Ferroptosis increases obesity: Crosstalk between adipocytes and the neuroimmune system

Abstract

Ferroptosis requires not only the accumulation of iron ions, but also changes in many ferroptosis-related regulators, including a decrease in GPX4 and inhibition of SLC7A11 for classical ferroptosis, a deletion of FSP1 or GCH1. Surprisingly, adipose tissue (AT) in the obesity conditions is also accompanied by iron buildup, decreased GSH, and increased ROS. On the neurological side, the pro-inflammatory factor released by AT may have first caused ferroptosis in the vagus nerve by inhibiting of the NRF2-GPX4 pathway, resulting in disorders of the autonomic nervous system. On the immune side, obesity may cause M2 macrophages ferroptosis due to damage to iron-rich ATMs (MFehi) and antioxidant ATMs (Mox), and lead to Treg cells ferroptosis through reductions in NRF2, GPX4, and GCH1 levels. At the same time, the reduction in GPX4 may also trigger the ferroptosis of B1 cells. In addition, some studies have also found the role of GPX4 in neutrophil autophagy, which is also worth pondering whether there is a connection with ferroptosis. In conclusion, this review summarizes the associations between neuroimmune regulation associated with obesity and ferroptosis, and on the basis of this, highlights their potential molecular mechanisms, proposing that ferroptosis in one or more cells in a multicellular tissue changes the fate of that tissue.

Comprehensive characterization of ferroptosis in hepatocellular carcinoma revealing the association with prognosis and tumor immune microenvironment

“…It has been found that obesity is closely related to the disturbance of iron metabolism, mainly characterized by high ferritin levels ( 78 ). Ferroptosis caused by iron accumulation is accompanied by elevated ROS, decreased GSH and inflammatory reactions, insulin resistance and mitochondrial dysfunction, leading to metabolic disorders and the development of obesity ( 79 – 81 ). In terms of immunity, obesity may lead to ferroptosis in Tregs and B1 cells by reducing the levels of NRF2, GPX4 and GCH1 ( 80 , 82 ).…”

“…Ferroptosis caused by iron accumulation is accompanied by elevated ROS, decreased GSH and inflammatory reactions, insulin resistance and mitochondrial dysfunction, leading to metabolic disorders and the development of obesity ( 79 – 81 ). In terms of immunity, obesity may lead to ferroptosis in Tregs and B1 cells by reducing the levels of NRF2, GPX4 and GCH1 ( 80 , 82 ). In our previous study, biological processes such as fatty acid and glucose metabolism were also enriched in ferroptosis cluster A.…”

Ferroptosis-based drug delivery system as a new therapeutic opportunity for brain tumors

“…The enzymatic process involved in the reaction is mainly lipoxygenase but also requires the participation of acetyl coenzyme A synthase long-chain family 4 (ACSL4) and lysophosphatidyl choline acyltransferase 3 (LPCAT3), which is associated with lipid remodelling (42). The reaction uses free PUFAs arachidonic acid as the primary phospholipid substrate, which is finally oxidized by lipoxygenase to form lipid peroxides after two-step esterification by ACSL4 and LPCAT3 (43).…”

Narrative review of ferroptosis in obesity

“…Furthermore, ferroptosis is closely related to many disease processes, such as oxidative stress, 32 inflammatory response 33 and autophagy 34 . In particular, ferroptosis is involved in the pathological process of obesity 35 . Excessive nutrient intake and fat storage in white adipose tissue (WAT) ultimately leads to obesity.…”

“…34 In particular, ferroptosis is involved in the pathological process of obesity. 35 Excessive nutrient intake and fat storage in white adipose tissue (WAT) ultimately leads to obesity. Insufficient iron intake is also linked to overweight or obesity in children and adolescents.…”