Blockade of α4 Integrin Signaling Ameliorates the Metabolic Consequences of High-Fat Diet–Induced Obesity

Feral, Chloé C.; Neels, Jaap G.; Kummer, Christiane; Slepak, Marina; Olefsky, Jerrold M.; Ginsberg, Mark H.

doi:10.2337/db07-1751

Cited by 45 publications

(33 citation statements)

References 47 publications

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“…32, No. 7 similar effect [36]. In mice deficient for caveolin-1, a membrane-associated protein implicated in endothelial barrier function, rescue of caveolin-1 in endothelial cells reduces macrophage content in adipose tissue.…”

Section: Reviewmentioning

confidence: 78%

Defining macrophage phenotype and function in adipose tissue

Dalmas

Clément

Guerre-Millo

2011

Trends in Immunology

213

173

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Section: Reviewmentioning

confidence: 78%

Defining macrophage phenotype and function in adipose tissue

Dalmas

Clément

Guerre-Millo

2011

Trends in Immunology

213

173

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“…Although inhibiting α4 integrin function and signalling has been shown to block inflammatory responses associated with mononuclear cell-mediated diseases such as multiple sclerosis and Crohn’s disease [80,81], their role in low-grade chronic inflammatory conditions, such as obesity-induced insulin resistance is not well studied. However, it is shown that mice bearing an α4 (Y991A) mutation are protected from development of HFD-induced insulin resistance through mediating the trafficking of monocytes into adipose tissues [82]. …”

Section: Ecm Receptors In the Adipose Tissuementioning

confidence: 99%

Adipose extracellular matrix remodelling in obesity and insulin resistance

Lin

Chun

2016

Biochemical Pharmacology

179

130

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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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“…14,77 In this context, it is of interest that mutation of the a4 chain of the a4b1integrin ligand for TF 14 in hematopoietic cells provides protection from adipose tissue inflammation, as seen with TF DCT mice. 78 In addition to their roles in macrophage recruitment, TF and PAR2 also regulate the activation of myeloid cells. 66,69 In microglia, lipopolysaccharide signaling in PAR2-expressing cells induces TNF-a and IL-6 production, whereas IL-10 is increased in PAR2-deficient cells.…”

Section: Cd11cmentioning

confidence: 99%

Inflammation, obesity, and thrombosis

Samad

Ruf

2013

Blood

336

229

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Clinical and epidemiological studies support a connection between obesity and thrombosis, involving elevated expression of the prothrombotic molecules plasminogen activator inhibitor-1 and tissue factor (TF) and increased platelet activation. Cardiovascular diseases and metabolic syndrome–associated disorders, including obesity, insulin resistance, type 2 diabetes, and hepatic steatosis, involve inflammation elicited by infiltration and activation of immune cells, particularly macrophages, into adipose tissue. Although TF has been clearly linked to a procoagulant state in obesity, emerging genetic and pharmacologic evidence indicate that TF signaling via G protein-coupled protease-activated receptors (PAR2, PAR1) additionally drives multiple aspects of the metabolic syndrome. TF–PAR2 signaling in adipocytes contributes to diet-induced obesity by decreasing metabolism and energy expenditure, whereas TF–PAR2 signaling in hematopoietic and myeloid cells drives adipose tissue inflammation, hepatic steatosis, and insulin resistance. TF-initiated coagulation leading to thrombin–PAR1 signaling also contributes to diet-induced hepatic steatosis and inflammation in certain models. Thus, in obese patients, clinical markers of a prothrombotic state may indicate a risk for the development of complications of the metabolic syndrome. Furthermore, TF-induced signaling could provide new therapeutic targets for drug development at the intersection between obesity, inflammation, and thrombosis.

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Blockade of α4 Integrin Signaling Ameliorates the Metabolic Consequences of High-Fat Diet–Induced Obesity

Cited by 45 publications

References 47 publications

Defining macrophage phenotype and function in adipose tissue

Defining macrophage phenotype and function in adipose tissue

Adipose extracellular matrix remodelling in obesity and insulin resistance

Inflammation, obesity, and thrombosis

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