Epigallocatechin Gallate Suppresses Inflammatory Responses by Inhibiting Toll-like Receptor 4 Signaling and Alleviates Insulin Resistance in the Livers of High-fat-diet Rats

Background: Toll-like receptor 4 (TLR4) is an innate proinflammatory mediator found in a wide variety of cell types including cardiomyocytes. The autophagy-lysosome pathway, a major pathway governing protein and organelle degradation and recycling, plays a pivotal role in maintaining cardiac homeostasis under physiological and pathological conditions. The aim of this study was to evaluate the impact of TLR4 knockout (TLR4 -/- ) on high fat diet (HFD)-induced cardiomyopathy and the underlying mechanisms involved, with a focus on inflammation and autophagy pathways. Methods: Wild type (WT) and TLR4 -/- mice were fed on low fat diet (LFD) or HFD for 12 weeks. Metabolic rate and glucose tolerance were measured in WT and TLR4 -/- mice at the end of fat diet intake. Echocardiographic, cardiomyocyte mechanical function, morphological feature, aconitase activity, ROS generation and immunoblotting were assessed. Results: TLR4 -/- did not prevent HFD-induced obesity and insulin resistance, as evidenced by body weight gain and glucose intolerance. In addition, there was little difference in metabolic parameters (V O2 , V CO2 , RER, energy expenditure and physical activity) between WT and TLR4 -/- mice fed with HFD. However, TLR4 -/- alleviated HFD-elicited cardiac hypertrophy and contractile dysfunction. HFD-feeding caused extensive mitochondrial injury and ROS generation, which were alleviated by TLR4 -/- . TLR4 -/- dramatically attenuated inflammation signaling (up-regulated p-IKβ, NF-κB and p-JNK) in the face of HFD intake. Cardiac autophagy was significantly suppressed by HFD, as evidenced by up-regulated p-mTOR, down-regulated p-AMPK, Atg5, Atg12, LC3BII, and up-regulated P62 in HFD-induced cardiomyopathy. Furthermore, in vitro study revealed that the TLR4 inhibitor-TAK-242 reconciled palmitic acid-induced cardiomyocyte autophagy and contractile anomalies. Conclusions: Our results suggested that TLR4 -/- does not prevent HFD-induced obesity and insulin resistance. However, TLR4 is a culprit factor for cardiac dysfunction following HFD intake. The cardioprotective effect of TLR4 -/- against HFD-induced cardiomyopathy is associated with attenuation of myocardial inflammation and recovery of cardiac autophagy activity.

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Abstract 15813: Loss-of-Function Mutation in Toll-Like Receptor 4 Partially Protects Against Peripheral and Cardiac Insulin Resistance During a Long-Term High-Fat Diet

Circulation ◽

10.1161/circ.130.suppl_2.15813 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Ellen Jackson ◽

Elizabeth Rendina-Ruedy ◽

Matt Priest ◽

Brenda Smith ◽

Veronique Lacombe

Keyword(s):

Insulin Resistance ◽

Protein Content ◽

Glucose Transport ◽

High Fat Diet ◽

Whole Body ◽

Toll Like Receptor ◽

Loss Of Function ◽

High Fat ◽

The Face ◽

Tlr4 Activation

Diabetes mellitus is an epidemic disease characterized by alterations in glucose transport, which is tightly regulated by a family of specialized proteins called the glucose transporters (GLUTs). Although diabetic cardiomyopathy is a common complication in diabetic patients, its pathogenesis is still not well understood. Toll-like receptor (TLR) 4, which plays a central role in pathogen recognition by the innate immune system, may also play a critical role in linking inflammation and metabolic disease. We hypothesized that TLR4 activation triggers cardiac insulin resistance. We used mice with a loss-of function mutation in TLR4 (C3H/HeJ) and age-matched wild-type (WT, C57BL/6N) mice (n=8/group) to investigate how feeding a high-fat diet (HFD, 60% kcal from fat) for 16 weeks affected whole-body and cardiac glucose metabolism. After 16 weeks, WT mice fed a HFD were obese and developed hyperglycemia and insulin resistance compared to WT mice on a control diet (10% kcal from fat). The C3H/HeJ mice were partially protected against HFD-induced obesity and insulin resistance. In the heart, WT mice fed a HFD had a 30% decrease (P<0.05) in GLUT4 protein content as measured by Western Blot of cardiac crude membrane protein extracts. In contrast, the loss-of-function point mutation in TLR4 partially rescued cardiac GLUT4 content in the face of a HFD. Interestingly, there was a 40% increase (P<0.05) in the novel GLUT isoform, GLUT8, in the heart when mice of either genotype were fed a HFD. Additionally, GLUT4 protein content was negatively (P<0.05) correlated with GLUT8 content in the myocardium, suggesting that GLUT8 may act as a compensatory mechanism in the face of HFD-induced GLUT4 downregulation. Phosphorylated Akt, a key protein of the insulin signaling pathway, was positively (P<0.05) correlated with GLUT4 content, while the basal/inactive form was negatively correlated. In conclusion, these data suggest that activation of TLR4 activation during diabetes and obesity alters glucose transport by an Akt mechanism, and as such is a pathogenic factor during peripheral and cardiac insulin resistance. Overall, TLR4 appears to be a key modulator in the cross-talk between inflammatory and metabolic pathways, as well as a potential therapeutic target for diabetes.

