Notch signaling in adipose tissue macrophages prevents diet‐induced inflammation and metabolic dysregulation

Abstract

The importance of macrophages in adipose tissue (AT) homeostasis and inflammation is well established. However, the potential cues that regulate their function remain incompletely understood. To bridge this important gap, we sought to characterize novel pathways involved using a mouse model of diet‐induced obesity. By performing transcriptomics analysis of AT macrophages (ATMs), we found that late‐stage ATMs from high‐fat diet mice presented with perturbed Notch signaling accompanied by robust proinflammatory and metabolic changes. To explore the hypothesis that the deregulated Notch pathway contributes to the development of AT inflammation and diet‐induced obesity, we employed a genetic approach to abrogate myeloid Notch1 and Notch2 receptors. Our results revealed that the combined loss of Notch1 and Notch2 worsened obesity‐related metabolic dysregulation. Body and AT weight gain was higher, blood glucose levels increased and metabolic parameters were substantially worsened in deficient mice fed high‐fat diet. Moreover, serum insulin and leptin were elevated as were triglycerides. Molecular analysis of ATMs showed that deletion of Notch receptors escalated inflammation through the induction of an M1‐like pro‐inflammatory phenotype. Our findings thus support a protective role of myeloid Notch signaling in adipose tissue inflammation and metabolic dysregulation.

RNA editing landscape of adipose tissue in polycystic ovary syndrome provides insight into the obesity-related immune responses

“…One previous study showed that IL-12 and TNFa levels in the plasma were increased in PCOS patients compared to controls (37), and another study revealed the correlation Notch signaling is reported to be activated in GCs in PCOS and regulates aberrant cumulus-oocyte complex (COC) expansion, which may lead to ovulatory dysfunction (41). It was also involved in adipose tissue inflammation and metabolic dysregulation (42). TUT4 belongs to RNA terminal uridyltransferases, and it has been suggested to play a role in post-transcriptional regulation of inflammation based on in vitro studies (43).…”

EGCG Suppresses Adipogenesis and Promotes Browning of 3T3-L1 Cells by Inhibiting Notch1 Expression

“…Notch1, as an inflammatory marker protein, exerts regulatory effects on obesity development. Previous studies have demonstrated that the activation of Notch1 signaling promotes adipocyte proliferation [ 19 ], while the modulation of the Notch1 signal in adipose tissue macrophages is crucial for regulating inflammation and metabolism [ 20 ]. Moreover, inhibiting Notch1 expression has been shown to significantly enhance brown fat thermogenesis, promote white fat browning, and ameliorate obesity [ 21 , 22 , 23 ].…”