ◽

Cited By ~ 1

Author(s):

Lisa Willemsen ◽

Annette E Neele ◽

Saskia van der Velden ◽

Koen H M Prange ◽

Myrthe den Toom ◽

...

Keyword(s):

Immune Response ◽

Weight Loss ◽

Adipose Tissue ◽

Cell Function ◽

Immune Cell ◽

Peritoneal Macrophages ◽

Macrophage Phenotype ◽

Adipose Tissue Macrophages ◽

Microbial Infections ◽

Impaired Immune Response

IntroductionObesity is recognized as a risk factor for various microbial infections. The immune system, which is affected by obesity, plays an important role in the pathophysiology of these infections and other obesity-related comorbidities. Weight loss is considered the most obvious treatment for obesity. However, multiple studies suggest that the comorbidities of obesity may persist after weight loss. Deregulation of immune cells including adipose tissue macrophages of obese individuals has been extensively studied, but how obesity and subsequent weight loss affect immune cell function outside adipose tissue is not well defined.Research design and methodsHere we investigated the phenotype of non-adipose tissue macrophages by transcriptional characterization of thioglycollate-elicited peritoneal macrophages (PM) from mice with diet-induced obesity and type 2 diabetes (T2D). Subsequently, we defined the characteristics of PMs after weight loss and mimicked a bacterial infection by exposing PMs to lipopolysaccharide.Results and conclusionsIn contrast to the proinflammatory phenotype of adipose tissue macrophages in obesity and T2D, we found a deactivated state of PMs in obesity and T2D. Weight loss could reverse this deactivated macrophage phenotype. Anti-inflammatory characteristics of these non-adipose macrophages may explain why patients with obesity and T2D have an impaired immune response against pathogens. Our data also suggest that losing weight restores macrophage function and thus contributes to the reduction of immune-related comorbidities in patients.

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