BAF60a Regulates Macrophage Activation To Control Adipose Tissue Inflammation In Obesity And Type 2 Diabetes

With the rapid development of the economy and the remarkable improvement of living standard,metabolic diseases have become the most common non-communicable diseases in the world,which pose a major threat to human life and health.Among them,chronic metabolic diseases such as obesity and diabetes are considered to be closely related to chronic mild inflammation,which is manifested by a large infiltration of immune cells and increased inflammatory factors in tissues.As a kind of immune cells,macrophages have the plasticity and heterogeneity of phenotype and function.The differential regulation of phenotype has profound effects on the progression of chronic metabolic and inflammatory diseases.Some studies have suggested that macrophage-mediated tissue homeostasis and reprogramming play an important role in systemic metabolic homeostasis in adipose tissue.However,the molecular triggering mechanisms,sensory receptors and signaling pathways of immune cell accumulation in adipose tissue are still unclear,especially the mechanisms of how macrophages are activated and regulated.Our previous research found that SWI/SNF chromatin remodeling complex BAF60 s is an important regulators of energy metabolism,and its epigenetic regulation is crucial for understanding metabolic diseases like obesity and diabetes.Therefore,in this dissertation,we take the chromatin remodeling complex BAF60 s as the breakthrough point to explore the effects of the complex on the ATM,adipose tissue and systemic metabolism of adipose tissue under the disorder of energy metabolism.We use cellular and animal models,respectively,to clarify its effects and mechanisms on the regulation of metabolism in immune cells,especially macrophages.In this thesis,we used macrophage-specific BAF60 a knockout mice as the main model and used the separation technology of SVF primary immune cells from adipose tissue to further study : the regulatory effect and mechanism of BAF60 a on macrophages.At the cellular level,macrophage-specific BAF60 a knockout under different in vitro stimuli induced its own activation toward M1-type cells and restricted toward M2-type.At the animal level,the metabolic homeostasis was disrupted in obese mice after macrophage-specific BAF60 a knockout at high nutritional levels,and a large number of M1-type macrophages releasing pro-inflammatory factors accumulated abnormally in adipose tissue,aggravated local inflammation and affected the level of systemic chronic inflammation.Further mechanistic studies have also confirmed that BAF60 a can affect the local inflammation of adipose tissue in obesity-induced T2 D by participating in activating immune cells and regulating immune response pathways.The research carried out in this thesis not only helps to promote the cognition of immune metabolism associated with epigenetics in metabolic diseases such as diabetes and obesity,but also helps to reverse the imbalance of macrophage activation in disease states,thus providing new ideas and strategies for the treatment of related diseases.