Tumor protein p53 at the interface of white adipocyte mitochondrial function and systemic metabolic homeostasis
Final Report Abstract
During this DFG Research Fellowship, I aimed to explore the interconnections of white adipocyte mitochondrial function, reactive oxygen species (ROS) generation, p53 activation, and systemic metabolic homeostasis. While I planned to address my central hypotheses making use of two particular transgenic mouse models, Adipo-mitoFerritin and Adipo-mitoNEET mice, that enable inducible, adipocyte-specific manipulations of mitochondrial iron content, ROS production, and function, I found neither model to be satisfactory for this purpose. Instead, I decided on an alternative approach to unravel how a loss of mitochondrial function impacts white adipocyte and systemic metabolism. I generated a new doxycycline-inducible transgenic mouse line, TRE-mitoKiller, that enables me to degrade mitochondrial DNA (mtDNA) and thereby deplete mitochondria from specific cell types in a controlled manner. Targeting adipocyte mitochondria in my Adipo-mitoKiller model, I could observe no immediate impact of adipocyte mtDNA degradation on glucose tolerance, insulin sensitivity, or triglyceride clearance upon acute feeding of a doxycycline-containing chow diet. Upon prolonged doxycycline application, Adipo-mitoKiller mice did however display intriguing body weight and fat mass dynamics with an initial acceleration of body weight and fat mass gain, followed by a collapse of both parameters, indicating that proper mitochondrial function is essential for the long-term maintenance of adipose tissue. While these observations are promising, I am still in the process of acquiring additional data in preparation of a future publication.
Publications
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Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication. J Lipid Res. 2019 Oct;60(10)1648-1684
Funcke, Jan-Bernd & Scherer, Philipp E.
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Dysregulation of amyloid precursor protein impairs adipose tissue mitochondrial function and promotes obesity. Nat Metab. 2019 Dec;1(12):1243-1257
An, Yu A.; Crewe, Clair; Asterholm, Ingrid Wernstedt; Sun, Kai; Chen, Shiuhwei; Zhang, Fang; Shao, Mengle; Funcke, Jan-Bernd; Zhang, Zhuzhen; Straub, Leon; Yoshino, Jun; Klein, Samuel; Kusminski, Christine M. & Scherer, Philipp E.
