Macrophage infiltration into obese adipose tissues suppresses the induction of UCP1 level in mice.
15 Apr 2016-American Journal of Physiology-endocrinology and Metabolism (American Physiological Society)-Vol. 310, Iss: 8
TL;DR: It is suggested that inflammation induced by infiltrated M1 Mϕ could cause not only insulin resistance but also reduction of energy expenditure in adipose tissues.
Abstract: Emergence of thermogenic adipocytes such as brown and beige adipocytes is critical for whole body energy metabolism. Promoting the emergence of these adipocytes, which increase energy expenditure, could be a viable strategy in treating obesity and its related diseases. However, little is known regarding the mechanisms that regulate the emergence of these adipocytes in obese adipose tissue. Here, we demonstrated that classically activated macrophages (M1 Mϕ) suppress the induction of thermogenic adipocytes in obese adipose tissues of mice. Cold exposure significantly induced the expression levels of uncoupling protein-1 (UCP1), which is a mitochondrial protein unique in thermogenic adipocytes, in C57BL/6 mice fed a normal diet. However, UCP1 induction was significantly suppressed in adipose tissues of C57BL/6 mice fed a high-fat diet, into which M1 Mϕ infiltrated. Depletion of M1 Mϕ using clodronate liposomes eliminated the suppressive effect and markedly reduced the mRNA level of tumor necrosis factor-α (TNFα) in the adipose tissues. Importantly, consistent with the observed changes in the expression levels of marker genes for thermogenic adipocytes, combination treatment of clodronate liposome and cold exposure resulted in metabolic benefits such as lowered body weight and blood glucose level in obese mice. Moreover, intraperitoneal injection of recombinant TNFα protein suppressed UCP1 induction in lean adipose tissues of mice. Collectively, our data indicate that infiltrated M1 Mϕ suppress the induction of thermogenic adipocytes in obese adipose tissues via TNFα. This report suggests that inflammation induced by infiltrated Mϕ could cause not only insulin resistance but also reduction of energy expenditure in adipose tissues.
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TL;DR: The connection between adipose tissue inflammation and the development of insulin resistance and catecholamine resistance is examined and the ensuing state of metabolic inflexibility is discussed.
Abstract: Adipose tissue not only has an important role in the storage of excess nutrients but also senses nutrient status and regulates energy mobilization. An overall positive energy balance is associated with overnutrition and leads to excessive accumulation of fat in adipocytes. These cells respond by initiating an inflammatory response that, although maladaptive in the long run, might initially be a physiological response to the stresses obesity places on adipose tissue. In this Review, we characterize adipose tissue inflammation and review the current knowledge of what triggers obesity-associated inflammation in adipose tissue. We examine the connection between adipose tissue inflammation and the development of insulin resistance and catecholamine resistance and discuss the ensuing state of metabolic inflexibility. Finally, we review the current and potential new anti-inflammatory treatments for obesity-associated metabolic disease.
776 citations
TL;DR: The mechanisms by which dysfunctional adipose tissue simultaneously promote T2DM and CVD, focusing on adipose tissues depot-specific adipokines, inflammatory profiles, and metabolism, will be the focus of this review.
Abstract: Adipose tissue plays essential roles in maintaining lipid and glucose homeostasis. To date several types of adipose tissue have been identified, namely white, brown, and beige, that reside in various specific anatomical locations throughout the body. The cellular composition, secretome, and location of these adipose depots define their function in health and metabolic disease. In obesity, adipose tissue becomes dysfunctional, promoting a pro-inflammatory, hyperlipidemic and insulin resistant environment that contributes to type 2 diabetes mellitus (T2DM). Concurrently, similar features that result from adipose tissue dysfunction also promote cardiovascular disease (CVD) by mechanisms that can be augmented by T2DM. The mechanisms by which dysfunctional adipose tissue simultaneously promote T2DM and CVD, focusing on adipose tissue depot-specific adipokines, inflammatory profiles, and metabolism, will be the focus of this review. The impact that various T2DM and CVD treatment strategies have on adipose tissue function and body weight also will be discussed.
476 citations
Cites background from "Macrophage infiltration into obese ..."
...Such BAT inflammation reportedly lowers the thermogenic potential of this tissue (359), presumably due to increased local insulin resistance (360, 362), which could reduce the glucose and fatty acid oxidizing capacity of BAT....
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TL;DR: This review focuses on inflammation in adipose tissue and its potential role in insulin resistance associated with obesity.
