title: Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance.
abstract: Obesity is associated with insulin resistance and a state of abnormal inflammatory response. The Toll-like receptor (TLR)4 has an important role in inflammation and immunity, and its expression has been reported in most tissues of the body, including the insulin-sensitive ones. Because it is activated by lipopolysaccharide and saturated fatty acids, which are inducers of insulin resistance, TLR4 may be a candidate for participation in the cross-talk between inflammatory and metabolic signals. Here, we show that C3H/HeJ mice, which have a loss-of-function mutation in TLR4, are protected against the development of diet-induced obesity. In addition, these mice demonstrate decreased adiposity, increased oxygen consumption, a decreased respiratory exchange ratio, improved insulin sensitivity, and enhanced insulin-signaling capacity in adipose tissue, muscle, and liver compared with control mice during high-fat feeding. Moreover, in these tissues, control mice fed a high-fat diet show an increase in IkappaB kinase complex and c-Jun NH(2)-terminal kinase activity, which is prevented in C3H/HeJ mice. In isolated muscles from C3H/HeJ mice, protection from saturated fatty acid-induced insulin resistance is observed. Thus, TLR4 appears to be an important mediator of obesity and insulin resistance and a potential target for the therapy of these highly prevalent medical conditions.
authors.affiliation: Department of Internal Medicine, State University of Campinas, Campinas, São Paulo, Brazil.
authors.forename: Daniela M L
authors.initials: DM
authors.lastname: Tsukumo
authors.forename: Marco A
authors.initials: MA
authors.lastname: Carvalho-Filho
authors.forename: José B C
authors.initials: JB
authors.lastname: Carvalheira
authors.forename: Patrícia O
authors.initials: PO
authors.lastname: Prada
authors.forename: Sandro M
authors.initials: SM
authors.lastname: Hirabara
authors.forename: André A
authors.initials: AA
authors.lastname: Schenka
authors.forename: Eliana P
authors.initials: EP
authors.lastname: Araújo
authors.forename: José
authors.initials: J
authors.lastname: Vassallo
authors.forename: Rui
authors.initials: R
authors.lastname: Curi
authors.forename: Lício A
authors.initials: LA
authors.lastname: Velloso
authors.forename: Mario J A
authors.initials: MJ
authors.lastname: Saad
mesh_terms: D000273:Adipose Tissue / Q000473:pathology / Q000648:ultrastructure; D000821:Animal Feed; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D048430:Cell Shape; D004041:Dietary Fats / Q000494:pharmacology; D004789:Enzyme Activation; D005227:Fatty Acids / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D010750:Phosphoproteins / Q000378:metabolism; D010768:Phosphoserine / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D005227:Fatty Acids; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D051197:Toll-Like Receptor 4; D014280:Triglycerides; D010768:Phosphoserine; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases