Medizinische Universität Graz - Research portal
Selected Publication:
Reinisch, I.
p53 in adipose tissue metabolism and homeostasis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2022. pp.
- Authors Med Uni Graz:
- Advisor:
- Deutsch Alexander
- Madl Tobias
- Prokesch Andreas
- Altmetrics:
- Abstract:
- Historically viewed as a passive site for energy storage, it is now well accepted that limitations in the degree of adipose tissue (AT) plasticity drive the progression of obesity-associated sequelae. As effective interventions against the metabolic syndrome, fasting regimens like intermittent fasting (IF) confer health benefits (like improved serum levels of cardiometabolic risk factors and amelioration of insulin resistance) beyond weight reduction. Tissue-specific metabolic adaptions to fasting include marked changes in AT morphology, physiology, and cellular composition. Recent studies emphasized an involvement of nutrient-responsive transcription factor p53 in regulating metabolism and tissue homeostasis in noncancerous settings, but the distinct function of p53 in the fasting response of adipocytes remains poorly characterized. Therefore, we generated an inducible, adipocyte-specific p53 knock-out (KO) mouse model and triggered obesity by high fat diet feeding. Selective ablation of p53 in obese mice accelerated the catabolic state during IF, as reflected by increased weight loss, decreased adipocyte size, and elevated plasma fatty acid levels. Furthermore, fasted obese p53 KO mice showed improved insulin sensitivity and trending decreased plasma TNFa levels. Morphologically, we observed an increase in the abundance of crown-like structures in epididymal white AT (eWAT) of IF-obese mice compared to ad libitum fed control, which was largely blunted in IF-p53 KO mice. Performing single-nuclei RNA sequencing of eWAT confirmed a marked increase in lipid-associated macrophage (LAM) infiltration upon IF. Strikingly, this fasting-mediated increase in LAMs was completely absent in obese p53 KO mice, in line with a significant reduction in the expression of pro-inflammatory marker genes and abundance of proteins involved in immune processes. In vitro studies of human, mature adipocytes confirmed the involvement of p53 in the regulation of adipocyte cytokine/chemokine signalling. Furthermore, a common, metabolically relevant SNP of p53 influenced the response of obese and diabetic humans to a fasting-mimicking diet, indicating a translational relevance of p53 in the nutritional control. Taken together, we showed that AT underlies a remarkable heterogeneity, flexibly adapting its composition according to metabolic demands to ensure systemic energy homeostasis in an AT-cell-type collaborative fashion. Importantly, we revealed adipocyte p53 as a master regulator of eWAT plasticity and innate immune cell composition upon IF in obese mice.