Abstract: Obesity is becoming an epidemic in the United States and worldwide and increases risk for many diseases, particularly insulin resistance, type 2 diabetes mellitus, and cardiovascular disease. The mechanisms linking obesity with these diseases remain incompletely understood. Over the past 2 to 3 decades, it has been recognized that in obesity, inflammation, with increased accumulation and inflammatory polarization of immune cells, takes place in various tissues, including adipose tissue, skeletal muscle, liver, gut, pancreatic islet, and brain and may contribute to obesity-linked metabolic dysfunctions, leading to insulin resistance and type 2 diabetes mellitus. Therapies targeting inflammation have shed light on certain obesity-linked diseases, including type 2 diabetes mellitus and atherosclerotic cardiovascular disease, but remain to be tested further and confirmed in clinical trials. This review focuses on inflammation in adipose tissue and its potential role in insulin resistance associated with obesity.
253 citations
Journal Article•
TL;DR: In this paper, the effects of a highly selective beta 3-adrenergic agonist, CL316,243 (CL), on UCP expression in skeletal muscle and adipose tissues were examined in mice.
Abstract: The mitochondrial uncoupling protein (UCP) is usually expressed only in brown adipose tissue (BAT) and a key molecule for metabolic thermogenesis. The effects of a highly selective beta 3-adrenergic agonist, CL316,243 (CL), on UCP expression in skeletal muscle and adipose tissues were examined in mice. Daily injection of CL (0.1 mg/kg, sc) to obese yellow KK mice for two weeks caused a significant reduction of body weight, associated with a marked decrease of white fat pad weight and hypertrophy of the interscapular BAT with a sixfold increase in UCP content. Clear signals of UCP protein and mRNA were detected by Western and Northern blot analyses in inguinal, mesenteric and retroperitoneal white fat pads, and also in gastrocnemius and quadriceps muscles, whereas no signal in saline-treated mice. The presence of UCP mRNA in muscle tissues was also confirmed by reverse transcription-PCR analysis. Weaker UCP signals were also detected in control C57BL mice treated with CL, but only in inguinal and retroperitoneal fat pads. Immunohistochemical examinations revealed that UCP stains in the white fat pads were localized on multilocular cells quite similar to typical brown adipocyte, and those in the muscle tissues on myocytes. The mitochondrial localization of UCP in myocytes was confirmed by immunoelectron microscopy. In addition to UCP protein, UCP mRNA was also detected in myocytes by in situ hybridization analysis. Thus, chronic stimulation of the beta 3-adrenergic receptor induces ectopic expression of UCP in adipose tissues conventionally considered as white fat and even in skeletal muscle, which probably contributes to the potent anti-obesity effect of the beta 3-adrenergic agonist.
195 citations
TL;DR: The prevalence of obesity has recently increased dramatically and has contributed to the increasing prevalence of various pathological conditions, including type 2 diabetes mellitus, nonalcoholic fatty liver disease, asthma, various types of cancer, cardiovascular and neurodegenerative diseases, and others.
Abstract: The prevalence of obesity has recently increased dramatically and has contributed to the increasing prevalence of various pathological conditions, including type 2 diabetes mellitus, nonalcoholic fatty liver disease, asthma, various types of cancer, cardiovascular and neurodegenerative diseases, and others. Accumulating evidence points to localized inflammation in adipose tissue, which, in turn, promotes systemic low-grade inflammation as a primary force contributing to the development of these pathologies. A better understanding of the underlying mechanisms behind obesity-induced adipose tissue inflammation is required to develop effective therapeutic or prophylactic strategies. This review is aimed to present the current knowledge of adipose tissue inflammation associated with obesity.
175 citations
Cites background from "Macrophage infiltration into obese ..."
...The precise mechanism by which adipocytes become insensitive to stimulation of -adrenergic receptors in obesity is as yet unknown and several possibilities have been suggested including reduced expression of -adrenergic receptors [138], reduced mitochondrial biogenesis [139], increased expression of TGF- receptor activin receptor-like kinase 7 (ALK7) [140] and reduced activity of post-receptor pathways [141]....
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References
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TL;DR: Dysfunction of the immune response and metabolic regulation interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease.
Abstract: Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily conserved throughout species. As a result, immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease. Collectively, these diseases constitute the greatest current threat to global human health and welfare.
