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

Poggi, Marjorie; Bastelica, Delphine; Gual, Philippe; Iglesias, M.; Grémeaux, Thierry; Knauf, Claude; Peiretti, Franck; Verdier, Monique; Juhan‐Vague, I.; Tanti, Jean‐François; Burcelin, Rémy; Alessi, Marie‐Christine

doi:10.1007/s00125-007-0654-8

Cited by 321 publications

(286 citation statements)

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“…Our data demonstrate that in absence of CD14, a high-fat diet could not induce inflammation as reflected by the total blunting of cytokine expression augmentation in the liver and adipose depot. Similarly, we recently reported that TLR4 mutant mice are protected against adipose tissue insulin resistance (44). Our finding is complementary to recent data that showed that free fatty acids can bind TLR4 to activate cells from the innate immune system (6) leading to the secretion of cytokines.…”

Section: Discussionsupporting

confidence: 88%

Metabolic Endotoxemia Initiates Obesity and Insulin Resistance

Cani

Amar

Iglesias³

et al. 2007

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Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPScontaining microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in highfat-fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not wholebody, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet-induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases. Diabetes 56: [1761][1762][1763][1764][1765][1766][1767][1768][1769][1770][1771][1772] 2007 T he outbreak of a fat-enriched diet in Western countries is becoming a problem of the utmost importance. Obesity is the result of a complex interaction between genetic and environmental factors. Among the latter, changes in eating habits to increase fat intake are involved in the increased occurrence of metabolic diseases, such as obesity and diabetes, which are bearing features of the metabolic syndrome. The major metabolic consequence of a high-fat diet is that insulin action and the regulatory mechanisms of body weight are impaired through a well-described lipotoxic effect (1). In addition, it has been recently determined that obesity and insulin resistance are associated with lowgrade chronic systemic inflammation (2). In models of diet-induced and genetic obesity, the adipose tissue presents increased expression and content of proinflammatory cytokines such as tumor necrosis factor (TNF)-␣ (3,4), interleukin (IL)-1 (3,4), and IL-6 (4). This cytokine production is then deleterious for muscle insulin action; for example, TNF-␣ has been shown to cause insulin resistance by increasing serine phosphorylation on insulin receptor substrate-1 (5), leading to its inactivation. The consequent insulin resistance will favor hyperinsulinemia and excessive hepatic and adipose tissue lipid storage. However, while extensive research is dedicated to the effects of an in...

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Section: Discussionsupporting

confidence: 88%

Metabolic Endotoxemia Initiates Obesity and Insulin Resistance

Cani

Amar

Iglesias³

et al. 2007

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“…Lack of Tlr4 in mice fed a HFD resulted in protection against obesity 67 , insulin resistance, 68 and inflammation in adipose tissues 69,70 , liver, skeletal muscle 71 , and vasculature 72 . Specific deletion of Tlr4 in haematopoietic cells ameliorated insulin resistance in hepatic and adipose tissue 73 and mice with a specific loss of Tlr4 in hepatocytes exhibited improved glucose tolerance, enhanced insulin sensitivity, and ameliorated hepatic steatosis 74 .…”

Section: [H3] Tlr4mentioning

confidence: 99%

Innate immunity in diabetes and diabetic nephropathy

2015

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Abstract:The innate immune system consists of several classes of pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) and nucleotide-binding domain leucine-rich oligomerization domain (NOD)-like receptors (NLRs).These receptors detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the extracellular and intracellular space. Intracellular NLRs constitute inflammasomes, which activate and release caspase-1, IL1β, and IL18 and thus initiate an inflammatory response. Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the development and progression of diabetes mellitus and diabetic nephropathy. TLR2, TLR4, and the NLRP3 inflammasome are critically involved in the inflammatory responses in pancreatic islets, adipose, liver and kidney tissues. This Review discusses how innate immune system-driven inflammatory processes can lead to apoptosis, tissue fibrosis, and organ dysfunction to cause insulin resistance, impaired insulin secretion, and renal failure. We propose that careful targeting of TLR2, TLR4, and NLRP3 signalling pathways may be beneficial for the treatment of diabetes mellitus and diabetic nephropathy. 2 Key points The innate immune system consists of several classes of pattern recognition receptors, including TLRs and NLRs, which detect pathogen-associated and danger-associated molecular patterns and initiate an inflammatory response  TLR2 and TLR4 are the predominant toll-like receptors expressed on pancreatic β cells that trigger an inflammatory response in insulitis during type 1 diabetes mellitus  TLR2 and TLR4 signaling, and activation of NLRP3 inflammasomes results in production of various proinflammatory cytokines that can induce insulin resistance in type 2 diabetes mellitus (T2DM) and obesity  Innate immune responses in T2DM and obesity are modulated by the status of the gut microbiota, autophagy, and adipokines  TLR2, TLR4, NOD2, and NLRP3 inflammasome-mediated inflammation are involved in the perpetuation of inflammation in diabetic nephropathy  The activation of TLRs and NLRs stimulates the expression of MCP-1, which is associated with the progression of diabetic nephropathy [H1] IntroductionThe prevalence of diabetes mellitus is estimated to be 8.3%, affecting ~387 million people as of 2014. The number of patients living with diabetes mellitus is expected to increase to ~592 million by 2035, as reported by the International Diabetes Federation 1 . The incidence of end-stage renal disease (ESRD) is also rapidly increasing worldwide but varies up to 15-fold by country. In 2012, the number of new diagnoses of ESRD worldwide ranged from 25 to 467 patients per million. The proportion of new cases of ESRD with diabetes mellitus as the primary cause also differs by country, with 66% cases reported in Singapore and 12-16% cases reported in Ukraine, Romania, and the Netherlands 2 . Although intensified multifactorial intervention in patients with type 2 diabete...

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“…Indeed, deficiency of Toll-like receptor 4 (TLR4) or TLR4 signaling protects against obesity-induced M1 macrophage polarization and adipose tissue inflammation in vivo [25][26][27][28]. On the other hand, peroxisome proliferatoractivated receptor γ (PPARγ) and PPARδ stimulate M2 polarization of adipose tissue macrophages and thus improve systemic insulin sensitivity [29][30][31].…”

Section: Heterogeneity Of Adipose Tissue Macrophagesmentioning

confidence: 99%