title: Loss of Toll-Like Receptor 4 Function Partially Protects against Peripheral and Cardiac Glucose Metabolic Derangements During a Long-Term High-Fat Diet.
abstract: Diabetes is a chronic inflammatory disease that carries a high risk of cardiovascular disease. However, the pathophysiological link between these disorders is not well known. We hypothesize that TLR4 signaling mediates high fat diet (HFD)-induced peripheral and cardiac glucose metabolic derangements. Mice with a loss-of-function mutation in TLR4 (C3H/HeJ) and age-matched control (C57BL/6) mice were fed either a high-fat diet or normal diet for 16 weeks. Glucose tolerance and plasma insulin were measured. Protein expression of glucose transporters (GLUT), AKT (phosphorylated and total), and proinflammatory cytokines (IL-6, TNF-α and SOCS-3) were quantified in the heart using Western Blotting. Both groups fed a long-term HFD had increased body weight, blood glucose and insulin levels, as well as impaired glucose tolerance compared to mice fed a normal diet. TLR4-mutant mice were partially protected against long-term HFD-induced insulin resistance. In control mice, feeding a HFD decreased cardiac crude membrane GLUT4 protein content, which was partially rescued in TLR4-mutant mice. TLR4-mutant mice fed a HFD also had increased expression of GLUT8, a novel isoform, compared to mice fed a normal diet. GLUT8 content was positively correlated with SOCS-3 and IL-6 expression in the heart. No significant differences in cytokine expression were observed between groups, suggesting a lack of inflammation in the heart following a HFD. Loss of TLR4 function partially restored a healthy metabolic phenotype, suggesting that TLR4 signaling is a key mechanism in HFD-induced peripheral and cardiac insulin resistance. Our data further suggest that TLR4 exerts its detrimental metabolic effects in the myocardium through a cytokine-independent pathway.
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma, United States of America.
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Jackson
authors.affiliation: Department of Nutritional Sciences, Oklahoma State University, Stillwater, Oklahoma, United States of America.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rendina-Ruedy
authors.affiliation: Department of Nutritional Sciences, Oklahoma State University, Stillwater, Oklahoma, United States of America.
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Smith
authors.affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma, United States of America.|Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
authors.forename: Veronique A
authors.initials: VA
authors.lastname: Lacombe
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D059305:Diet, High-Fat / Q000379:methods; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000378:metabolism; D005951:Glucose Tolerance Test / Q000379:methods; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015430:Weight Gain / Q000502:physiology
chemical_list: D001786:Blood Glucose; D051246:Glucose Transport Proteins, Facilitative; D015850:Interleukin-6; C498628:Slc2a8 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose