The extracellular matrix and insulin resistance

Williams, Ashley S.; Li, Kang; Wasserman, David H.

doi:10.1016/j.tem.2015.05.006

Cited by 182 publications

(229 citation statements)

References 101 publications

(145 reference statements)

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“…Hypoxia constitutes an essential factor contributing to AT inflammation and fibrosis 17 . HIF-1α induction by AT hypoxia triggers the upregulation of genes involved in the fibrotic response, resulting in the excess deposition of ECM components, which may cause adipocyte death and inflammation, being also strongly associated with systemic insulin resistance 60,61 . In line with this observation, our data showed that genes involved in the regulation of hypoxic response (Hif1a), inflammation (Tnf, Emr1), and excessive collagen deposition (Col6a1 and Col6a3) were highly enriched in EWAT of leptin-deficient ob/ob mice.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…It is recently ascertained that fibrosis, excess deposition of ECM components, in metabolically active, insulin-sensitive tissues, including the skeletal muscle, adipose tissue and liver has damaging impact on glucose homoeostasis [6,120,121]. Obesogenic ECM remodelling of white adipose tissues is closely linked with the increased levels of circulating ECM proteins and ECM-derived peptides in parallel with increased levels of adipose-derived cytokines.…”

Section: Discussionmentioning

confidence: 99%

“…pre-adipocytes, macrophages, and vascular endothelial cells, should contribute to adipose tissue inflammation, apoptosis, angiogenesis, and subsequent metabolic deteriorations in obesity. A similar concept has been proposed in the biology of the skeletal muscle and liver, which was recently reviewed elsewhere [6]. Despite a novel perception in the context of obesity and insulin resistance, ECM–ECM receptor pathways have been long implicated in the biology of pulmonary fibrosis, wound healing, and tumour growth [7–9].…”

Section: Introductionmentioning

confidence: 97%

Adipose extracellular matrix remodelling in obesity and insulin resistance

Lin

Chun

2016

Biochemical Pharmacology

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179

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The extracellular matrix (ECM) of adipose tissues undergoes constant remodelling to allow adipocytes and their precursor cells to change cell shape and function in adaptation to nutritional cues. Abnormal accumulation of ECM components and their modifiers in adipose tissues has been recently demonstrated to cause obesity-associated insulin resistance, a hallmark of type 2 diabetes. Integrins and other ECM receptors (e.g. CD44) that are expressed in adipose tissues have been shown to regulate insulin sensitivity. It is well understood that a hypoxic response is observed in adipose tissue expansion during obesity progression and that hypoxic response accelerates fibrosis and inflammation in white adipose tissues. The expansion of adipose tissues should require angiogenesis; however, the excess deposition of ECM limits the angiogenic response of white adipose tissues in obesity. While recent studies have focused on the metabolic consequences and the mechanisms of adipose tissue expansion and remodelling, little attention has been paid to the role played by the interaction between peri-adipocyte ECM and their cognate cell surface receptors. This review will address what is currently known about the roles played by adipose ECM, their modifiers, and ECM receptors in obesity and insulin resistance. Understanding how excess ECM deposition in the adipose tissue deteriorates insulin sensitivity would provide us hints to develop a new therapeutic strategy for the treatment of insulin resistance and type 2 diabetes.

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“…These structural abnormalities likely also contribute to the increased apoptosis that we observed in insulin-resistant livers. The link between hepatic ECM and architectural structural remodeling with insulin resistance has been studied sparingly (Williams et al, 2015a). In one study, tail-vein injection of HFD-fed mice with a hydrolase for hyaluronan, an ECM component, reduces features of muscle and liver insulin resistance (Kang et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Hepatic Dysfunction Caused by Consumption of a High-Fat Diet

Soltis

Kennedy

et al. 2017

Cell Reports

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SUMMARY Obesity is a major human health crisis that promotes insulin resistance and, ultimately, type 2 diabetes. The molecular mechanisms that mediate this response occur across many highly complex biological regulatory levels that are incompletely understood. Here, we present a comprehensive molecular systems biology study of hepatic responses to high-fat feeding in mice. We interrogated diet-induced epigenomic, transcriptomic, proteomic, and metabolomic alterations using high-throughput omic methods and used a network modeling approach to integrate these diverse molecular signals. Our model indicated that disruption of hepatic architecture and enhanced hepatocyte apoptosis are among the numerous biological processes that contribute to early liver dysfunction and low-grade inflammation during the development of diet-induced metabolic syndrome. We validated these model findings with additional experiments on mouse liver sections. In total, we present an integrative systems biology study of diet-induced hepatic insulin resistance that uncovered molecular features promoting the development and maintenance of metabolic disease.

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The extracellular matrix and insulin resistance

Cited by 182 publications

References 101 publications

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

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

Adipose extracellular matrix remodelling in obesity and insulin resistance

Hepatic Dysfunction Caused by Consumption of a High-Fat Diet

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