Adipose Tissue Hypoxia, Inflammation, and Fibrosis in Obese Insulin-Sensitive and Obese Insulin-Resistant Subjects

Lawler, Helen M.; Underkofler, Chantal; Kern, Philip A.; Erickson, Christopher B.; Bredbeck, Brooke C.; Rasouli, Neda

doi:10.1210/jc.2015-4125

Cited by 140 publications

(137 citation statements)

References 31 publications

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“…Although Mmp7 has known roles in tissue fibrosis (48), wound healing, and cell migration (47), its exact function in AT remains to be elucidated. A recent report describes a significant induction of Mmp7 expression in subcutaneous AT from obese, insulin-resistant humans when compared with obese, insulin-sensitive humans (49). Future studies will focus on the relationship of Mmp7 to adipocyte OSM signaling and AT inflammation in obesity.…”

Section: Discussionmentioning

confidence: 97%

Loss of Oncostatin M Signaling in Adipocytes Induces Insulin Resistance and Adipose Tissue Inflammation in Vivo

Elks

Zhao

Grant

et al. 2016

Journal of Biological Chemistry

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Oncostatin M (OSM) is a multifunctional gp130 cytokine.Although OSM is produced in adipose tissue, it is not produced by adipocytes. OSM expression is significantly induced in adipose tissue from obese mice and humans. The OSM-specific receptor, OSM receptor ␤ (OSMR), is expressed in adipocytes, but its function remains largely unknown. To better understand the effects of OSM in adipose tissue, we knocked down Osmr expression in adipocytes in vitro using siRNA. Adipose tissue (AT) 3 plays an important role in the maintenance of systemic metabolic homeostasis. Adipokine production is a critical AT function and is highly regulated in several physiological and pathological conditions, including AT expansion, insulin resistance, obesity, and type 2 diabetes. Obesity is closely associated with a chronic, low grade inflammatory state characterized by macrophage infiltration of AT and subsequent proinflammatory adipokine expression (1, 2). Adipokine modulation has been shown to be a key contributor to the insulin resistance often observed in obesity.Cytokines in the interleukin-6 (IL-6)/gp130 family include IL-6, IL-11, leukemia inhibitory factor, cardiotrophin-1, ciliary neurotrophic factor, and oncostatin M (OSM) (3). The gp130 cytokines regulate several physiological and biological processes (4), and some of these cytokines, namely IL-6 and ciliary neurotrophic factor, have profound effects on metabolism and as such have been previous targets for obesity treatment (5-8). Although originally identified for its ability to inhibit tumorigenesis (9), OSM modulates a host of other biological processes that are cell type-dependent (10). Elevated OSM levels have been observed in a variety of inflammatory diseases in humans, including rheumatoid arthritis and atherosclerosis (11,12). OSM also has important roles in hepatic insulin resistance and steatosis (13), inflammation (14), and cardiomyocyte remodeling (15) and has several well characterized actions in the liver (16 -18). Unlike other gp130 cytokines, OSM has its own specific receptor subunit (OSM receptor ␤; hereafter referred to as OSMR) that heterodimerizes with gp130 to create the functional OSM receptor complex, and this complex is responsible for the majority of OSM effects (19).Adipocytes and AT are highly responsive to OSM (20), and Osmr is highly expressed in AT compared with other tissues (21, 22). Significant induction of both Osm and Osmr expres-* This work was supported in part by National Institutes of Health Grant R01DK052968 (to J. M. S.) and National Institutes of Health Nutrition Obesity Research Centers Grant P30DK072476 entitled "Nutritional Programming: Environmental and Molecular Interactions." The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Section: Discussionmentioning

confidence: 97%

Loss of Oncostatin M Signaling in Adipocytes Induces Insulin Resistance and Adipose Tissue Inflammation in Vivo

