scholarly journals TLR4 and Insulin Resistance

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Jane J. Kim ◽  
Dorothy D. Sears
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Innate Immunity ◽  
Dietary Fatty Acids ◽  
Therapeutic Approaches ◽  
Toll Like Receptor 4 ◽  
Insulin Signal Transduction ◽  
Mediated Effects ◽  
Cell Type Specific ◽  
Tlr4 Activation

Chronic inflammation is a key feature of insulin resistance and obesity. Toll-Like Receptor 4 (TLR4), involved in modulating innate immunity, is an important mediator of insulin resistance and its comorbidities. TLR4 contributes to the development of insulin resistance and inflammation through its activation by elevated exogenous ligands (e.g., dietary fatty acids and enteric lipopolysaccharide) and endogenous ligands (e.g., free fatty acids) which are elevated in obese states. TLR4, expressed in insulin target tissues, activates proinflammatory kinases JNK, IKK, and p38 that impair insulin signal transduction directly through inhibitory phosphorylation of insulin receptor substrate (IRS) on serine residues. TLR4 activation also leads to increased transcription of pro-inflammatory genes, resulting in elevation of cytokine, chemokine, reactive oxygen species, and eicosanoid levels that promote further insulin-desensitization within the target cell itself and in other cells via paracrine and systemic effects. Increased understanding of cell type-specific TLR4-mediated effects on insulin action present the opportunity and challenge of developing related therapeutic approaches for improving insulin sensitivity while preserving innate immunity.

Exploring the LPS/TLR4 signal pathway with small molecules

2010 ◽  
Vol 38 (5) ◽  
pp. 1390-1395 ◽  
Author(s):  
Francesco Peri ◽  
Matteo Piazza ◽  
Valentina Calabrese ◽  
Gaetana Damore ◽  
Roberto Cighetti
Keyword(s):  
Innate Immunity ◽  
Small Molecules ◽  
Innate Immune ◽  
Toll Like Receptor 4 ◽  
Innate Immunity Cells ◽  
Specific Receptors ◽  
Extracellular Side ◽  
Tlr4 Activation ◽  
Lps Binding

The identification of the bacterial endotoxin receptors for innate immunity, most notably TLR4 (Toll-like receptor 4), has sparked great interest in therapeutic manipulation of the innate immune system. In the present mini-review, several natural and synthetic molecules that modulate the TLR4-mediated LPS (lipopolysaccharide) signalling in animals and humans are considered, and their mechanisms of action are discussed. The process of LPS sensing and signal amplification in humans is based on the sequential action of specific receptors situated in the extracellular side of the innate immunity cells, which bind and transfer LPS to TLR4: LBP (LPS-binding protein), CD14, MD-2 (myeloid differentiation protein 2). We classified the compounds active on TLR4 pathway depending on the specific molecular targets (LPS, LBP, CD14, MD-2 or TLR4). Small molecules developed by our group are described that inhibit LPS-stimulated TLR4 activation by selectively targeting the LPS–CD14 interaction. These compounds have an interesting antiseptic shock, anti-inflammatory and anti-neuropathic pain activity in vivo.

scholarly journals Oleate Blocks Palmitate-Induced Abnormal Lipid Distribution, Endoplasmic Reticulum Expansion and Stress, and Insulin Resistance in Skeletal Muscle

Endocrinology ◽  
2011 ◽  
Vol 152 (6) ◽  
pp. 2206-2218 ◽  
Author(s):  
Gong Peng ◽  
Linghai Li ◽  
Yanbo Liu ◽  
Jing Pu ◽  
Shuyan Zhang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Insulin Sensitivity ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Dietary Fatty Acids ◽  
Akt Phosphorylation ◽  
Stress Relieving

Pathological elevation of plasma fatty acids reduces insulin sensitivity. Although several regulation pathways have been reported, the molecular mechanisms of insulin sensitivity remain elusive, especially in skeletal muscle where most glucose is consumed. This study focuses on how two major dietary fatty acids affect insulin signaling in skeletal muscle cells. Palmitic acid (PA) not only reduced insulin-stimulated phosphorylation of Akt but also induced endoplasmic reticulum (ER) expansion and ER stress. Relieving ER stress using 4-phenyl butyric acid blocked PA-mediated protein kinase R-like ER kinase phosphorylation and ER expansion and reversed the inhibitory effect of PA on insulin-stimulated Akt phosphorylation. Importantly, oleic acid (OA) could also recover PA-reduced Akt phosphorylation and abolish both PA-mediated ER expansion and ER stress. The competition between these two fatty acids was further verified in rat skeletal muscle using venous fatty acid infusion. 3H-labeled PA was converted mainly to active lipids (phospholipids and diacylglycerol) in the absence of OA, but to triacylglycerol in the presence of OA. Subcellular triacylglycerol and adipocyte differentiation-related protein from PA-treated cells cofractionated with the ER in the absence of OA but switched to the low-density fraction in the presence of OA. Taken together, these data suggest that the PA-mediated lipid composition and localization may cause ER expansion and consequently cause ER stress and insulin resistance in skeletal muscle.

scholarly journals Insulin resistance: the conflict between biological settings of energy metabolism and human lifestyle (a glance at the problem from evolutionary viewpoint)

2016 ◽  
Vol 19 (4) ◽  
pp. 286-294 ◽  
Author(s):  
Vladimir Nicolaevich Titov ◽  
Vladimir Pavlovich Shirinsky
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Atp Synthesis ◽  
Insulin Resistance Syndrome ◽  
Dietary Fatty Acids ◽  
Striated Muscles ◽  
Energy Deficiency ◽  
Atp Production

A biological function of the phylogenetically late humoral mediator insulin is to provide energy substrates for locomotion, i.e. movement resulting from contraction of striated muscles. Insulin is able to meet this evolutionary demand of an organism by means of the effective ATP production in the mitochondria. Exogenous fatty acids, optimised endogenous fatty acids produced from glucose and glucose itself are the major substrates for ATP synthesis. Cells stimulated by insulin produce ω-9 С18:1 oleic acid from glucose. This fatty acid is oxidised by the mitochondria at a higher rate than exogenous and endogenous C16:0 palmitic fatty acid. In the normal state of insulin system and mitochondria, the frequent cause of insulin resistance is the non-optimal properties of dietary fatty acids supplied for oxidation by the mitochondria. Dietary excess of saturated palmitic fatty acid over monogenic oleic fatty acid causes insulin resistance to develop. Insulin resistance syndrome is the condition of in vivo energy deficiency and insufficient production of ATP for the realisation of the biological adaptation and compensation. Insulin effectively inhibits lipolysis only in phylogenetically late subcutaneous adipocytes but not in phylogenetically early visceral fat cells of the omentum. Discrepancy in the regulation of energy substrate metabolism against the background of a ‘relative biological perfection’ of higher mammals is the aetiological basis of insulin resistance.

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