Increased Macrophage Migration Into Adipose Tissue in Obese Mice

Oh, Da Young; Morinaga, Hidetaka; Talukdar, Saswata; Bae, Eun Ju; Olefsky, Jerrold M.

doi:10.2337/db11-0860

Cited by 326 publications

(300 citation statements)

References 31 publications

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“…We observed increased expression of these three cell surface glycoproteins in macrophages from hIAPP Tg/o islets associated with elevated Il1b and decreased Il1rn and Il10 expression. Macrophages that migrate into adipose tissue during high-fat feeding also express elevated CD11b, CD11c, F4/80, and Ly6C compared with resident tissue macrophages, and this M1-like subpopulation is highly proinflammatory (36,50). The present data suggest that hIAPP aggregation may affect the differentiation state of monocytes entering the islet and that hIAPP skews resident cells toward a proinflammatory phenotype, consistent with the microenvironment driving macrophage plasticity (51).…”

Section: Discussionsupporting

confidence: 58%

Resident Macrophages Mediate Islet Amyloid Polypeptide–Induced Islet IL-1β Production and β-Cell Dysfunction

2014

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Islet amyloid polypeptide (IAPP) aggregates to form amyloid fibrils in patients with type 2 diabetes and acts as a potent stimulus for interleukin (IL)-1b secretion by bone marrow-derived macrophages. We sought to determine the contribution of resident islet macrophages to IAPP-induced inflammation and b-cell dysfunction. In cultured islets, macrophages (F4/80+ cells) were required for IAPP-induced mRNA expression of the proinflammatory cytokines IL-1b, tumor necrosis factor-a, and IL-6 and the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist. Moreover, IAPP-induced IL-1b synthesis and caspase-1 activation were detected in macrophages but not other islet cell types. Transgenic mice with b-cell human IAPP (hIAPP) expression had impaired glucose tolerance, elevated islet Il1b mRNA, and decreased Il10 and Il1rn expression following highfat feeding. Islet macrophages were the major source of these transcripts and expressed increased cell surface Ly6C and CD11c in hIAPP transgenic mice. Clodronate liposome-mediated depletion of islet macrophages improved glucose tolerance and blocked proinflammatory gene expression in hIAPPexpressing mice, despite increasing the amount of islet amyloid. These data provide the first evidence that IAPP aggregates skew resident islet macrophages toward a proinflammatory phenotype and suggest a mechanism by which antiinflammatory therapies may protect b-cells from IAPP-induced islet dysfunction.

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Section: Discussionsupporting

confidence: 58%

Resident Macrophages Mediate Islet Amyloid Polypeptide–Induced Islet IL-1β Production and β-Cell Dysfunction

2014

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“…MCP-1 is a CC chemokine, and most CC chemokines act on monocytes, T-cells, eosinophils and neutrophils [37]. Circulating proinflammatory (Ly-6C high ) monocytes that express high levels of CC chemokine receptor type 2 (CCR2), an MCP-1 receptor, infiltrate adipose tissue and differentiate into pro-inflammatory macrophages [38]. MCP-1 also promotes the release of pro-inflammatory monocytes from bone marrow.…”

Section: Cbl-b In Aging-induced Macrophage Activationmentioning

confidence: 99%

Ubiquitin ligase Cbl-b and obesity-induced insulin resistance [Review]

Abe

Hirasaka

Kohno³

et al. 2014

Endocr J

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Abstract. Obesity causes type 2 diabetes, atherosclerosis and cardiovascular diseases by inducing systemic insulin resistance. It is now recognized that obesity is related to chronic low-grade inflammation in adipose tissue. Specifically, activated immune cells infiltrate adipose tissue and cause inflammation. There is increasing evidence that activated macrophages accumulate in the hypertrophied adipose tissue of rodents and humans and induce systemic insulin resistance by secreting inflammatory cytokines. Accordingly, a better understanding of the molecular mechanisms underlying macrophage activation in adipose tissue will facilitate the development of new therapeutic strategies. Currently, little is known about the regulation of macrophage activation, although E3 ubiquitin ligase Casitas B-lineage lymphoma (Cbl)-b was identified recently as a novel negative regulator of macrophage activation in adipose tissue. Cbl-b, which is a suppressor of T-and B-cell activation, inhibits intracellular signal transduction by targeting some tyrosine kinases. Notably, preventing Cbl-b-mediated macrophage activation improves obesity-induced insulin resistance in mice. c-Cbl is another member of the Cbl family that is associated with insulin resistance in obesity. These reports suggest that Cbl-b and c-Cbl are potential therapeutic targets for treating obesity-induced insulin resistance. In this review, we focus on the importance of Cbl-b in macrophage activation in aging-induced and high-fat diet-induced obesity.

