巨噬细胞HDAC3通过GDF3介导的炎症反应和染色质重塑，促进肥胖及脂肪组织代谢失调。

Abstract

HDAC3 links ATMs activation to insulin resistance in obesity. • GDF3 mediates metabolic stress-induced transcriptional reprogramming. • HDAC3 interacts with GDF3, facilitating inflammation and fibrosis in obesity. • Epigenetic mechanism through GDF3 connects immune-metabolic crosstalk. Chronic inflammation is a hallmark of obesity and its associated metabolic disorders. Adipose tissue macrophages (ATMs) play a crucial role in maintaining tissue homeostasis and orchestrating metabolic inflammation. Importantly, the regulation of proinflammatory gene translation is critical for macrophage activation, a process that has been closely linked to the onset of insulin resistance and type 2 diabetes. Histone deacetylase 3 (HDAC3) is a contributing factor of inflammatory gene expression; however, its precise role in modulating adipose tissue inflammation and type 2 diabetes remains poorly understood. This study demonstrates that metabolically stressed-induced HDAC3 mediates ATMs inflammation. HDAC3 deficiency in macrophages reduces adipose tissue macrophage infiltration and fibrosis, improves hyperglycemia, and reduced weight gain, adiposity in diet-induced obesity mice. HDAC3 deficiency mitigated the chronic inflammation and fibrosis in adipose tissue by suppressing inflammatory cytokine production via H3K4Me3/H3K27Ac-mediated chromatin remodeling. Mechanistically, growth differentiation factor 3 (GDF3) functions as a sensor of metabolic stress, interacts with HDAC3 through histone modification-mediated chromatin remodeling of inflammation genes. Critically, HDAC3 and GDF3 co-expression increased in adipose tissue/ATMs of obese humans, correlating positively with BMI, blood glucose, and proinflammatory gene levels. Our finding identifies HDAC3 as a molecular nexus connecting ATMs activation to systemic insulin resistance and type 2 diabetes. The GDF3-HDAC3 axis drives transcriptional reprogramming through H3K4Me3/H3K27Ac modifications, revealing a novel therapeutic targe