Dissertation committee:
Kαλτσάς Γρηγόριος, Καθηγητή, Ιατρική Σχολή, ΕΚΠΑ
Πρωτογέρου Αθανάσιος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Κασσή Ευανθία, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Κόκκινος Αλέξανδρος, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Μαυραγάνη Κλειώ, Επίκουρη Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Χατζηγερωργίου Αντώνιος Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ανδρεάκος Ευάγγελος, Ερευνητής Α', ΙΙΒΕΑΑ
Summary:
This study involves the investigation of the role of Notch signaling in obesity and the potential interplay between Notch and adipose tissue macrophages (ATMs) in the development of obesity-associated metabolic dysfunction and inflammation. Obesity poses significant health risks, including diabetes and cardiovascular diseases. Chronic inflammation in adipose tissue (AT) plays a key role, with ATMs being a major driver. These ATMs exhibit a range of functional differences, but their relationship with the Notch signaling pathway has been largely unexplored.Notch signaling is a vital pathway in development and immune regulation. Recent studies suggest its involvement in conditions like hepatic insulin resistance and atherosclerosis, but its role in obesity-related inflammation remains unclear. More importantly, Notch activation has been also linked to pro-inflammatory responses in macrophages. The current study describes the characteristics of macrophages in the epididymal white adipose tissue (epiWAT) using a diet-induced obesity (DIO) mouse model. Specifically, we identify ATMs both in the lean state, in which they express M2-like macrophages markers and, in the inflamed obese epiWAT, where ATMs are significantly increased. This increase is accompanied by elevated CD11c expression, commonly linked to M1-like macrophages, highlighting the phenotypic changes in ATMs during obesity-induced inflammation. Using RNA sequencing, we offer a comprehensive analysis of ATMs gene expression data from ATMs of mice fed either a normal diet (NCD) or a high-fat diet (HFD). Analysis shows distinct transcriptional profiles of ATMs in homeostasis and obesity-induced inflammation while proves that prolonged HFD exposure induces significant alterations in ATMs with various pro-inflammatory genes being overexpressed. Notably, Notch signaling emerges as a significant discriminator between NCD and HFD ATMs. This perturbed Notch cascade is associated with obesity-induced changes in macrophage function and insulin resistance. The current study, suggests that, deleting Notch1 and Notch2 receptors from myeloid cells (N1N2flCre) leads to significantly increased body weight, insulin resistance, elevated triglyceride levels, and altered metabolism in response to HFD. However, these effects are not observed in mice on NCD, suggesting that the Notch pathway selectively contributes to the development of obesity and insulin resistance in response to HFD, not during normal dietary conditions. More importantly, we show that, ATMs deficient in myeloid Notch1 and Notch2, present elevated pro-inflammatory gene expression (Nos2, Arg1, IFNγ) and reduced Il10. Furthermore, we show that genes related to insulin resistance and glucose handling (Irs1, Irs2, Igf1r, Hk2) are affected in these deficient ATMs, suggesting a potential interplay between impaired Notch signaling and metabolic disturbances. Notably, deletion of Notch1 and Notch2 leads to a distinct transcriptional profile in ATMs with ECM remodeling and immune response-related pathways to participate among the most affected processes. Over-represented pathways include also those related to immune cell proliferation, T cell differentiation, inflammation, and metabolic processes. These findings support the notion that the Notch pathway plays a crucial role in regulating the pro-inflammatory response and metabolic changes in ATMs during obesity-induced inflammation and suggest that targeting Notch signaling in ATMs or myeloid cells may be a potential therapeutic strategy for obesity-related metabolic disorders.
Keywords:
Macrophages, Adipose tissue, Insulin resistance, Obesity
