Abstract 15583: Toll-Like Receptor 4 Knockout Preserves Cardiac Function in High Fat Diet-Induced Obesity

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Nan Hu ◽  
Yingmei Zhang ◽  
Jun Ren
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Body Weight Gain ◽  
Ros Generation ◽  
Myocardial Inflammation ◽  
Toll Like Receptor ◽  
High Fat ◽  
Toll Like Receptor 4 ◽  
Major Pathway ◽  
The Impact

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.

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 ◽  
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.

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

2015 ◽  
Vol 12 (2) ◽  
pp. 2589-2597 ◽  
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

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

2015 ◽  
Vol 309 (3) ◽  
pp. R304-R313 ◽  
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.

scholarly journals PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling

2018 ◽  
Vol 115 (38) ◽  
pp. E8996-E9005 ◽  
Author(s):  
Brandon M. Gassaway ◽  
Max C. Petersen ◽  
Yulia V. Surovtseva ◽  
Karl W. Barber ◽  
Joshua B. Sheetz ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Phosphorylation ◽  
Cross Talk ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Large Scale ◽  
Kinase Assay ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
The Impact

Insulin resistance drives the development of type 2 diabetes (T2D). In liver, diacylglycerol (DAG) is a key mediator of lipid-induced insulin resistance. DAG activates protein kinase C ε (PKCε), which phosphorylates and inhibits the insulin receptor. In rats, a 3-day high-fat diet produces hepatic insulin resistance through this mechanism, and knockdown of hepatic PKCε protects against high-fat diet-induced hepatic insulin resistance. Here, we employed a systems-level approach to uncover additional signaling pathways involved in high-fat diet-induced hepatic insulin resistance. We used quantitative phosphoproteomics to map global in vivo changes in hepatic protein phosphorylation in chow-fed, high-fat–fed, and high-fat–fed with PKCε knockdown rats to distinguish the impact of lipid- and PKCε-induced protein phosphorylation. This was followed by a functional siRNA-based screen to determine which dynamically regulated phosphoproteins may be involved in canonical insulin signaling. Direct PKCε substrates were identified by motif analysis of phosphoproteomics data and validated using a large-scale in vitro kinase assay. These substrates included the p70S6K substrates RPS6 and IRS1, which suggested cross talk between PKCε and p70S6K in high-fat diet-induced hepatic insulin resistance. These results identify an expanded set of proteins through which PKCε may drive high-fat diet-induced hepatic insulin resistance that may direct new therapeutic approaches for T2D.

scholarly journals Luteolin Improves Insulin Resistance in Postmenopausal Obese Mice by Altering Macrophage Polarization (FS12-01-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Yunjung Baek ◽  
Mi Nam Lee ◽  
Dayong Wu ◽  
Munkyong Pae
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Ovarian Function ◽  
Body Weight Gain ◽  
Adipose Tissue Inflammation ◽  
High Fat ◽  
Tissue Inflammation ◽  
Ovariectomized Mice

Abstract Objectives Previously, we showed that loss of ovarian function in mice fed high-fat diet exacerbated insulin resistance and adipose tissue inflammation. In the current study, we tested whether consumption of luteolin, an anti-inflammatory flavonoid, could mitigate adipose tissue inflammation and insulin resistance in obese ovariectomized mice. Methods Nine-week-old ovariectomized C57BL/6 mice were fed a low-fat diet (LFD), high-fat diet (HFD), or HFD supplemented with 0.005% luteolin (HFD + L) for 16 weeks. The anti-inflammatory drug salicylate was used as a positive control. Fasting blood glucose, insulin, and insulin resistance index HOMA-IR were measured every 4 weeks. Adipose tissue and spleen were characterized for tissue inflammation by real-time PCR and immune cell populations by flow cytometry after 16 weeks of feeding. Results HFD resulted in more body weight gain than LFD in ovariectomized mice and supplementing HFD with 0.005% luteolin did not affect the body weight gain. In addition, HFD elicited a significant elevation in fat mass, which were comparable between HFD and HFD + L groups. However, luteolin supplementation resulted in a significant decrease in CD11c+ macrophages in gonadal adipose tissue, as well as a trend of decrease in macrophage infiltration. Luteolin supplementation also significantly decreased mRNA expression of inflammatory and M1 markers MCP-1, CD11c, TNF-a, and IL-6, while maintaining expression of M2 marker MGL1. We further found that luteolin treatment protected mice from insulin resistance induced by HFD consumption; this improved insulin resistance was correlated with reductions in CD11c+ adipose tissue macrophages. Conclusions Our findings indicate that dietary luteolin supplementation attenuates adipose tissue inflammation and insulin resistance found in mice with loss of ovarian function coupled with a HFD intake, and this effect may be partly mediated through suppressing M1-like polarization of macrophages in adipose tissue. These results have clinical implication in implementing dietary intervention for prevention of metabolic syndrome associated with postmenopause and obesity. Funding Sources Supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF-2018R1A1A1A05078886).

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