2412-P: Inhibition of Histone Acetylation Protects against TNF-α–Mediated Metabolic Inflammation

Introduction and Objective: Obesity-driven metabolic inflammation promotes insulin resistance and fatty liver disease, with TNF-α as a key mediator. Although histone acetylation is linked to TNF-α activation, direct causal evidence is lacking. This study presents a proof-of-concept investigation to determine whether histone acetylation directly drives persistent TNF-α transcription in obesity. Methods: To establish a causal link between histone acetylation and sustained TNF-α transcription in obesity, male C57BL/6J-mice were fed a high-fat diet for 16 weeks to induce diet-induced obesity (DIO) and subsequently treated for 4 weeks with either the histone acetyltransferase inhibitor anacardic acid or a vehicle control. Metabolic and immunological profiling was done. Chromatin immunoprecipitation (ChIP-qPCR), RNA sequencing, qRT-PCR, IHC, and ELISA techniques were employed. Results: DIO markedly increased TNF-α expression and elevated global and promoter-specific H3K9/H3K18 acetylation in liver and adipose tissue. Enrichment of these histone marks at the TNF-α promoter correlated with body-weight gain, insulin resistance, and hepatic steatosis. DIO mice treated with anacardic acid showed a significant reduction in H3K9/H3K18 acetylation at the TNF-α promoter and decreased NF-κB promoter binding, resulting in lower TNF-α transcription. These epigenetic improvements were accompanied by reduced inflammatory markers, including CCL2 expression, macrophage (F4/80+) infiltration in both liver and visceral fat tissue. Anacardic acid intervention improves metabolic impairment. Conclusion: DIO establishes a transcriptionally permissive chromatin environment at the TNF-α locus through H3K9/H3K18 acetylation, enabling sustained NF-κB-dependent TNF-α expression and metabolic deterioration. Pharmacological inhibition of H3K9/H3K18 acetylation reverses transcriptional changes, providing direct causal evidence for the role of chromatin remodeling in obesity-driven inflammation, insulin resistance and hepatic steatosis in obesity. Disclosure F. Bahman: None. S. Kochumon: None. N. Benobaid: None. T.K. Jacob: None. A. Al Madhoun: None. F. Al-Mulla: None. R. Ahmad: None. Funding Kuwait Foundation for the Advancement of Sciences(KFAS)