Defense Date

2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Integrative Life Sciences

First Advisor

Andrew Larner

Abstract

Obesity develops when energy intake exceeds energy expenditure. Defect in the function of brown fat and skeletal muscle, two of the major tissues that contribute towards energy expenditure, lead to the development of obesity and metabolic syndrome. Our previous findings suggest that Tyk2 deficient mice become obese and develop the metabolic syndrome. Tyk2, which is a tyrosine kinase of the JAK-STAT signaling family, is important for optimal brown development and function. Since brown fat and skeletal muscle, both are derived from the Myf5+ lineage of mesenchymal stem cells, we also characterized the role of Tyk2 in the development and function of skeletal muscle. We found that Tyk2 deficient mice do not display a structural defect in skeletal muscle development; however, the function of skeletal muscle is severely impaired in these mice. Expression of troponins, which regulate the muscle contraction and muscle creatine kinase, which regulates the levels of phosphocreatine, a major fuel for skeletal muscle, is downregulated in Tyk2 deficient mice. Skeletal muscle mitochondria also display an abnormal morphology along with decreased respiration capacity, which is a function of decreased activity of complex IV of the electron transport chain. Interestingly, Tyk2 deficient mice also exhibit an increased proportion of fast, glycolytic, Type II fibers in the skeletal muscle. Using an in-vitro system for skeletal muscle differentiation, we found that Tyk2 levels increase during differentiation, suggesting a role for Tyk2 in proper development and function of the skeletal muscle. Our previous studies suggested that a kinase-inactive (Tyk2KD) form of Tyk2 is also efficient in restoring the function of Tyk2 deficient brown fat preadipocytes. We generated transgenic mice that expressed a wild type (Tyk2WT) and kinase inactive (Tyk2 KD) form of tyk2 in brown fat and skeletal muscle under Myf5 cre and in skeletal muscle using MCK cre mice. Expression of Tyk2 using the Myf5 cre (E8.0) reverts the obese and the metabolic phenotype observed in the Tyk2 deficient mice. Interestingly, expressing Tyk2 under MCK cre (E13.0) also reverts the obese phenotype, suggesting that the temporal and spatial expression of Tyk2 is critical in regulating energy expenditure. Our studies also highlight the role of Tyk2, not as a kinase, but as a component of the transcriptional assembly regulating the expression of genes invo

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

August 2013

Included in

Life Sciences Commons

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