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“…In humans and animals, obesity triggers the recruitment of macrophages to white adipose tissue, which is followed by release of inflammatory mediators and the onset of insulin resistance (26,29). When this response is interrupted in mice fed a high fat diet, either through macrophage depletion or genetic knock-out of macrophage chemoattractants, the animals are protected against insulin resistance despite an equivalent extent of obesity (19, 21,28). Macrophages coexpressing F4/80 and CD11c appear to be a key leukocyte subset involved in the inflammatory and metabolic effects of a highfat diet (17, 21).…”

mentioning

confidence: 99%

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

Schilling

Machkovech

Kim

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Schilling JD, Machkovech HM, Kim AH, Schwedwener R, Schaffer JE. Macrophages modulate cardiac function in lipotoxic cardiomyopathy. Am J Physiol Heart Circ Physiol 303: H1366 -H1373, 2012. First published October 5, 2012; doi:10.1152/ajpheart.00111.2012.-Diabetes is associated with myocardial lipid accumulation and an increased risk of heart failure. Although cardiac myocyte lipid overload is thought to contribute to the pathogenesis of cardiomyopathy in the setting of diabetes, the mechanism(s) through which this occurs is not well understood. Increasingly, inflammation has been recognized as a key pathogenic feature of lipid excess and diabetes. In this study, we sought to investigate the role of inflammatory activation in the pathogenesis of lipotoxic cardiomyopathy using the ␣-myosin heavy chain promoter-driven long-chain acylCoA synthetase 1 (MHC-ACS) transgenic mouse model. We found that several inflammatory cytokines were upregulated in the myocardium of MHC-ACS mice before the onset of cardiac dysfunction, and this was accompanied by macrophage infiltration. Depletion of macrophages with liposomal clodrolip reduced the cardiac inflammatory response and improved cardiac function. Thus, in this model of lipotoxic cardiac injury, early induction of inflammation and macrophage recruitment contribute to adverse cardiac remodeling. These findings have implications for our understanding of heart failure in the setting of obesity and diabetes. heart failure; diabetes; inflammation OBESITY AND DIABETES ARE SIGNIFICANT risk factors for the development of heart failure (11). In many diabetic patients, this can occur in the absence of underlying coronary artery disease or hypertension, a phenomenon known as diabetic cardiomyopathy (1). The pathogenesis of diabetic cardiomyopathy is complex; however, myocardial lipid overload is a pathologic feature of this condition in humans and in animal models (6,7,12,25). The observation that cardiac myocyte lipid overload causes cardiomyopathy in genetic mouse models, without systemic abnormalities of insulin or glucose metabolism, supports the notion that excess lipids can be cardiotoxic (4,5,7,32). Membrane lipid remodeling, endoplasmic reticulum and oxidative stress, and production of toxic lipid species, such as ceramides, have been implicated as potential mechanisms of cardiac lipotoxicity (12,23).Systemic inflammation is another hallmark of obesity and diabetes and has been shown to correlate with the risk of heart failure in patients with these metabolic conditions (2). This raises the intriguing possibility that lipid-induced inflammatory responses might contribute to cardiac dysfunction in obesity and diabetes. Much of what is known regarding the link between diabetes and inflammation has come from investigations of adipose tissue. In humans and animals, obesity triggers the recruitment of macrophages to white adipose tissue, which is followed by release of inflammatory mediators and the onset of insulin resistance (26,29). When this response is interrupted in mice fed...

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Increased Macrophage Migration Into Adipose Tissue in Obese Mice

Cited by 326 publications

References 31 publications

Resident Macrophages Mediate Islet Amyloid Polypeptide–Induced Islet IL-1β Production and β-Cell Dysfunction

Resident Macrophages Mediate Islet Amyloid Polypeptide–Induced Islet IL-1β Production and β-Cell Dysfunction

Ubiquitin ligase Cbl-b and obesity-induced insulin resistance [Review]

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

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