Elks

Zhao

Grant

et al. 2016

Journal of Biological Chemistry

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“…Obesity constitutes a chronic low-grade inflammatory condition, leading to robust morphological and functional changes within adipose tissue (AT), including the accumulation of immune cells, the dynamic remodeling of the extracellular matrix (ECM), and the altered production of adipokines, among others 1,2 . An increased macrophage recruitment into AT and their polarization towards a proinflammatory M1 phenotype represents a hallmark of obesity-associated inflammation [3][4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C

et al. 2018

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Background/Objectives: Obesity is related to a dynamic extracellular matrix (ECM) remodeling, which involves the synthesis and degradation of different proteins, such as tenascin C (TNC) in the adipose tissue (AT). Given the functional relationship between leptin and inducible nitric oxide synthase (iNOS), our aim was to analyze the impact of the absence of the iNOS gene in AT inflammation and ECM remodeling in ob/ob mice. Subjects/Methods: The expression of genes involved in inflammation and ECM remodeling was evaluated in 10-week-old male double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes as well as in ob/ob mice classified into three groups [control, leptin-treated (1 mg kg −1 day −1 ) and pair-fed]. Results: Leptin deficiency increased inflammation and fibrosis in AT. As expected, leptin treatment improved the obesity phenotype. iNOS deficiency in ob/ob mice improved insulin sensitivity, AT inflammation, and ECM remodeling, as evidenced by lower AT macrophage infiltration and collagen deposition, a downregulation of proinflammatory and profibrogenic genes Tnf, Emr1, Hif1a, Col6a1, Col6a3, and Tnc, as well as lower circulating TNC levels. Interestingly, leptin upregulated TNC expression and release in 3T3-L1 adipocytes, and iNOS knockdown in 3T3-L1 fat cells produced a significant decrease in basal and leptin-induced Tnc expression. Conclusions: Ablation of iNOS in leptin-deficient mice improved AT inflammation and ECM remodeling-related genes, attenuating fibrosis, and metabolic dysfunction. The activation of iNOS by leptin is necessary for the synthesis and secretion of TNC in adipocytes, suggesting an important role of this alarmin in the development of AT inflammation and fibrosis.

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“…We and others have reported decreased adipose tissue pO 2 in obese as compared to lean participants 24 28. However, Goossens et al 29 reported reduced oxygen extraction by adipose tissue resulting in increased adipose tissue pO 2 in obese versus lean participants.…”

Section: Evidence Of Adipose Tissue Hypoxia In Obese Humanmentioning

confidence: 51%

“…Perhaps inconsistent results were due to small sample size of these studies or differences in methods used to measure oxygen tension. Goossens et al 29 measured pO 2 continuously in the perfusate of a microdialysis probe whereas others24 28 used a small Clarke electrode placed directly in touch with adiposytes. The decreased oxygen extraction by adipose tissue of obesity reported by Goossens et al 29 is in contrast with a recent study in mice which showed HFD-induced obesity resulted in uncoupling of adipocyte respiration leading to increased oxygen consumption and relative adipocyte hypoxia 30…”

Section: Evidence Of Adipose Tissue Hypoxia In Obese Humanmentioning

confidence: 99%

Adipose Tissue Hypoxia and Insulin Resistance

Rasouli

2016

Journal of Investigative Medicine

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Despite the well-established association of obesity with insulin resistance and inflammation, the underlying mechanisms and sequence of events leading to inflammation and insulin resistance remain unknown. Adipose tissue hypoxia has been proposed as one of the possible key events during the process of fat expansion that leads to adipose tissue dysfunction. The focus of this paper is reviewing the evidence on adipose tissue hypoxia in obesity and its relation to insulin resistance.

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Adipose Tissue Hypoxia, Inflammation, and Fibrosis in Obese Insulin-Sensitive and Obese Insulin-Resistant Subjects

Cited by 140 publications

References 31 publications

Loss of Oncostatin M Signaling in Adipocytes Induces Insulin Resistance and Adipose Tissue Inflammation in Vivo

Loss of Oncostatin M Signaling in Adipocytes Induces Insulin Resistance and Adipose Tissue Inflammation in Vivo

Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C

Adipose Tissue Hypoxia and Insulin Resistance

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