7,536 citations
"Macrophage infiltration into obese ..." refers background in this paper
...Chronic inflammation of obese WAT can lead to the development of metabolic disorders (14, 15)....
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TL;DR: It is proposed that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue, and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance.
Abstract: Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance However, the underlying molecular pathways are largely unknown In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO) The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue
6,165 citations
"Macrophage infiltration into obese ..." refers background in this paper
...M1 M have been shown to secrete a variety of proinflammatory cytokines, such as TNF (19, 39), leading to insulin resistance (47)....
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TL;DR: Diet-induced obesity leads to a shift in the activation state of ATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1 proinflammatory state that contributes to insulin resistance.
Abstract: Adipose tissue macrophages (ATMs) infiltrate adipose tissue during obesity and contribute to insulin resistance. We hypothesized that macrophages migrating to adipose tissue upon high-fat feeding may differ from those that reside there under normal diet conditions. To this end, we found a novel F4/80(+)CD11c(+) population of ATMs in adipose tissue of obese mice that was not seen in lean mice. ATMs from lean mice expressed many genes characteristic of M2 or "alternatively activated" macrophages, including Ym1, arginase 1, and Il10. Diet-induced obesity decreased expression of these genes in ATMs while increasing expression of genes such as those encoding TNF-alpha and iNOS that are characteristic of M1 or "classically activated" macrophages. Interestingly, ATMs from obese C-C motif chemokine receptor 2-KO (Ccr2-KO) mice express M2 markers at levels similar to those from lean mice. The antiinflammatory cytokine IL-10, which was overexpressed in ATMs from lean mice, protected adipocytes from TNF-alpha-induced insulin resistance. Thus, diet-induced obesity leads to a shift in the activation state of ATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1 proinflammatory state that contributes to insulin resistance.
4,046 citations
"Macrophage infiltration into obese ..." refers background in this paper
...M1 M have been shown to secrete a variety of proinflammatory cytokines, such as TNF (19, 39), leading to insulin resistance (47)....
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...Two populations of M have been recognized in adipose tissues: the classically activated M (M1 M ) that exhibit proinflammatory properties and the alternatively activated M (M2 M ) that display anti-inflammatory properties (19)....
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...3D) macrophages, which are considered to be M1 M (19) in the crown-like structures of the clodronate liposome-injected group....
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...Hematoxylin-eosin staining revealed that the numbers of crown-like structures, which were considered to be the accumulation of immune cells such as M (19), were increased in IWAT of HFD-fed C57BL/6 mice....
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TL;DR: Defined regions of functionally active brown adipose tissue are present in adult humans, are more frequent in women than in men, and may be quantified noninvasively with the use of (18)F-FDG PET-CT.
Abstract: Background Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the expression of uncoupling protein 1 (UCP1), but brown adipose tissue has been considered to have no physiologic relevance in adult humans. Methods We analyzed 3640 consecutive 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomographic and computed tomographic (PET–CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of 18F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from t...
3,805 citations
"Macrophage infiltration into obese ..." refers background in this paper
...Numerous recent studies have indicated that adult humans maintain potentially active BAT, making this highly energetic tissue a promising therapeutic target for the treatment of obesity (8, 35, 42, 44)....
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TL;DR: Brown adipose tissue may be metabolically important in men, and the fact that it is reduced yet present in most overweight or obese subjects may make it a target for the treatment of obesity.
Abstract: Background Studies in animals indicate that brown adipose tissue is important in the regulation of body weight, and it is possible that individual variation in adaptive thermogenesis can be attributed to variations in the amount or activity of brown adipose tissue. Until recently, the presence of brown adipose tissue was thought to be relevant only in small mammals and infants, with negligible physiologic relevance in adult humans. We performed a systematic examination of the presence, distribution, and activity of brown adipose tissue in lean and obese men during exposure to cold temperature. Brown-adipose-tissue activity was studied in relation to body composition and energy metabolism. Methods We studied 24 healthy men — 10 who were lean (body-mass index [BMI] [the weight in kilograms divided by the square of the height in meters], <25) and 14 who were overweight or obese (BMI, ≥25) — under thermoneutral conditions (22°C) and during mild cold exposure (16°C). Putative brown-adipose-tissue activity was ...
3,114 citations
"Macrophage infiltration into obese ..." refers background in this paper
...Numerous recent studies have indicated that adult humans maintain potentially active BAT, making this highly energetic tissue a promising therapeutic target for the treatment of obesity (8, 35, 42, 44)....
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