Tumorprotein p53 an der Schnittstelle zwischen der mitochondrialen Funktion weißer Fettzellen und der metabolischen Homöostase des Körpers
Zusammenfassung der Projektergebnisse
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.
Projektbezogene Publikationen (Auswahl)
- Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication. J Lipid Res. 2019 Oct;60(10)1648-1684
Funcke J. B. & Scherer P. E.
(Siehe online unter https://doi.org/10.1194/jlr.r094060) - Dysregulation of amyloid precursor protein impairs adipose tissue mitochondrial function and promotes obesity. Nat Metab. 2019 Dec;1(12):1243-1257
An Y. A., Crewe C., Asterholm I. W., Sun K., Chen S., Zhang F., Shao M., Funcke J. B., Zhang Z., Straub L., Yoshino J., Klein S., Kusminski C. M., Scherer P. E.
(Siehe online unter https://doi.org/10.1038/s42255-019-0149-1)
