Ablation of CD11c-Positive Cells Normalizes Insulin Sensitivity in Obese Insulin Resistant Animals

Patsouris, David; Li, Ping Ping; Thapar, Divya; Chapman, Justin; Olefsky, Jerrold M.; Neels, Jaap G.

doi:10.1016/j.cmet.2008.08.015

Cited by 725 publications

(653 citation statements)

References 35 publications

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“…This 12 week dietary intervention resulted in marked obesity, insulin resistance and inflammation as evidenced by the significant increases in Tnf-α, iNos, F4/80 and Cd11c (also known as Itgax) mRNA expression and IKKβ phosphorylation in adipose tissue. The degree of obesity (~40 g body weight on high-fat diet) and white adipose tissue inflammation (Tnf-α, iNos, F4/80, Cd11c gene induction) in this study was remarkably similar to that seen in other studies using BMT mice, even under conditions of longer-term high-fatdiet feeding (16-20 weeks) using the diet in which 60% of energy is from fat [8,9,36], thus demonstrating the effectiveness of the type of high-fat diet used and the duration of the feeding protocol. Despite the high-fat-dietinduced inflammation and insulin resistance, deletion of IL-10 from the immune cells did not exacerbate this proinflammatory phenotype.…”

Section: Discussionsupporting

confidence: 73%

“…Once resident within the adipose tissue, factors secreted by macrophages, such as TNFα, activate pro-inflammatory signalling molecules, such as c-Jun N-terminal kinase (JNK) and IκB kinase β (IKKβ), and initiate a state of local and, ultimately, systemic insulin resistance [5][6][7][8]. Underscoring the critical role of macrophages in the development of obesity-induced insulin resistance, the conditional deletion of CD11c + -expressing macrophages in obese mice results in a marked reduction in local and systemic inflammation and, importantly, normalisation of insulin sensitivity [9].…”

Section: Introductionmentioning

confidence: 99%

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Deficiency of haematopoietic-cell-derived IL-10 does not exacerbate high-fat-diet-induced inflammation or insulin resistance in mice

et al. 2011

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Aims/hypothesis Recent work has identified the important roles of M1 pro-inflammatory and M2 anti-inflammatory macrophages in the regulation of insulin sensitivity. Specifically, increased numbers of M2 macrophages and a decrease in M1 macrophages within the adipose tissue are associated with a state of enhanced insulin sensitivity. IL-10 is an anti-inflammatory cytokine and is a critical effector molecule of M2 macrophages. Methods In the present study, we examined the contribution of haematopoietic-cell-derived IL-10 to the development of obesity-induced inflammation and insulin resistance. We hypothesised that haematopoietic-cell-restricted deletion of IL-10 would exacerbate obesity-induced inflammation and insulin resistance. Lethally irradiated wild-type recipient mice receiving bone marrow from either wild-type or Il10-knockout mice were placed on either a chow or a high-fat diet for a period of 12 weeks and assessed for alterations in body composition, tissue inflammation and glucose and insulin tolerance. Results Contrary to our hypothesis, neither inflammation, as measured by the activation of pro-inflammatory stress kinases and gene expression of several pro-inflammatory cytokines in the adipose tissue and liver, nor diet-induced obesity and insulin resistance were exacerbated by the deletion of haematopoietic-cell-derived IL-10. Interestingly, however, Il10 mRNA expression and IL-10 protein production in liver and/or adipose tissue were markedly elevated in Il10-knockout bone-marrow-transplanted mice relative to wild-type bone marrow-transplanted mice. Conclusions/interpretation These data show that deletion of IL-10 from the haematopoietic system does not potentiate high-fat diet-induced inflammation or insulin resistance.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Deficiency of haematopoietic-cell-derived IL-10 does not exacerbate high-fat-diet-induced inflammation or insulin resistance in mice

et al. 2011

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“…Such conditional ablation resulted in a profound reduction of proinflammatory ATM accumulation, accompanied by rapid whole-body normalization of insulin sensitivity (43). This further highlights the direct contribution of these cells toward local and systemic insulin sensitivity.…”

Section: Macrophages Major Constituents Of At and Mediators Of Remodmentioning

confidence: 82%

“…In light of this, Patsouris and colleagues utilized a conditional cell-ablation system based on the transgenic expression of the diphtheria toxin receptor, under the control of the CD11c promoter, to specifically ablate CD11c + macrophages in the AT of HFD-fed obese mice (43). Such conditional ablation resulted in a profound reduction of proinflammatory ATM accumulation, accompanied by rapid whole-body normalization of insulin sensitivity (43).…”

