Aberrant Accumulation of Undifferentiated Myeloid Cells in the Adipose Tissue of CCR2-Deficient Mice Delays Improvements in Insulin Sensitivity

Gutierrez, Dario A.; Kennedy, Arion; Orr, Jeb S.; Anderson, Emily K.; Webb, Corey D.; Gerrald, William K.; Hasty, Alyssa H.

doi:10.2337/db11-0314

Cited by 41 publications

(57 citation statements)

References 34 publications

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“…It must be acknowledged however, that a parasitic infection most certainly modulates a number of other immune cells, and it is unknown how propolis influences other immune processes; for this reason, it is not possible to by guest, on www.jlr.org Downloaded from say the increased eosinophils are definitively responsible for the improved glucose tolerance in such models as they were non-specific modulations of eosinophils. In our own studies, we found that despite specifically elevating numbers of WAT eosinophils in obese mice with either recombinant IL-5 (rIL-5) treatment or using CCR2 deficient mice, there was no improvement in glucose tolerance [72,110,123]. Several studies have utilized IL-33 to increase ILC2s, eosinophils, and/or M2-like macrophages in WAT, often associated with weight loss and improved glucose control [31,94,106,112,115,117,119].…”

Section: Downloaded Frommentioning

confidence: 99%

Contributions of innate type 2 inflammation to adipose function

Bolus

Hasty

2019

Journal of Lipid Research

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A critical contributor to health consequences of the obesity epidemic is dysregulated adipose tissue (AT) homeostasis. While white, brown, and beige AT function are all altered in obesity-related disease, white AT is marked by progressive inflammation & adipocyte dysfunction and has been the focus of extensive "immunometabolism" research in the past decade. The exact triggering events initiating and sustaining AT inflammation are still under study, but it has been shown that reducing inflammation improves insulin action in AT. Scientific efforts continue seeking interventions to mitigate obesity-associated AT inflammation, and many groups are now determining how lean healthy AT homeostasis is maintained in order to leverage these mechanisms as therapeutic targets. Such studies have revealed an elaborate network of immune cells, cytokines, and other cellular mediators coordinate AT function. Recent studies elucidated the involvement of the innate immune system in AT homeostasis (e.g. beiging and insulin sensitivity), including M2-like macrophages, eosinophils, innate lymphoid type 2 cells, and several others. In this review, we summarize the existing literature on innate type 2 inflammation in AT; additionally we draw attention to areas of debate where seemingly conflicting data promises to yield more surprising and elegant biology as studies continue to dissect AT physiology. prospective analyses of nearly a million adults, showed that obesity can decrease a person's life span up to 10 years [7]. Thus, a better understanding of adipose tissue (AT), the organ that expands the most in size during obesity, should provide solutions to this health concern.When discussing AT, white adipose tissue (WAT) is most commonly considered; however, other types of AT, brown adipose tissue (BAT) and beige AT also exist.Adipocytes in WAT and BAT are generated from unique progenitors. WAT stores excess energy in the form of triglycerides. BAT can store small amounts of triglycerides; however, its primary role is to burn fatty acids to generate heat. Beige fat has brown-like properties but is transiently present in WAT depots (especially subcutaneous) upon beta-adrenergic stimulation. Regulation of all three of these fat depots is critically important for lipid and energy homeostasis.WAT consists of spatially distinct beds: visceral, omental, subcutaneous, perivascular, epicardial, and many others. These depots serve to cushion organs they BAT is localized primarily in subscapular regions in rodents, and was only discovered in adult humans in the past decade [10,11]. BAT has a characteristic brown appearance grossly, and is easily distinguished from WAT. This distinctive color is due to the presence of concentrated mitochondria within each brown adipocyte, accompanied by high iron concentrations required for activation of the electron transport chain during beta-oxidation. High expression of uncoupling protein 1 (UCP-1) causes this beta-oxidation to result in generation of heat rather than ATP (thermogenesis), thus assistin...

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Section: Downloaded Frommentioning

confidence: 99%

Contributions of innate type 2 inflammation to adipose function

Bolus

Hasty

2019

Journal of Lipid Research

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“…With regard to Ϫ/Ϫ mice after 16 wk of HF feeding were separated based on lean body mass Ͻ23 g (C) and lean body mass Ͼ23 g (D) (n ϭ 11-18 mice/group). the receptor for CCL2, CCR2, most studies have shown a reduction in ATMs (9,19,39). Strikingly though, differences in ATM numbers, inflammation, and insulin sensitivity are not detected until after long periods of HF diet feeding despite a nearly complete absence of circulating inflammatory monocytes.…”

