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C3H/HeJ mice carrying a Toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

University of Toulouse, Tolosa de Llenguadoc, Midi-Pyrénées, France
Diabetologia (Impact Factor: 6.67). 06/2007; 50(6):1267-76. DOI: 10.1007/s00125-007-0654-8
Source: PubMed

ABSTRACT

Inflammation is associated with obesity and has been implicated in the development of diabetes and atherosclerosis. During gram-negative bacterial infection, lipopolysaccharide causes an inflammatory reaction via toll-like receptor 4 (TLR4), which has an essential function in the induction of innate and adaptative immunity. Our aim was to determine what role TLR4 plays in the development of metabolic phenotypes during high-fat feeding.
We evaluated metabolic consequences of a high-fat diet in TLR4 mutant mice (C3H/HeJ) and their respective controls.
TLR4 inactivation reduced food intake without significant modification of body weight, but with higher epididymal adipose tissue mass and adipocyte hypertrophy. It also attenuated the inflammatory response and increased glucose transport and the expression levels of adiponectin and lipogenic markers in white adipose tissue. In addition, TLR4 inactivation blunted insulin resistance induced by lipopolysaccharide in differentiated adipocytes. Increased feeding efficiency in TLR4 mutant mice was associated with lower mass and lower expression of uncoupling protein 1 gene in brown adipose tissue. Finally, TLR4 inactivation slowed the development of hepatic steatosis, reducing the liver triacylglycerol content and also expression levels of lipogenic and fibrosis markers.
TLR4 influences white adipose tissue inflammation and insulin sensitivity, as well as liver fat storage, and is important in the regulation of metabolic phenotype during a fat-enriched diet.

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Available from: Franck Peiretti, Aug 14, 2014
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    • "This may be particularly important role in diabetes mellitus. For example, mice with an inactive TLR4 gene are significantly less prone to dietinduced insulin resistance [22] [23], but deficiency of TLR3 protects animals from diet-induced insulin resistance and improves plasma lipid profile [24]. This study is intended to explore TLR3 and TLR4 expression, and their downstream signaling and readouts in PCI patients, with and without type 2 diabetes mellitus, compared with controls. "
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    • "In these organs, there is mounting evidence that the immune Toll-like receptor 4 (TLR4) acts as a key regulator in fibrogenesis (Aoyama et al., 2010; Campbell et al., 2011; Seki et al., 2007). A role for TLR4 in AT macrophage response has been shown, but its direct contribution to AT fibrosis remains elusive (Poggi et al., 2007; Saberi et al., 2009; Shi et al., 2006). Despite its importance in the dynamics of AT remodeling and consequences on metabolic status, the mechanisms controlling AT fibrosis remain poorly understood. "
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    • "In these organs, there is mounting evidence that the immune Toll-like receptor 4 (TLR4) acts as a key regulator in fibrogenesis (Aoyama et al., 2010; Campbell et al., 2011; Seki et al., 2007). A role for TLR4 in AT macrophage response has been shown, but its direct contribution to AT fibrosis remains elusive (Poggi et al., 2007; Saberi et al., 2009; Shi et al., 2006). Despite its importance in the dynamics of AT remodeling and consequences on metabolic status, the mechanisms controlling AT fibrosis remain poorly understood. "
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