The Janus kinase, Tyk2, plays a pivotal role in controlling the expression of genes involved in immune responses, cell transformation and maintaining homeostasis. Results in this proposal define a new function for Tyk2 as a key mediator of brown adipocyte differentiation. Mice that do not express Tyk2 become obese and have a defect in brown fat cell-specific gene expression. Furthermore, mice placed on a high fat diet and obese humans show decreased expression of Tyk2 in skeletal muscle. Differentiation of Tyk2-/- preadipocytes in vitro and in transgenic animals is rescued by the expression of Tyk2, as well as a kinase-inactive form of the enzyme that cannot be activated by cytokines. Furthermore, there is a pool of Tyk2 in the nucleus that interacts with transcription factors that are required for differentiation of brown adipose tissue (BAT). Experiments are proposed to understand the mechanisms by which expression of Tyk2 regulates BAT differentiation and prevents the development of obesity.

Public Health Relevance

Mice which do not express the Jak kinase Tyk2 become spontaneously obese due to a defect in differentiation of brown adipose tissue (BAT). Differentiation of BAT in Tyk2-/- preadipocytes is rescued by the expression of Tyk2, as well as kinase inactive form of the protein. Furthermore, expression of Tyk2 or kinse inactive Tyk2 in Tyk2-/- mice restores the differentiation of brown adipocyte suggesting a completely novel role for Tyk2 in control of energy metabolism and the etiology of obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK099732-02
Application #
8895311
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Haft, Carol R
Project Start
2014-07-21
Project End
2017-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
2
Fiscal Year
2015
Total Cost
$307,757
Indirect Cost
$102,757
Name
Virginia Commonwealth University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Raje, Vidisha; Derecka, Marta; Cantwell, Marc et al. (2017) Kinase Inactive Tyrosine Kinase (Tyk2) Supports Differentiation of Brown Fat Cells. Endocrinology 158:148-157
Sisler, Jennifer D; Morgan, Magdalena; Raje, Vidisha et al. (2015) The Signal Transducer and Activator of Transcription 1 (STAT1) Inhibits Mitochondrial Biogenesis in Liver and Fatty Acid Oxidation in Adipocytes. PLoS One 10:e0144444