Section: Macrophages Major Constituents Of At and Mediators Of Remodmentioning

confidence: 99%

Adipose tissue remodeling and obesity

Sun¹,

Kusminski²,

Scherer³

2011

J. Clin. Invest.

1,542

1,381

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To fulfill its role as the major energy-storing tissue, adipose has several unique properties that cannot be seen in any other organ, including an almost unlimited capacity to expand in a non-transformed state. As such, the tissue requires potent mechanisms to remodel, acutely and chronically. Adipocytes can rapidly reach the diffusional limit of oxygen during growth; hypoxia is therefore an early determinant that limits healthy expansion. Proper expansion requires a highly coordinated response among many different cell types, including endothelial precursor cells, immune cells, and preadipocytes. There are therefore remarkable similarities between adipose expansion and growth of solid tumors, a phenomenon that presents both an opportunity and a challenge, since pharmacological interventions supporting healthy adipose tissue adaptation can also facilitate tumor growth. IntroductionAdipose tissue (AT) can respond rapidly and dynamically to alterations in nutrient deprivation and excess through adipocyte hypertrophy and hyperplasia, thereby fulfilling its major role in wholebody energy homeostasis. AT remodeling is an ongoing process that is pathologically accelerated in the obese state, and thus, features such as reduced angiogenic remodeling, ECM overproduction, a heightened state of immune cell infiltration and subsequent proinflammatory responses prevail in many obese fat-pads (1). However, not all AT expansion is necessarily associated with pathological changes. The concept of the "metabolically healthy obese" state (2) suggests that some individuals can preserve systemic insulin sensitivity on the basis of "healthy" AT expansion, bypassing all of the aforementioned pathological consequences associated with obesity (3), thereby also avoiding the obesity-associated lipotoxic side effects. Many physiologically relevant processes important for human AT remodeling can be studied in rodent models, with the added advantage that processes related to AT expansion and reduction can occur at an extremely rapid rate. A 24-hour fast in a mouse is associated with a dramatic loss of AT mass and an acute remodeling process that involves rapid infiltration of macrophages; moreover, merely 24 to 48 hours of exposure to a high-fat diet (HFD) can cause a prompt increase in adipocyte size (4). AT is therefore an ideal model system to study rapid alterations in tissue expansion and reduction, as it adapts to a differential nutrient supply. Here, we will focus on key aspects of the intricate dynamics of AT remodeling and subsequent inflammatory consequences that arise from obesity.

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“…Several rodent studies demonstrate that an increase in adipose tissue macrophages worsens insulin sensitivity (Hirasaka et al, 2007;Kamei et al, 2006). Likewise, a decrease in adipose tissue macrophages (ATM) results in a decrease in adipose tissue inflammation and inhibits obesity-induced insulin resistance (Patsouris et al, 2008). Furthermore, genetic ablation of macrophage signaling by knockout of IB kinase-beta (IKK-) or c-Jun N-terminal kinase 1 (JNK1) protects mice from dietinduced insulin resistance (Arkan et al, 2005;Solinas et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

An inflammatory micro-environment promotes human adipocyte apoptosis

Keuper

Blüher

Schön

et al. 2011

Molecular and Cellular Endocrinology

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Obesity-associated macrophage infiltration into adipose tissue is responsible for both local and systemic inflammation. Recent findings suggest fat cell apoptosis as an initiator of macrophage recruitment.Here, we investigated the effects of an inflammatory micro-environment on fat cells by using human THP-1 macrophages and SGBS adipocytes. Macrophage-secreted factors induced insulin resistance, inhibited insulin-stimulated Akt phosphorylation, and induced apoptosis of adipocytes. The apoptosisinducing effect was even more pronounced in direct co-cultures of adipocytes and macrophages. Our data suggest a link between insulin resistance and apoptosis sensitivity. Accordingly, pharmacological and genetic inhibition of insulin signaling at the level of Akt2 sensitized adipocytes to apoptosis induction by macrophage-secreted factors.In conclusion, we describe here a novel interaction of macrophages and fat cells, i.e. induction of apoptosis. Our data suggest a feed-forward cycle in which macrophages further drive the inflammatory process by inducing insulin resistance and concomitant apoptosis of adipocytes.

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Ablation of CD11c-Positive Cells Normalizes Insulin Sensitivity in Obese Insulin Resistant Animals

Cited by 725 publications

References 35 publications

Deficiency of haematopoietic-cell-derived IL-10 does not exacerbate high-fat-diet-induced inflammation or insulin resistance in mice

Deficiency of haematopoietic-cell-derived IL-10 does not exacerbate high-fat-diet-induced inflammation or insulin resistance in mice

Adipose tissue remodeling and obesity

An inflammatory micro-environment promotes human adipocyte apoptosis

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