Section: E902 Ccr5 Deficiency In Diet-induced Obese Micementioning

confidence: 99%

“…Kanda et al (13) demonstrated that overexpression of CCL2 increases recruitment of AT macrophages (ATMs), leading to IR. Our group and others have demonstrated that CCR2 Ϫ/Ϫ mice fed a high-fat (HF) diet for a prolonged period of time are partially protected against ATM infiltration, inflammation, and glucose intolerance (9,19,39). Similarly, CXCL5 and its receptor CXCR2 have been shown to reduce ATM content and improve insulin sensitivity in obese mice (8,26,36).…”

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confidence: 94%

Loss of CCR5 results in glucose intolerance in diet-induced obese mice

Kennedy

Webb

Hill

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Kennedy A, Webb CD, Hill AA, Gruen ML, Jackson LG, Hasty AH. Loss of CCR5 results in glucose intolerance in diet-induced obese mice. Am J Physiol Endocrinol Metab 305: E897-E906, 2013. First published August 13, 2013; doi:10.1152/ajpendo.00177.2013.-Macrophage and T cell infiltration into metabolic tissues contributes to obesityassociated inflammation and insulin resistance (IR). C-C chemokine receptor 5 (CCR5), expressed on macrophages and T cells, plays a critical role in the recruitment and activation of proinflammatory M1 and T H1 immune cells to tissues and is elevated in adipose tissue (AT) and liver of obese humans and mice. Thus, we hypothesized that deficiency of CCR5 would protect against diet-induced inflammation and IR. CCR5-deficient (CCR5 Ϫ/Ϫ ) mice and C57BL/6 (WT) controls were fed 10% low-fat (LF) or 60% high-fat (HF) diets for 16 wk. HF feeding increased adiposity, blood glucose, and plasma insulin levels equally in both genotypes. Opposing our hypothesis, HF-fed CCR5Ϫ/Ϫ mice were significantly more glucose intolerant than WT mice. In AT, there was a significant reduction in the M1-associated gene CD11c, whereas M2 associated genes were not different between genotypes. In addition, HF feeding caused a twofold increase in CD4 ϩ T cells in the AT of CCR5Ϫ/Ϫ compared with WT mice. In liver and muscle, no differences in immune cell infiltration or inflammatory cytokine expression were detected. However, in AT and muscle, there was a mild reduction in insulin-induced phosphorylation of AKT and IR␤ in CCR5 Ϫ/Ϫ compared with WT mice. These findings suggest that whereas CCR5 plays a minor role in regulating immune cell infiltration and inflammation in metabolic tissues, deficiency of CCR5 impairs systemic glucose tolerance as well as AT and muscle insulin signaling.

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“…Why inflamed adipose tissue is an attractive site for macrophage infiltration is yet unclear. No doubt MCP1 is a chemoattractant for macrophage migration but CCR2 deficient mice have been shown to be protected from HFD-induced insulin resistance and macrophage accumulation 85,86 . Moreover, a few reports indicate that MCP1 is not sufficient for the amount of macrophage that infiltrates during adipose tissue inflammation 87 .…”

Section: Macrophage Participation In Adipose Tissue Inflammation: a Cmentioning

confidence: 99%

Lipid Links Inflammation, Immunity and Insulin Resistance to Cause Epidemic Diabetes

Bhattacharya¹,

Mukherjee²

2016

Current Science

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Incidence of type 2 diabetes (T2D) is dramatically increasing in the past few decades and presently affecting more than 350 million people all over the globe. Oversupply of lipid is one of the major forces behind T2D. Excess of lipid decreases insulin sensitivity or activity that causes insulin resistance, a stage which occupies the centre of pathogenesis in T2D. Lipid induces adipose tissue inflammation that accompanies certain critical defects in adipocytes, a major cell in abdominal adipose tissue. These include increased population of hypertrophied adipocytes, decline in adipokines secretion, attenuation of adipogenesis, and increased lipotoxicity effecting greater deposition of fat which interferes with glucose uptake by insulin target cells. Inflammation of adipose tissue is further intensified due to the infiltration of macrophages, a member of the innate immune system, and their transformation from anti-inflammatory M2 to proinflammatory M1 phenotype. Hence, secretion of proinflammatory cytokines from both M1 macrophage and inflamed adipocytes is greatly elevated which adversely causes insulin resistance that leads to T2D. Association between lipid-induced inflammation and insulin resistance makes diabetes a critical disease.

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Aberrant Accumulation of Undifferentiated Myeloid Cells in the Adipose Tissue of CCR2-Deficient Mice Delays Improvements in Insulin Sensitivity

Cited by 41 publications

References 34 publications

Contributions of innate type 2 inflammation to adipose function

Contributions of innate type 2 inflammation to adipose function

Loss of CCR5 results in glucose intolerance in diet-induced obese mice

Lipid Links Inflammation, Immunity and Insulin Resistance to Cause Epidemic Diabetes

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