Inflammation and adipose tissue macrophages in lipodystrophic mice

Herrero, Laura; Shapiro, Hagit; Nayer, Ali; Lee, Jongsoon; Shoelson, Steven E.

doi:10.1073/pnas.0905310107

Cited by 141 publications

(115 citation statements)

References 36 publications

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“…This notion has been challenged by a recent report that showed increased adipocyte apoptosis in obese humans and DIO mice ( 38 ). Moreover, insulin-resistant lipodystrophic mice demonstrated increased apoptotic cell death in adipose tissues ( 39 ). While there is still an ac- Fig.…”

Section: Discussionmentioning

confidence: 79%

Mast cells, macrophages, and crown-like structures distinguish subcutaneous from visceral fat in mice

Altintas

Azad

Nayer

et al. 2011

Journal of Lipid Research

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166

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This article is available online at http://www.jlr.org is of grave consequence to human health. In fact, cardiovascular diseases, mostly as a result of long-standing metabolic dysregulations, are the leading cause of morbidity and mortality in many parts of the world.The pathogenesis of obesity-linked insulin resistance is only partially understood. Accumulating evidence has revealed a strong association between obesity-linked insulin resistance and infl ammation ( 2 ). Tumor necrosis factor-a (TNF-a ), a prototypical pro-infl ammatory cytokine, was upregulated in the epididymal fat of obese rodents, and neutralization of TNF-a ameliorated insulin resistance ( 3 ). Moreover, obese mice lacking TNF-a demonstrated improved insulin sensitivity ( 4 ). In addition, increased numbers of macrophages and their transcripts were reported in the epididymal fat of genetically and dietinduced obese (DIO) mice ( 5, 6 ). These adipose tissue macrophages (ATM) were found scattered between adipocytes (herein referred to as solitary ATM ) or forming clusters around adipocytes. Based on ultrastructural and immunohistochemical alterations, it was argued that most ATM in obese mice and humans surround dead adipocytes, forming so-called crown-like structures (CLS) ( 7 ). Subsequently, we reported that CLS were distributed differentially in abdominal fat depots of DIO mice ( 8 ). Consistent with our fi ndings, it was recently reported that CLS were also more prevalent in visceral than subcutaneous fat of leptin-defi cient ob/ob and leptin receptor-defi cient db/db mice ( 9 ).Although macrophages are critical in innate and adaptive immunity, most immune responses are the result of interplay between multiple cell types and mediators of the immune system ( 10 ). Therefore, it comes as no surprise to learn that regulatory T cells ( 11 ), CD8+ effector T cells Over the past several decades a steady increase in the prevalence of obesity across the continents, especially in the US, has been observed ( 1 ). Increased caloric intake, mostly due to consumption of a high-fat diet, and decreased physical activity seem to be major contributors. Insulin resistance, hypertension, and dyslipidemia often accompany obesity. The constellation, referred to as metabolic syndrome, This work was supported by generous funds from the Katz Family Foundation.

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Section: Discussionmentioning

confidence: 79%

Mast cells, macrophages, and crown-like structures distinguish subcutaneous from visceral fat in mice

Altintas

Azad

Nayer

et al. 2011

Journal of Lipid Research

Self Cite

166

163

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“…Macrophages were the first immune cells reported to participate in obesity-induced insulin resistance (56). This highlights their pathological role in adipose tissue in addition to their traditional involvement in tissue repair and in response to dead and dying adipocytes (5,14). Fat is an active endocrine tissue that secretes hormones such as leptin, adiponectin, or resistin and inflammatory cytokines such as TNF-␣, IL-6, IL-1␤, etc.…”

mentioning

confidence: 99%

Enhanced fatty acid oxidation in adipocytes and macrophages reduces lipid-induced triglyceride accumulation and inflammation

Malandrino

Fucho

Weber

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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-Lipid overload in obesity and type 2 diabetes is associated with adipocyte dysfunction, inflammation, macrophage infiltration, and decreased fatty acid oxidation (FAO). Here, we report that the expression of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme in mitochondrial FAO, is higher in human adipose tissue macrophages than in adipocytes and that it is differentially expressed in visceral vs. subcutaneous adipose tissue in both an obese and a type 2 diabetes cohort. These observations led us to further investigate the potential role of CPT1A in adipocytes and macrophages. We expressed CPT1AM, a permanently active mutant form of CPT1A, in 3T3-L1 CAR⌬1 adipocytes and RAW 264.7 macrophages through adenoviral infection. Enhanced FAO in palmitate-incubated adipocytes and macrophages reduced triglyceride content and inflammation, improved insulin sensitivity in adipocytes, and reduced endoplasmic reticulum stress and ROS damage in macrophages. We conclude that increasing FAO in adipocytes and macrophages improves palmitate-induced derangements. This indicates that enhancing FAO in metabolically relevant cells such as adipocytes and macrophages may be a promising strategy for the treatment of chronic inflammatory pathologies such as obesity and type 2 diabetes.

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“…Although adiposity causes the development of insulin resistance and inflammation, it remains unclear whether adiposity and hyperlipidemia are necessary for insulin resistance. In fact, lipodystrophy causes severe inflammation in adipose tissue without adiposity [61,62]. Finally, we investigated the importance of TLR4 in the development of insulin resistance in Cbl-b -/-mice fed a HFD for 5 weeks by using Eritoran, a TLR4 antagonist [63].…”

Section: Cbl-b In Hfd-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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Inflammation and adipose tissue macrophages in lipodystrophic mice

Cited by 141 publications

References 36 publications

Mast cells, macrophages, and crown-like structures distinguish subcutaneous from visceral fat in mice

Mast cells, macrophages, and crown-like structures distinguish subcutaneous from visceral fat in mice

Enhanced fatty acid oxidation in adipocytes and macrophages reduces lipid-induced triglyceride accumulation and inflammation

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

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