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Deficiency of Tyk2 kinase in mice leads to obesity and insulin resistance
Author(s) -
Gornicka Agnieszka Olga,
Millward Carrie,
Croniger Colleen,
Larner Andrew
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.614.3
Subject(s) - endocrinology , medicine , lipogenesis , insulin resistance , leptin , tyrosine kinase 2 , white adipose tissue , insulin receptor , biology , insulin , glut4 , adipose tissue , brown adipose tissue , steatosis , obesity , receptor , platelet derived growth factor receptor , growth factor
The prevalence of obesity and type 2 diabetes has reached epidemic proportions worldwide. Tyk2 is one of the Janus (JAK) kinases that are stimulated by several cytokines, IL‐12, IL‐10, IL‐18. The JAK/STAT pathway can be also activated by leptin and indirectly by insulin. To study the role of Tyk2 in the development of obesity and diabetes, we analyzed mice with a gene‐targeted deletion of Tyk2 kinase (Tyk2 −/− mice). Tyk2−/− mice and wild type (WT) mice were fed a chow diet (17% fat) for 3 and 12 months. The animals gained similar weight at 3 months of age, but by 12 months of age, the Tyk2 −/− mice had increased body weight (40.8 %) compared to WT mice. The food intake in both Tyk2 −/− and WT mice was very similar suggesting alterations in overall energy expenditure. To understand the underlying mechanism, we analyzed expression of genes involved in lipogenesis and overall energy metabolism. Both 3 month‐old and 12 month‐old Tyk2 −/− had very low expression of uncoupling proteins 1 and 3 (UCP‐1 and UCP‐3) in muscle, brown and white adipose tissue compared to WT mice. Plasma levels of insulin, leptin, triglycerides and cholesterol were elevated in 12 months old Tyk2 −/− mice. The Tyk2−/− mice had impaired glucose tolerance tests and they developed steatosis by 12 months. The Tyk2 −/− mice had increased expression of hepatic lipogenic genes, acetyl CoA carboxylase (ACC) and fatty acid synthase (FAS). Interestingly, levels of β‐oxidation genes in brown adipose tissue and muscle were reduced in both 3 moths old and 12 months old Tyk2 −/− mice and may contribute to the underlying mechanism for the development of obesity. The above data indicate that Tyk2−/− mice develop obesity and type 2 diabetes as they age and thus Tyk2 kinase plays an important role in the development of these diseases.