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Apolipoprotein E deficiency and high-fat diet cooperate to trigger lipidosis and inflammation in the lung via the toll-like receptor 4 pathway

Molecular Medicine Reports ◽

10.3892/mmr.2015.3774 ◽

2015 ◽

Vol 12 (2) ◽

pp. 2589-2597 ◽

Cited By ~ 9

Author(s):

QIUFANG OUYANG ◽

ZIYANG HUANG ◽

HUILI LIN ◽

JINGQIN NI ◽

HUIXIA LU ◽

...

Keyword(s):

Apolipoprotein E ◽

High Fat Diet ◽

Toll Like Receptor ◽

High Fat ◽

Toll Like Receptor 4

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Betaine Protects Against High-Fat-Diet-Induced Liver Injury by Inhibition of High-Mobility Group Box 1 and Toll-Like Receptor 4 Expression in Rats

Digestive Diseases and Sciences ◽

10.1007/s10620-013-2775-x ◽

2013 ◽

Vol 58 (11) ◽

pp. 3198-3206 ◽

Cited By ~ 44

Author(s):

Wei Zhang ◽

Lu-wen Wang ◽

Li-kun Wang ◽

Xun Li ◽

Hong Zhang ◽

...

Keyword(s):

Liver Injury ◽

High Fat Diet ◽

High Mobility ◽

High Mobility Group ◽

Toll Like Receptor ◽

High Fat ◽

Toll Like Receptor 4

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Selective overexpression of Toll-like receptor-4 in skeletal muscle impairs metabolic adaptation to high-fat feeding

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00139.2015 ◽

2015 ◽

Vol 309 (3) ◽

pp. R304-R313 ◽

Cited By ~ 8

Author(s):

Ryan P. McMillan ◽

Yaru Wu ◽

Kevin Voelker ◽

Gabrielle Fundaro ◽

John Kavanaugh ◽

...

Keyword(s):

Skeletal Muscle ◽

High Fat Diet ◽

Whole Body ◽

Metabolic Adaptation ◽

Acid Oxidation ◽

Chow Diet ◽

Toll Like Receptor ◽

High Fat ◽

Toll Like Receptor 4 ◽

Fat Feeding

Toll-like receptor-4 (TLR-4) is elevated in skeletal muscle of obese humans, and data from our laboratory have shown that activation of TLR-4 in skeletal muscle via LPS results in decreased fatty acid oxidation (FAO). The purpose of this study was to determine whether overexpression of TLR-4 in skeletal muscle alters mitochondrial function and whole body metabolism in the context of a chow and high-fat diet. C57BL/6J mice (males, 6–8 mo of age) with skeletal muscle-specific overexpression of the TLR-4 (mTLR-4) gene were created and used for this study. Isolated mitochondria and whole muscle homogenates from rodent skeletal muscle (gastrocnemius and quadriceps) were investigated. TLR-4 overexpression resulted in a significant reduction in FAO in muscle homogenates; however, mitochondrial respiration and reactive oxygen species (ROS) production did not appear to be affected on a standard chow diet. To determine the role of TLR-4 overexpression in skeletal muscle in response to high-fat feeding, mTLR-4 mice and WT control mice were fed low- and high-fat diets for 16 wk. The high-fat diet significantly decreased FAO in mTLR-4 mice, which was observed in concert with elevated body weight and fat, greater glucose intolerance, and increase in production of ROS and cellular oxidative damage compared with WT littermates. These findings suggest that TLR-4 plays an important role in the metabolic response in skeletal muscle to high-fat feeding.

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