162-OR: Sustained TNF-a Transcription Triggered in Obesity through H3K9/K18 Acetylation Is Associated with Metabolic Impairments

Obesity-induced metabolic inflammation contributes to the development of various metabolic disorders and can be induced by the consumption of high-fat diets (HFD) rich in saturated fatty acids. The role of the TNF-α in metabolic dysfunction is now clear, although the pathways that promote and sustain the transcriptional regulatory process of the TNF-α gene under the setting of obesity remain incompletely understood. To identify the obesity-mediated transcriptional regulatory program of TNF-α, we used a murine model of diet-induced obesity (DIO). Male C57BL6/J mice were fed a palmitate oil-based HFD or a control diet (CD) for 16 weeks. Compared to CD, mice with DIO displayed elevated levels of TNF-α along with increased acetylation levels of epigenetic marks histone H3 lysine 9 and 18 acetylation (H3K9/K18) in adipose tissue and liver. Determination of permissive histone acetylation marks in the promoter region of TNF-α in both adipose tissue and liver was achieved through the Chromatin Immunoprecipitation (ChIP) assay. ChIP-qPCR analysis data show that obesity led to increased levels of the transcriptionally permissive acetylation marks H3K9/K18 in the TNF-α promoter in adipose tissue and liver compared to lean mice. Increased TNF-α expression in obese adipose tissue and fatty liver at the chromatin level corresponds to the changes in the level of histone acetylation marks H3K9/K18. Moreover, TNF-α and histone acetylation marks are positively associated with body weight gain, insulin resistance, and liver steatosis. In conclusion, our findings support a model in which DIO creates a setting for sustained transcriptional regulation of the TNF-α gene via chromatin remodeling, enabling TNF-α to contribute to metabolic dysfunction. We also propose that acetylation of H3K9/H3K18 may be considered valuable prognostic factors for metabolic impairment and liver steatosis in obesity.