GENETIC AND CELLULAR MODELS FOR THE STUDY OF PTK2B AND ADAM10 IN ADAPTIVE THERMOGENESIS AND METABOLISM
Doctor of Philosophy
Clinical and Translational Sciences
Francesco S. Celi, MD, MHSc
Rebecca K. Martin, PhD
Antonio Abbate, MD, PhD
Andrew Larner, MD, PhD
Youngman Oh, PhD
In a cellular model, we demonstrate that the non-receptor protein tyrosine kinase 2 beta (PTK2B) plays a critical role in mouse cultured beige adipocyte differentiation. CRISPR/Cas9-mediated knock-out of Ptk2b results in non-differentiating white adipocytes and differentiated beige adipocytes with significantly reduced thermogenic gene and protein expression, enlarged lipid droplet size, and altered mitochondrial respiration. Together, these data in a cell culture system provide evidence for a role of PTK2B in the differentiation of mouse beige adipocytes.
In the process of developing a new mouse model utilizing the adipocyte selective Adipoq-Cre transgenic mouse, strong genetic linkage between a gene of interest, Adam10, and the Adipoq-Cre transgene was discovered. Whole genome sequencing of the Adipoq-Cre transgenic mouse model identified the genomic insertion site within the Tbx18 gene locus on chromosome 9 and this insertion causes a significant decrease in Tbx18 gene expression in adipose tissue. Insertion of genes Kng2, Kng1, Eif4a2 and Rfc4 also occurred in the Adipoq-Cre transgenic mouse, and these passenger genes may have functional consequences in various tissues.
We generated adipocyte specific Adam10 knockout (A10 ADIPKO) mice and studied these mice under dietary and environmental challenges. Chow fed A10 ADIPKO mice had elevated thermogenic gene programs in inguinal and perigonadal white adipose tissue and were leaner compared to their littermate controls. Furthermore, in a model of diet-induced-obesity A10 ADIPKO mice exhibited improved glucose tolerance, despite no weight difference compared to littermate controls. These studies reveal a new role for ADAM10 in adaptive thermogenesis and protection from obesity-induced glucose intolerance.
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Available for download on Friday, March 07, 2025
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