The toll-like receptor gene targeted in this strain is a sensor for monomeric flagellin, a component of bacterial flagella known to be a virulence factor. These mice have been used to investigate the mechanism of flagellin detection and signalling in antibacterial immune responses to Salmonella typhimurium and Pseudomonas aeruginosa. The gene has been found to be essential for the recognition of bacterial flagellin both in vivo and ex vivo. Mice that are homozygous for this targeted deletion are viable and fertile. Transcripts of this gene are absent from bone marrow-derived macrophages in homozygotes.
Relative to controls, homozygotes have increased fat mass throughout the body, particularly in visceral fat, a substantial increase in serum triglyceride and cholesterol levels, increased blood pressure, and higher than normal production of pro-inflammatory cytokines interferon gamma and interleukin 1 beta in adipose tissue. Basal insulin levels and insulin production in response to a glucose challenge are significantly elevated, and the response to exogenous insulin is reduced compared with that of controls. The ability to restore blood glucose to baseline levels after administration of a bolus of glucose is impaired, and a mild elevation in blood glucose levels is found after an overnight fast. After 8 weeks on a high fat diet fasting glucose concentrations exceed 120 mg/dL, inflammatory infiltrates are found in the pancreatic islets, and hepatic steatosis is observed.
Homozygotes offer a model of metabolic syndrome for which the hyperphagia, obesity, hyperglycemia, insulin resistance, colomegaly, and increased pro-inflammatory cytokines can be transferred from diseased homozygotes to wild-type hosts by tranplanting gut microbiota. Treatment of homozygotes with broad spectrum antibiotics for 12 weeks corrects the metabolic syndrome. Hysterectomy re-derivation to upgrade the microbial flora of homozygotes results in diminished severity of colitis and a more uniform phenotype of mild inflammation and obesity, including a 20% increase in body mass at 20 weeks of age.
