Obese Adipose Tissue Secretion Induces Inflammation in Preadipocytes: Role of Toll-Like Receptor-4

In obesity, the dysfunctional adipose tissue (AT) releases increased levels of proinflammatory adipokines such as TNFα, IL-6, and IL-1β and free fatty acids (FFAs), characterizing a chronic, low-grade inflammation. Whilst FFAs and proinflammatory adipokines are known to elicit an inflammatory response within AT, their relative influence upon preadipocytes, the precursors of mature adipocytes, is yet to be determined. Our results demonstrated that the conditioned medium (CM) derived from obese AT was rich in FFAs, which guided us to evaluate the role of TLR4 in the induction of inflammation in preadipocytes. We observed that CM derived from obese AT increased reactive oxygen species (ROS) levels and NF-ĸB nuclear translocation together with IL-6, TNFα, and IL-1β in 3T3-L1 cells in a TLR4-dependent manner. Furthermore, TLR4 signaling was involved in the increased expression of C/EBPα together with the release of leptin, adiponectin, and proinflammatory mediators, in response to the CM derived from obese AT. Our results suggest that obese AT milieu secretes lipokines, which act in a combined paracrine/autocrine manner, inducing inflammation in preadipocytes via TLR4 and ROS, thus creating a paracrine loop that facilitates the differentiation of adipocytes with a proinflammatory profile.

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Adipose tissue inflammation and metabolic dysfunction: a clinical perspective

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2013-0032 ◽

2013 ◽

Vol 15 (1) ◽

Cited By ~ 2

Author(s):

Charmaine S. Tam ◽

Leanne M. Redman

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Low Grade ◽

Metabolic Dysfunction ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Proinflammatory Mediators ◽

Low Grade Inflammation

AbstractObesity is characterized by a state of chronic low-grade inflammation due to increased immune cells, specifically infiltrated macrophages into adipose tissue, which in turn secrete a range of proinflammatory mediators. This nonselective low-grade inflammation of adipose tissue is systemic in nature and can impair insulin signaling pathways, thus, increasing the risk of developing insulin resistance and type 2 diabetes. The aim of this review is to provide an update on clinical studies examining the role of adipose tissue in the development of obesity-associated complications in humans. We will discuss adipose tissue inflammation during different scenarios of energy imbalance and metabolic dysfunction including obesity and overfeeding, weight loss by calorie restriction or bariatric surgery, and conditions of insulin resistance (diabetes, polycystic ovarian syndrome).

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The Role of Epicardial Adipose Tissue Lymphocytes in Low-Grade Inflammation and Coronary Artery Disease

Diabetes ◽

10.2337/db18-469-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 469-P

Author(s):

MILOS MRAZ ◽

ANNA CINKAJZLOVA ◽

ZDENA LACINOVÁ ◽

JANA KLOUCKOVA ◽

HELENA KRATOCHVILOVA ◽

...

Keyword(s):

Coronary Artery Disease ◽

Adipose Tissue ◽

Coronary Artery ◽

Epicardial Adipose Tissue ◽

Low Grade ◽

Artery Disease ◽

Low Grade Inflammation

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Osteopontin Expression in Human and Murine Obesity: Extensive Local Up-Regulation in Adipose Tissue but Minimal Systemic Alterations

Endocrinology ◽

10.1210/en.2007-1312 ◽

2007 ◽

Vol 149 (3) ◽

pp. 1350-1357 ◽

Cited By ~ 94

Author(s):

Florian W. Kiefer ◽

Maximilian Zeyda ◽

Jelena Todoric ◽

Joakim Huber ◽

René Geyeregger ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Plasma Concentrations ◽

Morbidly Obese ◽

Low Grade ◽

Obese Patients ◽

Multifunctional Protein ◽

Inflammatory Processes ◽

Low Grade Inflammation

Obesity is associated with a chronic low-grade inflammation characterized by macrophage infiltration of adipose tissue (AT) that may underlie the development of insulin resistance and type 2 diabetes. Osteopontin (OPN) is a multifunctional protein involved in various inflammatory processes, cell migration, and tissue remodeling. Because these processes occur in the AT of obese patients, we studied in detail the regulation of OPN expression in human and murine obesity. The study included 20 morbidly obese patients and 20 age- and sex-matched control subjects, as well as two models (diet-induced and genetic) of murine obesity. In high-fat diet-induced and genetically obese mice, OPN expression was drastically up-regulated in AT (40 and 80-fold, respectively) but remained largely unaltered in liver (<2-fold). Moreover, OPN plasma concentrations remained unchanged in both murine models of obesity, suggesting a particular local but not systemic importance for OPN. OPN expression was strongly elevated also in the AT of obese patients compared with lean subjects in both omental and sc AT. In addition, we detected three OPN isoforms to be expressed in human AT and, strikingly, an obesity induced alteration of the OPN isoform expression pattern. Analysis of AT cellular fractions revealed that OPN is exceptionally highly expressed in AT macrophages in humans and mice. Moreover, OPN expression in AT macrophages was strongly up-regulated by obesity. In conclusion, our data point toward a specific local role of OPN in obese AT. Therefore, OPN could be a critical regulator in obesity induced AT inflammation and insulin resistance.

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Hypertension and Erectile Dysfunction: Breaking Down the Challenges

American Journal of Hypertension ◽

10.1093/ajh/hpaa143 ◽

2020 ◽

Author(s):

Amanda Almeida de Oliveira ◽

Kenia Pedrosa Nunes

Keyword(s):

Erectile Dysfunction ◽

Innate Immune System ◽

Innate Immune ◽

Low Grade ◽

Oxygen Species ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Corpora Cavernosa ◽

Inflammatory State ◽

Antioxidant Mechanisms

Abstract A diagnostic of hypertension increases the risk of erectile dysfunction (ED); likewise, ED can be an early sign of hypertension. In both cases, there is evidence that endothelial dysfunction is a common link between the 2 conditions. During hypertension, the sustained and widespread release of procontractile factors (e.g., angiotensin II, endothelin 1, and aldosterone) impairs the balance between vasoconstrictors and vasodilators and, in turn, detrimentally impacts vascular and erectile structures. This prohypertensive state associates with an enhancement in the generation of reactive oxygen species, which is not compensated by internal antioxidant mechanisms. Recently, the innate immune system, mainly via Toll-like receptor 4, has also been shown to actively contribute to the pathophysiology of hypertension and ED not only by inducing oxidative stress but also by sustaining a low-grade inflammatory state. Furthermore, some drugs used to treat hypertension can cause ED and, consequently, reduce compliance with the prescribed pharmacotherapy. To break down these challenges, in this review, we focus on discussing the well-established as well as the emerging mechanisms linking hypertension and ED with an emphasis on the signaling network of the vasculature and corpora cavernosa, the vascular-like structure of the penis.

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Role of the adipocyte-specific NF-κB activity in the regulation of IP-10 and T cell migration

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00143.2010 ◽

2011 ◽

Vol 300 (2) ◽

pp. E304-E311 ◽

Cited By ~ 12

Author(s):

Patricia Krinninger ◽

Cornelia Brunner ◽

Pedro A. Ruiz ◽

Elisabeth Schneider ◽

Nikolaus Marx ◽

...

Keyword(s):

Adipose Tissue ◽

Cell Migration ◽

T Cell ◽

Interferon Γ ◽

Low Grade ◽

Human Adipocytes ◽

Migration Assay ◽

T Cell Migration ◽

Low Grade Inflammation

Infiltration of immune cells into adipose tissue plays a central role in the pathophysiology of obesity-associated low-grade inflammation. The aim of this study was to analyze the role of adipocyte NF-κB signaling in the regulation of the chemokine/adipokine interferon-γ-induced protein 10 kDa (IP-10) and adipocyte-mediated T cell migration. Therefore, the regulation of IP-10 was investigated in adipose tissue of male C57BL/6J mice, primary human and 3T3-L1 preadipocytes/adipocytes. To specifically block the NF-κB pathway, 3T3-L1 cells stably overexpressing a transdominant mutant of IκBα were generated, and the chemical NF-κB inhibitor Bay117082 was used. Adipocyte-mediated T cell migration was assessed by a migration assay. It could be shown that IP-10 expression was higher in mature adipocytes compared with preadipocytes. Induced IP-10 expression and secretion were completely blocked by an NF-κB inhibitor in 3T3-L1 and primary human adipocytes. Stable overexpression of a transdominant mutant of IκBα in 3T3-L1 adipocytes led to an inhibition of basal and stimulated IP-10 expression and secretion. T cell migration was induced by 3T3-L1 adipocyte-conditioned medium, and both basal and induced T cell migration was strongly inhibited by stable overexpression of a transdominant IκBα mutant. In addition, with the use of an anti-IP-10 antibody, a significant decrease of adipocyte-induced T cell migration was shown. In conclusion, in this study, we could demonstrate that the NF-κB pathway is essential for the regulation of IP-10 in 3T3-L1 and primary human adipocytes. Adipocytes rather than preadipocytes contribute to NF-κB-dependent IP-10 expression and secretion. Furthermore, NF-κB-dependent factors and especially IP-10 represent novel signals from adipocytes to induce T cell migration.

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Scutellarin Attenuates Hypertension-Induced Expression of Brain Toll-Like Receptor 4/Nuclear Factor Kappa B

Mediators of Inflammation ◽

10.1155/2013/432623 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 17

Author(s):

Xingyong Chen ◽

Xiaogeng Shi ◽

Xu Zhang ◽

Huixin Lei ◽

Simei Long ◽

...

Keyword(s):

Blood Pressure ◽

Nuclear Factor Kappa B ◽

Interleukin 1 ◽

Low Grade ◽

Nuclear Factor ◽

Toll Like Receptor ◽

Hypertensive Rats ◽

Toll Like Receptor 4 ◽

Nuclear Factor Kappa ◽

Proinflammatory Mediators

Hypertension is associated with low-grade inflammation, and Toll-like receptor 4 (TLR4) has been shown to be linked to the development and maintenance of hypertension. This study aimed to investigate the effects of scutellarin (administered by oral gavage daily for 2 weeks) on brain TLR4/nuclear factor kappa B-(NF-κB-) mediated inflammation and blood pressure in renovascular hypertensive (using the 2-kidney, 2-clip method) rats. Immunofluorescence and western immunoblot analyses revealed that hypertension contributed to the activation of TLR4 and NF-κB, accompanied by significantly enhanced expression of proinflammatory mediators, such as tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), and interleukin-18 (IL-18). Furthermore, expression of the antiapoptotic protein, myeloid cell leukemia-1 (Mcl1), was decreased, and the pro-apoptotic proteins, Bax and cleavedcaspase-3 p17 were increased in combined cerebral cortical/striatal soluble lysates. Scutellarin significantly lowered blood pressure and attenuated the number of activated microglia and macrophages in brains of hypertensive rats. Furthermore, scutellarin significantly reduced the expression of TLR4, NF-κB p65, TNF-α, IL-1β, IL-18, Bax and cleaved-caspase-3 p17, and increased the expression of Mcl1. Overall, these results revealed that scutellarin exhibits anti-inflammatory and anti-apoptotic properties and decreases blood pressure in hypertensive rats. Therefore, scutellarin may be a potential therapeutic agent in hypertension-associated diseases.

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Adipose tissue macrophages in aging-associated adipose tissue function

The Journal of Physiological Sciences ◽

10.1186/s12576-021-00820-2 ◽

2021 ◽

Vol 71 (1) ◽

Author(s):

Bangchao Lu ◽

Liang Huang ◽

Juan Cao ◽

Lingling Li ◽

Wenhui Wu ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Therapeutic Targets ◽

Visceral Adiposity ◽

Low Grade ◽

Recent Advances ◽

Adipose Tissue Macrophages ◽

Low Grade Inflammation

Abstract“Inflammaging” refers to the chronic, low-grade inflammation that characterizes aging. Aging, like obesity, is associated with visceral adiposity and insulin resistance. Adipose tissue macrophages (ATMs) have played a major role in obesity-associated inflammation and insulin resistance. Macrophages are elevated in adipose tissue in aging. However, the changes and also possibly functions of ATMs in aging and aging-related diseases are unclear. In this review, we will summarize recent advances in research on the role of adipose tissue macrophages with aging-associated insulin resistance and discuss their potential therapeutic targets for preventing and treating aging and aging-related diseases.

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Fatty Acids Modulate Toll-like Receptor 4 Activation through Regulation of Receptor Dimerization and Recruitment into Lipid Rafts in a Reactive Oxygen Species-dependent Manner

Journal of Biological Chemistry ◽

10.1074/jbc.m109.044065 ◽

2009 ◽

Vol 284 (40) ◽

pp. 27384-27392 ◽

Cited By ~ 336

Author(s):

Scott W. Wong ◽

Myung-Ja Kwon ◽

Augustine M. K. Choi ◽

Hong-Pyo Kim ◽

Kiichi Nakahira ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Fatty Acids ◽

Lipid Rafts ◽

Reactive Oxygen ◽

Dependent Manner ◽

Oxygen Species ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Receptor Dimerization

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The Role of Oxidative Stress and Inflammation in Cardiovascular Aging

BioMed Research International ◽

10.1155/2014/615312 ◽

2014 ◽

Vol 2014 ◽

pp. 1-13 ◽

Cited By ~ 92

Author(s):

Junzhen Wu ◽

Shijin Xia ◽

Bill Kalionis ◽

Wenbin Wan ◽

Tao Sun

Keyword(s):

Oxidative Stress ◽

Cardiovascular Disease ◽

Ventricular Hypertrophy ◽

Left Ventricular ◽

Low Grade ◽

Oxygen Species ◽

Age Related ◽

Vascular Elasticity ◽

Low Grade Inflammation

Age is an independent risk factor of cardiovascular disease, even in the absence of other traditional factors. Emerging evidence in experimental animal and human models has emphasized a central role for two main mechanisms of age-related cardiovascular disease: oxidative stress and inflammation. Excess reactive oxygen species (ROS) and superoxide generated by oxidative stress and low-grade inflammation accompanying aging recapitulate age-related cardiovascular dysfunction, that is, left ventricular hypertrophy, fibrosis, and diastolic dysfunction in the heart as well as endothelial dysfunction, reduced vascular elasticity, and increased vascular stiffness. We describe the signaling involved in these two main mechanisms that include the factors NF-κB, JunD, p66Shc, and Nrf2. Potential therapeutic strategies to improve the cardiovascular function with aging are discussed, with a focus on calorie restriction, SIRT1, and resveratrol.

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